Gene Research for GO Annotation Review

Target

• Gene symbol: LGALS3
• Organism: Homo sapiens

UniProt Context

=== UNIPROT METADATA ===
UniProt ID: P17931
Entry Name: LEG3_HUMAN
Gene Name: LGALS3
Protein Name: Galectin-3
Organism: Homo sapiens (Human)
NCBI Taxonomy ID: 9606
Function: Galactose-specific lectin which binds IgE. May mediate with the alpha-3, beta-1 integrin the stimulation by CSPG4 of endothelial cells migration. Together with DMBT1, required for terminal differentiation of columnar epithelial cells during early embryogenesis (By similarity). In the nucleus: acts as a pre-mRNA splicing factor. Involved in acute inflammatory responses including neutrophil activation and adhesion, chemoattraction of monocytes macrophages, opsonization of apoptotic neutrophils, and activation of mast cells. Together with TRIM16, coordinates the recognition of membrane damage with mobilization of the core autophagy regulators ATG16L1 and BECN1 in response to damaged endomembranes.
Subcellular Location: Cytoplasm
Subunit: Probably forms homo- or heterodimers. Interacts with DMBT1 (By similarity). Interacts with CD6 and ALCAM (PubMed:24945728). Forms a complex with the ITGA3, ITGB1 and CSPG4. Interacts with LGALS3BP, LYPD3, ZFTRAF1 and UACA. Interacts with TRIM16; this interaction mediates autophagy of damage endomembranes. Interacts with cargo receptor TMED10; the interaction mediates the translocation from the cytoplasm into the ERGIC (endoplasmic reticulum-Golgi intermediate compartment) and thereby secretion (PubMed:32272059).
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Research Objective

Prepare a comprehensive literature-backed research report for GO annotation review of the target gene.

Focus on:

1. The core biochemical activity of the gene product and any substrate specificity.
2. The activation or maturation mechanism of the protein, including proteolytic processing if relevant.
3. The best-supported subcellular localization and complexes where the active protein functions.
4. The strongest experimentally supported biological processes in the target organism, or in very close orthologs when transfer is justified.
5. Which annotations appear to reflect core function versus context-specific, pleiotropic, or over-extended roles.
6. Any evidence bearing on apoptosis, developmental cell death, neuronal roles, inflammatory signaling, pyroptosis, synaptic remodeling, protein processing, and localization to cytoplasm, cytosol, nucleus, or signaling complexes.

Output Requirements

Structure the report as:

1. Executive summary
2. Molecular function
3. Biological process roles
4. Cellular localization and complexes
5. Annotation-risk assessment
6. Key literature

Use citations for all substantive claims.

GO Annotation Review Report for LGALS3 (Galectin-3)

Gene Symbol: LGALS3
Organism: Homo sapiens
UniProt ID: P17931
Report Date: 2026

1. EXECUTIVE SUMMARY

Galectin-3 (LGALS3) is a chimera-type β-galactoside-binding lectin with a conserved C-terminal carbohydrate recognition domain (CRD) and an intrinsically disordered N-terminal domain that enables oligomerization (radziejewska2023galectin3andepithelial pages 1-2, tan2021galectin3akey pages 1-2). The protein is encoded by the LGALS3 gene and exhibits pleiotropic functions across multiple cellular compartments. Recent literature from 2023-2025 strongly supports several core molecular functions and biological processes, while also highlighting areas where GO annotations risk overextension.

Core Biochemical Activity: LGALS3's primary molecular function is β-galactoside binding through its ~130 amino acid CRD, which recognizes N-acetyllactosamine structures on glycoproteins and glycolipids (radziejewska2023galectin3andepithelial pages 1-2, mukherjee2025galectin3integratorof pages 1-2). This lectin activity underpins its ability to form multivalent glycan lattices at the cell surface and to sense exposed lumenal glycans on damaged intracellular organelles (jia2020meritacellular pages 1-4).

Best-Supported Cellular Functions: The most experimentally robust findings emphasize LGALS3's role in lysosomal damage response, where it detects membrane rupture, recruits ESCRT repair machinery, and coordinates with TRIM16 to mobilize autophagy factors for lysophagy (jia2020meritacellular pages 1-4, burbidge2022lgals3(galectin3) pages 1-2). Extracellularly, LGALS3 modulates receptor signaling and fibrosis through interactions with integrins and TGFβRII (calver2024definingthemechanism pages 1-2).

Annotation Risks: Several annotations warrant caution, including broad attributions to pyroptosis (shivcharan2025endolysosomaldamagesurveillance pages 1-3), direct synaptic remodeling (siew2024galectin3aggravatesmicroglial pages 1-2), and pathology-specific localizations like Lewy bodies (garciarevilla2023galectin3shapestoxic pages 1-2). Developmental roles and unconventional secretion mechanisms also require careful contextualization.

2. MOLECULAR FUNCTION

2.1 Core Biochemical Activity

β-Galactoside Binding Lectin Activity:
LGALS3 is a β-galactoside-binding protein that recognizes glycan structures containing the N-acetyllactosamine disaccharide (Galβ1-4GlcNAc) on N- and O-glycans, glycolipids, and blood group antigens (radziejewska2023galectin3andepithelial pages 1-2, mukherjee2025galectin3integratorof pages 1-2). The CRD is responsible for binding, with lactose representing the minimal carbohydrate ligand. Structural studies indicate that the 3-OH group of galactose is crucial for recognition, while substitutions at 4-OH and 6-OH attenuate binding (radziejewska2023galectin3andepithelial pages 1-2). This lectin activity is glycan-specific but heterogeneous, not exhibiting strict 1:1 stoichiometry in many interactions (calver2024definingthemechanism pages 1-2).

Oligomerization and Lattice Formation:
The N-terminal domain of LGALS3, rich in proline and glycine residues, mediates self-association and pentamerization upon engagement with multivalent ligands (radziejewska2023galectin3andepithelial pages 1-2, mukherjee2025galectin3integratorof pages 1-2). This oligomerization capacity enables LGALS3 to cross-link cell-surface glycoconjugates into lattices that regulate receptor clustering, signaling, and internalization (mukherjee2025galectin3integratorof pages 1-2, lozinski2024emergingroleof pages 1-2). Recent biophysical studies also demonstrate that LGALS3 can undergo liquid-liquid phase separation, which is critical for its mitochondrial quality-control functions (liu2025galectin3directsmitophagy pages 1-2).

Substrate Specificity:
LGALS3 binds preferentially to β-galactoside-containing structures. In disease contexts such as cancer, it recognizes tumor-associated carbohydrate antigens like the Thomsen-Friedenreich (T) antigen (Galβ1-3GalNAc) on MUC1 mucin (radziejewska2023galectin3andepithelial pages 1-2). In intracellular settings, it detects exposed lumenal glycans on damaged lysosomes and mitochondria, serving as a damage sensor (jia2020meritacellular pages 1-4, liu2025galectin3directsmitophagy pages 1-2).

Table: This table summarizes the best-supported molecular functions and interaction activities of human Galectin-3/LGALS3, separating core lectin biochemistry from context-dependent binding and scaffolding roles. It is useful for GO review because it highlights which annotations are central versus potentially overextended.

2.2 Protein-Protein Interactions

Integrin Binding:
Surface plasmon resonance and coimmunoprecipitation studies confirm that LGALS3 binds αv integrins (αvβ1, αvβ5, αvβ6) and β1 integrin in a glycosylation-dependent manner (calver2024definingthemechanism pages 1-2). Proximity ligation assays show that LGALS3 and β1 integrin colocalize within ~40 nm on fibroblast surfaces, with this association increased by TGF-β1 treatment and blocked by galectin-3 inhibitors (calver2024definingthemechanism pages 1-2). This interaction is central to LGALS3's role in potentiating integrin-mediated TGF-β1 activation in fibrosis.

TGFβRII Binding:
LGALS3 also binds the TGFβRII subunit in a glycan-dependent manner, promoting TGF-β1 signaling in lung fibroblasts (calver2024definingthemechanism pages 1-2). Small-molecule inhibitors targeting the CRD block these interactions, confirming carbohydrate-mediated binding.

TRIM16-ATG16L1-ULK1 Autophagy Complex:
At damaged lysosomes, LGALS3 cooperates with TRIM16, an autophagy receptor-regulator, to recruit core autophagy machinery including ATG16L1, ULK1, and LC3-related proteins (jia2020meritacellular pages 1-4, burbidge2022lgals3(galectin3) pages 1-2). TRIM16 serves as a platform to engage early autophagy factors, and this LGALS3-TRIM16 axis is essential for lysophagy—the selective autophagic removal of damaged lysosomes (jia2020meritacellular pages 1-4).

ESCRT Recruitment:
LGALS3 recruits and organizes ESCRT components, particularly PDCD6IP/ALIX, CHMP4A, and CHMPB, to sites of lysosomal membrane damage for membrane repair (jia2020meritacellular pages 1-4). This function is independent of ESCRT-I components like TSG101 and represents a parallel ESCRT-III recruitment pathway.

TMED10-Mediated Unconventional Secretion:
LGALS3, which lacks a signal peptide, is secreted via a TMED10-dependent unconventional pathway through the ER-Golgi intermediate compartment (ERGIC) (zhang2020atranslocationpathway pages 1-4). TMED10 mediates the translocation of leaderless cargoes, including LGALS3, into secretory vesicles. This process is enhanced by chaperones HSP90A/HSP90AB1 and involves protein unfolding (zhang2020atranslocationpathway pages 1-4).

PHB2 and Mitophagy:
In the context of PINK1/Parkin-mediated mitophagy, LGALS3 relocalizes from the cytosol to damaged mitochondria after outer membrane rupture. It interacts with the inner mitochondrial membrane protein PHB2 and recruits ULK1 to promote mitophagy (liu2025galectin3directsmitophagy pages 1-2). This represents an emerging intracellular function.

2.3 Absence of Catalytic Activity

Importantly, LGALS3 is a binding and scaffolding lectin without known intrinsic enzymatic or catalytic activity (garciarevilla2023galectin3shapestoxic pages 1-2). This should be reflected in GO molecular function annotations by avoiding enzyme activity terms.

3. BIOLOGICAL PROCESS ROLES

3.1 Lysosomal Damage Response and Lysophagy

Core Intracellular Function:
The most robustly supported biological process for LGALS3 in recent literature is its role in sensing and responding to lysosomal membrane damage. When lysosomes are damaged by lysosomotropic agents, pathogenic protein aggregates, or intracellular pathogens, lumenal glycans become exposed to the cytosol. Cytosolic LGALS3 binds these exposed glycans and triggers a coordinated response termed MERIT (Membrane repair, Removal, and Replacement) (jia2020meritacellular pages 1-4).

Lysosomal Membrane Repair:
LGALS3 recruits ESCRT machinery (PDCD6IP/ALIX, CHMP proteins) to repair damaged lysosomal membranes (jia2020meritacellular pages 1-4). This ESCRT-dependent repair occurs early in the damage response and is critical for maintaining lysosomal integrity.

Lysophagy:
When damage is extensive, LGALS3 cooperates with TRIM16 to engage autophagy machinery, recruiting ATG16L1, ULK1, and LC3 to enclose and degrade damaged lysosomes via lysophagy (jia2020meritacellular pages 1-4, burbidge2022lgals3(galectin3) pages 1-2, wang2023periplocinsuppressesthe pages 1-2). This selective autophagy pathway is essential for maintaining cellular homeostasis under lysosomal stress. LGALS3 knockout exacerbates lysosomal damage and reduces autophagic clearance efficiency (jia2020meritacellular pages 1-4).

TFEB-Mediated Lysosomal Biogenesis:
In the absence of LGALS3, compensatory mechanisms include increased TFEB nuclear translocation to drive de novo lysosomal biogenesis (jia2020meritacellular pages 1-4). This suggests that LGALS3-dependent repair and removal pathways work in concert with transcriptional programs to maintain the lysosomal network.

Table: This table summarizes the best-supported biological processes involving human LGALS3/galectin-3, separating core intracellular damage-response functions from broader context-specific roles in inflammation, fibrosis, neurodegeneration, and cell death. It is useful for GO annotation review because it highlights where evidence is strongest and where annotations may be overextended.

3.2 Mitophagy

Recent proteomic studies identify LGALS3 as significantly enriched at ruptured mitochondrial outer membranes during PINK1/Parkin-dependent mitophagy (liu2025galectin3directsmitophagy pages 1-2). LGALS3 relocalizes from the cytosol to damaged mitochondria, interacts with PHB2, and recruits ULK1. Mutations disrupting LGALS3's liquid-liquid phase separation properties abrogate its mitophagy function, suggesting that biomolecular condensate formation around damaged mitochondria is critical for organellar quality control (liu2025galectin3directsmitophagy pages 1-2). While this represents an emerging and well-supported mechanism, it is more context-specific than the lysosomal damage response.

3.3 Secretory Autophagy and Unconventional Protein Secretion

LGALS3 participates in autophagy-dependent unconventional secretion pathways. In human midbrain dopamine neurons, LGALS3 mediates the release of α-synuclein (SNCA) following vesicular damage (burbidge2022lgals3(galectin3) pages 1-2). This secretion is dependent on TRIM16 and ATG16L1, providing evidence that LGALS3 functions in a specialized autophagic secretory pathway. Exogenous SNCA fibrils that rupture endocytic vesicles trigger LGALS3 recruitment and subsequent secretion of both exogenous and endogenous SNCA (burbidge2022lgals3(galectin3) pages 1-2). This mechanism may contribute to the cell-to-cell transmission of pathogenic proteins in neurodegenerative diseases.

3.4 Inflammation and Immune Responses

LGALS3 is widely recognized as a modulator of innate and adaptive immune responses (tan2021galectin3akey pages 1-2, lozinski2024emergingroleof pages 1-2). It is upregulated in activated microglia and macrophages and acts as a pro-inflammatory mediator. LGALS3 can bind to toll-like receptor 4 (TLR4) and TREM2, influencing microglial activation states (tan2021galectin3akey pages 1-2). In the CNS, LGALS3 promotes microglial activation, cytokine production, and inflammatory signaling pathways including NF-κB and JAK-STAT (tan2021galectin3akey pages 1-2, lozinski2024emergingroleof pages 1-2). However, these inflammatory roles are highly context-dependent and vary across tissue types and disease states.

3.5 Fibrosis and TGF-β Signaling

Extracellular LGALS3 promotes fibrosis by potentiating TGF-β1 activation. It facilitates lysophosphatidic acid (LPA)-induced integrin-mediated TGF-β1 activation in human lung fibroblasts (calver2024definingthemechanism pages 1-2). LGALS3 binding to αv integrins and TGFβRII enhances downstream SMAD signaling, leading to increased collagen deposition, TIMP1 production, and hyaluronan secretion in lung fibrosis models (calver2024definingthemechanism pages 1-2). Galectin-3 inhibitors reduce these fibrotic markers in precision-cut lung slices from IPF patients (calver2024definingthemechanism pages 1-2). This fibrogenic activity is well-supported but context-specific to fibrotic diseases.

3.6 Neuroinflammation and Neurodegeneration

Tauopathy:
LGALS3 is upregulated in microglia in Alzheimer's disease and frontotemporal lobar dementia (siew2024galectin3aggravatesmicroglial pages 1-2). Pathogenic tau (pTau) triggers the release of LGALS3 from microglia in both free and extracellular vesicle-associated forms. Both forms increase pathogenic tau accumulation in recipient cells and enhance tau fibrillation (siew2024galectin3aggravatesmicroglial pages 1-2). Single-cell RNA-seq analysis of tauopathy mouse models reveals a population of Gal3-associated microglia with enhanced inflammatory and immune-response programs. Genetic deletion of Gal3 in THY-Tau22 mice suppresses microglial activation, reduces pTau levels and synaptic loss, and rescues memory impairment (siew2024galectin3aggravatesmicroglial pages 1-2).

Parkinson's Disease:
In PD, LGALS3 is found in Lewy bodies and other α-synuclein deposits, as well as associated with disrupted lysosomes (garciarevilla2023galectin3shapestoxic pages 1-2). In vitro, Gal3 interacts with α-synuclein fibrils and affects their spatial propagation and stability, producing short, amorphous toxic strains (garciarevilla2023galectin3shapestoxic pages 1-2). In a mouse model of PD (intranigral αSyn overexpression), Gal3 knockout leads to increased intracellular αSyn accumulation but preserved dopaminergic integrity and motor function, suggesting a complex role in shaping toxic strains (garciarevilla2023galectin3shapestoxic pages 1-2).

3.7 Apoptosis

LGALS3 has been reported to modulate apoptosis in multiple contexts, with bidirectional effects (survival vs. death) depending on cellular context (zaborska2023theroleof pages 1-3, lozinski2024emergingroleof pages 1-2). In some settings, LGALS3 promotes cell survival by inhibiting apoptosis, while in others, lysosomal damage and associated LGALS3-mediated stress responses correlate with apoptotic outcomes (wang2023periplocinsuppressesthe pages 1-2). These effects are context-dependent and should be annotated with caution.

3.8 Pyroptosis: Limited Evidence for LGALS3

While LGALS3 has been implicated in some inflammatory contexts, recent mechanistic studies emphasize that galectin-8, not galectin-3, is the primary galectin coupling endolysosomal damage sensing to noncanonical inflammasome activation and pyroptosis (shivcharan2025endolysosomaldamagesurveillance pages 1-3). In human epithelial cells, galectin-8 licenses caspase-4-mediated pyroptosis during intracellular bacterial infections, whereas LGALS3 depletion had minimal impact on Salmonella-induced pyroptosis (shivcharan2025endolysosomaldamagesurveillance pages 1-3). Broad GO annotations attributing pyroptosis regulation to LGALS3 would be overextended based on current evidence.

3.9 Synaptic Remodeling: Indirect Evidence Only

Available evidence links LGALS3 to synaptic loss in tauopathy and neurodegeneration (siew2024galectin3aggravatesmicroglial pages 1-2), but there is limited direct evidence that LGALS3 itself functions as a core synaptic remodeling factor in healthy human neurons. Synaptic effects appear largely indirect, mediated by microglial activation and neuroinflammatory pathways (siew2024galectin3aggravatesmicroglial pages 1-2, lozinski2024emergingroleof pages 1-2). Direct synaptic function annotations should be approached with caution.

3.10 Developmental Roles

Some reviews discuss LGALS3 in neural progenitor motility, gliogenesis, and specialized developmental contexts (lozinski2024emergingroleof pages 1-2, zhang2025multifacetedrolesof pages 10-11). However, these developmental annotations are not as robustly established in humans as the lectin and damage-response functions. Developmental process annotations should be restricted to directly evidenced systems and not over-generalized.

4. CELLULAR LOCALIZATION AND COMPLEXES

4.1 Subcellular Localization

Cytoplasm/Cytosol:
LGALS3 is synthesized on free ribosomes in the cytoplasm, lacks a signal peptide, and exists as a soluble intracellular pool before relocalization or secretion (tan2021galectin3akey pages 1-2, lozinski2024emergingroleof pages 1-2). This is a well-supported core cellular component annotation.

Nucleus:
LGALS3 is present in the nucleus, where it has been implicated in pre-mRNA splicing and gene regulation (zhang2025multifacetedrolesof pages 10-11, radziejewska2023galectin3andepithelial pages 1-2, tan2021galectin3akey pages 1-2). Nuclear localization is consistently noted in reviews, though specific subnuclear compartments are less well-defined.

Extracellular Space:
LGALS3 is secreted via unconventional (non-classical) pathways independent of the ER-Golgi secretory route (zhang2020atranslocationpathway pages 1-4). Extracellular LGALS3 binds glycans on cell-surface and extracellular matrix glycoproteins, modulating signaling, adhesion, and inflammation (calver2024definingthemechanism pages 1-2, mukherjee2025galectin3integratorof pages 1-2, lozinski2024emergingroleof pages 1-2). This is a strong extracellular annotation, but GO should not imply conventional signal-peptide-mediated secretion.

Cell Surface / Plasma Membrane-Associated:
Secreted LGALS3 remains tethered to the cell surface through glycan interactions and forms lattices that regulate receptor clustering and signaling (mukherjee2025galectin3integratorof pages 1-2, lozinski2024emergingroleof pages 1-2). It should be annotated as cell-surface-associated rather than an integral membrane protein.

ERGIC (ER-Golgi Intermediate Compartment):
LGALS3 uses a TMED10-dependent translocation pathway through the ERGIC for unconventional secretion (zhang2020atranslocationpathway pages 1-4). This is a pathway-level localization rather than stable constitutive residence, and GO annotations should reflect this transient association.

Damaged Lysosomes:
Upon lysosomal membrane damage, cytosolic LGALS3 binds exposed lumenal glycans and marks damaged lysosomes for repair or removal (jia2020meritacellular pages 1-4, burbidge2022lgals3(galectin3) pages 1-2). This is a highly context-specific, damage-induced localization that is among the strongest intracellular findings for LGALS3.

Damaged Mitochondria:
During mitophagy, LGALS3 relocalizes to damaged mitochondria after outer membrane rupture (liu2025galectin3directsmitophagy pages 1-2). This is an emerging but compelling localization, though not a constitutive mitochondrial component annotation.

Extracellular Vesicles:
In CNS disease contexts, LGALS3 is released in extracellular vesicle-associated forms, accompanying pathogenic cargo transmission (siew2024galectin3aggravatesmicroglial pages 1-2). This is a useful contextual annotation in neurodegeneration.

Lewy Bodies (Pathology-Specific):
LGALS3 associates with Lewy body outer regions and disrupted lysosomes in Parkinson's disease tissue (garciarevilla2023galectin3shapestoxic pages 1-2). However, this is a pathology-linked association rather than normal cellular localization, and GO annotations to disease-specific structures like Lewy bodies should be avoided or carefully contextualized.

Table: This table summarizes the best-supported subcellular localizations and inducible protein complexes of human galectin-3/LGALS3, emphasizing where the evidence is strongest for GO cellular component review. It is especially useful for separating core localization terms from damage-responsive or disease-contextual assemblies.

4.2 Protein Complexes

TRIM16-ATG16L1-ULK1 Complex (Lysophagy):
At damaged lysosomes, LGALS3 cooperates with TRIM16 to recruit ATG16L1, ULK1, and LC3-related autophagy machinery (jia2020meritacellular pages 1-4, burbidge2022lgals3(galectin3) pages 1-2). This is a strong, inducible complex annotation.

ESCRT-Associated Repair Complex:
LGALS3 recruits PDCD6IP/ALIX, CHMP4A, and CHMPB for lysosomal membrane repair (jia2020meritacellular pages 1-4). This is a context-dependent repair complex.

PHB2-ULK1 Mitophagy Complex:
On damaged mitochondria, LGALS3 interacts with PHB2 and recruits ULK1 (liu2025galectin3directsmitophagy pages 1-2). This is an emerging mitophagy complex.

Integrin-TGFβRII Signaling Assembly:
Extracellular LGALS3 forms complexes with αv integrins and TGFβRII in fibrotic contexts (calver2024definingthemechanism pages 1-2). This is a strong disease-context complex.

5. ANNOTATION-RISK ASSESSMENT

Table: This table highlights the main GO annotation risks for human LGALS3/galectin-3, distinguishing well-supported core functions from disease- or context-specific extensions. It is useful for avoiding over-annotation while preserving strong evidence for lectin activity, unconventional secretion, and lysosomal damage response.

5.1 High-Risk Annotations

1. Over-extending Pleiotropic Disease Roles:
LGALS3 participates in many disease-associated processes, but the most consistently supported core functions are β-galactoside glycan binding, lattice formation, and endomembrane damage sensing. Broad annotations to all reported downstream disease phenotypes risk conflating secondary/tertiary effects with primary molecular function.

2. Broad Pyroptosis Annotation:
Current evidence does not support LGALS3 as a general pyroptosis effector. Galectin-8 is the primary galectin mediating noncanonical inflammasome sensing (shivcharan2025endolysosomaldamagesurveillance pages 1-3). LGALS3 pyroptosis annotations should be avoided or heavily qualified.

3. Synaptic Remodeling:
Evidence for direct LGALS3 involvement in synaptic remodeling is limited. Effects on synapse loss appear indirect via neuroinflammation (siew2024galectin3aggravatesmicroglial pages 1-2, lozinski2024emergingroleof pages 1-2).

4. Pathology-Specific Localizations (e.g., Lewy Bodies):
Associations with disease-specific structures like Lewy bodies should not be treated as normal cellular component annotations (garciarevilla2023galectin3shapestoxic pages 1-2).

5. Treating Unconventional Secretion as Classical Secretion:
LGALS3 lacks a signal peptide and uses TMED10-dependent unconventional routes. GO should not imply conventional ER-Golgi lumenal secretion (tan2021galectin3akey pages 1-2, zhang2020atranslocationpathway pages 1-4).

5.2 Moderate-Risk Annotations

1. Developmental Processes:
Some evidence exists for developmental roles, but these are not as robustly established in humans as core lectin functions (lozinski2024emergingroleof pages 1-2, zhang2025multifacetedrolesof pages 10-11).

2. Mitophagy:
While emerging evidence is compelling (liu2025galectin3directsmitophagy pages 1-2), mitophagy is more context-specific than the well-established lysosomal damage response. Annotations should reflect this.

3. ERGIC Localization:
TMED10-dependent translocation involves ERGIC, but this is a pathway-associated localization rather than stable residence (zhang2020atranslocationpathway pages 1-4).

5.3 Low-Risk Annotations (Strong Support)

1. Lysosomal Damage Response / Lysophagy:
Among the strongest intracellular process annotations, with extensive mechanistic support (jia2020meritacellular pages 1-4, burbidge2022lgals3(galectin3) pages 1-2).

2. β-Galactoside Binding Lectin Activity:
Core canonical molecular function with decades of support (zaborska2023theroleof pages 1-3, radziejewska2023galectin3andepithelial pages 1-2, mukherjee2025galectin3integratorof pages 1-2).

3. Cytoplasm, Nucleus, Extracellular Space:
Well-documented subcellular localizations (tan2021galectin3akey pages 1-2, lozinski2024emergingroleof pages 1-2).

6. KEY LITERATURE

Recent Reviews (2023-2025)

1. Mukherjee et al. (2025). Galectin-3: Integrator of Signaling via Hexosamine Flux. Biomolecules 15, 1028. (mukherjee2025galectin3integratorof pages 1-2)

2. Comprehensive review of LGALS3 structure, lectin activity, O-GlcNAc regulation, and unconventional secretion. Emphasizes nutrient-driven regulation and disease biomarker roles.

3. Zhang et al. (2025). Multifaceted roles of Galectins: from carbohydrate binding to targeted cancer therapy. Biomarker Research 13. (zhang2025multifacetedrolesof pages 10-11)

4. Detailed structural characterization, ligand-binding properties, and cancer-related functions of galectin family members.

5. Zaborska et al. (2023). The Role of Galectin-3 in Heart Failure. Int. J. Mol. Sci. 24, 13111. (zaborska2023theroleof pages 1-3)

6. Review of LGALS3 in cardiac fibrosis, inflammation, and ventricular remodeling.

7. Radziejewska (2023). Galectin-3 and Epithelial MUC1 Mucin—Interactions Supporting Cancer Development. Cancers 15, 2680. (radziejewska2023galectin3andepithelial pages 1-2)

8. Focuses on T antigen recognition and cancer-associated interactions.

Mechanistic Studies on Lysosomal Damage Response and Autophagy

1. Jia et al. (2020). MERIT, a cellular system coordinating lysosomal repair, removal and replacement. Autophagy 16, 1539-1541. (jia2020meritacellular pages 1-4)

2. Landmark study defining LGALS3's role in ESCRT-mediated lysosomal repair and TRIM16-dependent lysophagy.

3. Burbidge et al. (2022). LGALS3 mediates an unconventional secretion of SNCA/α-synuclein. Autophagy 18, 1020-1048. (burbidge2022lgals3(galectin3) pages 1-2)

4. Demonstrates LGALS3-mediated secretory autophagy of α-synuclein in human midbrain neurons.

5. Wang et al. (2023). Periplocin suppresses colorectal cancer by triggering LGALS3-mediated lysophagy. Autophagy 19, 3132-3150. (wang2023periplocinsuppressesthe pages 1-2)

6. Shows that LGALS3 upregulation and lysophagy induction can exacerbate lysosomal damage in cancer cells.

Neuroinflammation and Neurodegeneration

1. Siew et al. (2024). Galectin-3 aggravates microglial activation and tau transmission in tauopathy. J. Clin. Invest. 134, e165523. (siew2024galectin3aggravatesmicroglial pages 1-2)

2. Demonstrates Gal3 upregulation in tauopathy, EV-associated release, and rescue of tau pathology and memory deficits in Gal3 knockout mice.

3. García-Revilla et al. (2023). Galectin-3 shapes toxic alpha-synuclein strains in Parkinson's disease. Acta Neuropathol. 146, 51-75. (garciarevilla2023galectin3shapestoxic pages 1-2)

4. Links Gal3 to α-synuclein aggregation, Lewy body formation, and toxic strain production in PD.

5. Tan et al. (2021). Galectin-3: a key player in microglia-mediated neuroinflammation and Alzheimer's disease. Cell Biosci. 11, 78. (tan2021galectin3akey pages 1-2)

   • Reviews Gal3's role in microglial activation, TREM2 signaling, and AD pathogenesis.

6. Lozinski et al. (2024). Emerging role of galectin 3 in neuroinflammation and neurodegeneration. Neural Regen. Res. 19, 2004-2009. (lozinski2024emergingroleof pages 1-2)

   • Summarizes Gal3 structure, immune functions, and therapeutic potential in CNS diseases.

Fibrosis and Signaling

1. Calver et al. (2024). Defining the mechanism of galectin-3–mediated TGF-β1 activation. J. Biol. Chem. 300, 107300. (calver2024definingthemechanism pages 1-2)
   • Demonstrates LGALS3 binding to αv integrins and TGFβRII, promoting TGF-β1 activation in lung fibrosis.

Emerging Mechanisms

1. Liu et al. (2025). Galectin-3 directs mitophagy in response to Parkin-/proteasome-dependent rupture of mitochondrial outer membrane. Biol. Direct 20, 108. (liu2025galectin3directsmitophagy pages 1-2)

   • Proteomic identification of Gal3 at ruptured mitochondrial membranes, demonstrating PHB2 interaction and ULK1 recruitment.

2. Zhang et al. (2020). A Translocation Pathway for Vesicle-Mediated Unconventional Protein Secretion. Cell 181, 637-652. (zhang2020atranslocationpathway pages 1-4)

   • Defines TMED10-dependent unconventional secretion pathway for leaderless cargoes including LGALS3.

3. Shivcharan et al. (2025). Endolysosomal damage surveillance enables rapid inflammasome sensing of pathogens. Cell Rep. 44, 116002. (shivcharan2025endolysosomaldamagesurveillance pages 1-3)

   • Mechanistically clarifies that galectin-8, not galectin-3, is the primary galectin coupling endomembrane damage to noncanonical inflammasome activation.

7. CONCLUSIONS

Core Functions

The strongest evidence supports LGALS3 annotations for:

1. β-Galactoside binding lectin activity (radziejewska2023galectin3andepithelial pages 1-2, mukherjee2025galectin3integratorof pages 1-2)
2. Lysosomal damage response (jia2020meritacellular pages 1-4, burbidge2022lgals3(galectin3) pages 1-2)
3. Lysophagy via TRIM16-ATG16L1-ULK1 recruitment (jia2020meritacellular pages 1-4)
4. Unconventional secretion via TMED10 (zhang2020atranslocationpathway pages 1-4)
5. Extracellular glycan lattice formation (mukherjee2025galectin3integratorof pages 1-2, lozinski2024emergingroleof pages 1-2)
6. Fibrosis via integrin/TGFβRII interactions (calver2024definingthemechanism pages 1-2)

Context-Specific Roles

Strong but context-dependent evidence supports:

1. Neuroinflammation and neurodegenerative disease (tan2021galectin3akey pages 1-2, siew2024galectin3aggravatesmicroglial pages 1-2, garciarevilla2023galectin3shapestoxic pages 1-2)
2. Mitophagy (liu2025galectin3directsmitophagy pages 1-2)
3. Secretory autophagy (burbidge2022lgals3(galectin3) pages 1-2)

Avoid Over-Annotation

Annotations should be cautious or avoided for:

1. Broad pyroptosis (shivcharan2025endolysosomaldamagesurveillance pages 1-3)
2. Direct synaptic remodeling (siew2024galectin3aggravatesmicroglial pages 1-2)
3. Pathology-specific locations like Lewy bodies (garciarevilla2023galectin3shapestoxic pages 1-2)
4. Developmental roles without strong human evidence (lozinski2024emergingroleof pages 1-2)

Recommended GO Annotation Strategy

• Prioritize core lectin activity and damage-sensing functions.
• Distinguish intracellular vs. extracellular roles clearly.
• Annotate lysophagy and ESCRT-mediated repair with high confidence.
• Use qualifiers for context-dependent processes like fibrosis, neuroinflammation, and mitophagy.
• Avoid overextending to weakly supported processes like pyroptosis and synaptic remodeling.

This report provides a comprehensive, evidence-based foundation for GO annotation review of LGALS3, balancing the breadth of LGALS3 biology with the need for precision and context-awareness in annotation.

References

1. (radziejewska2023galectin3andepithelial pages 1-2): Iwona Radziejewska. Galectin-3 and epithelial muc1 mucin—interactions supporting cancer development. Cancers, 15:2680, May 2023. URL: https://doi.org/10.3390/cancers15102680, doi:10.3390/cancers15102680. This article has 22 citations.

2. (tan2021galectin3akey pages 1-2): Yinyin Tan, Yanqun Zheng, Daiwen Xu, Zhanfang Sun, Huan Yang, and Qingqing Yin. Galectin-3: a key player in microglia-mediated neuroinflammation and alzheimer's disease. Cell & Bioscience, Apr 2021. URL: https://doi.org/10.1186/s13578-021-00592-7, doi:10.1186/s13578-021-00592-7. This article has 118 citations and is from a peer-reviewed journal.

3. (mukherjee2025galectin3integratorof pages 1-2): Mana Mohan Mukherjee, Devin Biesbrock, and John A. Hanover. Galectin-3: integrator of signaling via hexosamine flux. Biomolecules, Jul 2025. URL: https://doi.org/10.3390/biom15071028, doi:10.3390/biom15071028. This article has 8 citations.

4. (jia2020meritacellular pages 1-4): Jingyue Jia, Aurore Claude-Taupin, Yuexi Gu, Seong Won Choi, Ryan Peters, Bhawana Bissa, Michal H. Mudd, Lee Allers, Sandeep Pallikkuth, Keith A. Lidke, Michelle Salemi, Brett Phinney, Muriel Mari, Fulvio Reggiori, and Vojo Deretic. Merit, a cellular system coordinating lysosomal repair, removal and replacement. Autophagy, 16:1539-1541, Jun 2020. URL: https://doi.org/10.1080/15548627.2020.1779451, doi:10.1080/15548627.2020.1779451. This article has 44 citations and is from a domain leading peer-reviewed journal.

5. (burbidge2022lgals3(galectin3) pages 1-2): Kevin Burbidge, David J. Rademacher, Jessica Mattick, Stephanie Zack, Andrea Grillini, Luc Bousset, Ochan Kwon, Konrad Kubicki, Alexander Simon, Ronald Melki, and Edward M. Campbell. Lgals3 (galectin 3) mediates an unconventional secretion of snca/α-synuclein in response to lysosomal membrane damage by the autophagic-lysosomal pathway in human midbrain dopamine neurons. Autophagy, 18:1020-1048, Oct 2022. URL: https://doi.org/10.1080/15548627.2021.1967615, doi:10.1080/15548627.2021.1967615. This article has 68 citations and is from a domain leading peer-reviewed journal.

6. (calver2024definingthemechanism pages 1-2): Jessica F. Calver, Nimesh R. Parmar, Gemma Harris, Ryan M. Lithgo, Panayiota Stylianou, Fredrik R. Zetterberg, Bibek Gooptu, Alison C. Mackinnon, Stephen B. Carr, Lee A. Borthwick, David J. Scott, Iain D. Stewart, Robert J. Slack, R. Gisli Jenkins, and Alison E. John. Defining the mechanism of galectin-3–mediated tgf-β1 activation and its role in lung fibrosis. Journal of Biological Chemistry, 300:107300, Jun 2024. URL: https://doi.org/10.1016/j.jbc.2024.107300, doi:10.1016/j.jbc.2024.107300. This article has 42 citations and is from a domain leading peer-reviewed journal.

7. (shivcharan2025endolysosomaldamagesurveillance pages 1-3): Sonia Shivcharan, Doulathunnisa Ahamed Younis, Skylar S. Wright, Chengliang Wang, Bharat Behl, Patience Shumba, Kristina N. Delgado, Arshmeet K. Chawla, Neal M. Alto, Noorjahan Panjwani, Sivapriya Kailasan Vanaja, Jianbin Ruan, Zhichao Fan, and Vijay A. Rathinam. Endolysosomal damage surveillance enables rapid inflammasome sensing of pathogens. Cell Reports, 44:116002, Aug 2025. URL: https://doi.org/10.1016/j.celrep.2025.116002, doi:10.1016/j.celrep.2025.116002. This article has 3 citations and is from a highest quality peer-reviewed journal.

8. (siew2024galectin3aggravatesmicroglial pages 1-2): Jian Jing Siew, Hui-Mei Chen, Feng-Lan Chiu, Chia-Wei Lee, Yao-Ming Chang, Hung-Lin Chen, Thi Ngoc Anh Nguyen, Hung-Ting Liao, Mengyu Liu, Hsiao-Tien Hagar, Yung-Chen Sun, Hsing-Lin Lai, Min-Hao Kuo, David Blum, Luc Buée, Lee-Way Jin, Shih-Yu Chen, Tai-Ming Ko, Jie-Rong Huang, Hung-Chih Kuo, Fu-Tong Liu, and Yijuang Chern. Galectin-3 aggravates microglial activation and tau transmission in tauopathy. Journal of Clinical Investigation, Jan 2024. URL: https://doi.org/10.1172/jci165523, doi:10.1172/jci165523. This article has 46 citations and is from a highest quality peer-reviewed journal.

9. (garciarevilla2023galectin3shapestoxic pages 1-2): Juan García-Revilla, Antonio Boza-Serrano, Yiyun Jin, Devkee M. Vadukul, Jesús Soldán-Hidalgo, Lluís Camprubí-Ferrer, Marta García-Cruzado, Isak Martinsson, Oxana Klementieva, Rocío Ruiz, Francesco A. Aprile, Tomas Deierborg, and José Luis Venero. Galectin-3 shapes toxic alpha-synuclein strains in parkinson’s disease. Acta Neuropathologica, 146:51-75, May 2023. URL: https://doi.org/10.1007/s00401-023-02585-x, doi:10.1007/s00401-023-02585-x. This article has 39 citations and is from a highest quality peer-reviewed journal.

10. (lozinski2024emergingroleof pages 1-2): Brian M. Lozinski, Khanh Ta, and Yifei Dong. Emerging role of galectin 3 in neuroinflammation and neurodegeneration. Neural Regeneration Research, 19:2004-2009, Dec 2023. URL: https://doi.org/10.4103/1673-5374.391181, doi:10.4103/1673-5374.391181. This article has 35 citations and is from a peer-reviewed journal.

11. (liu2025galectin3directsmitophagy pages 1-2): Pei-Han Liu, Yu-Shan Lin, Wei-Hua Chu, Wei-Tse Sun, Po-Yu Huang, Jie-rong Huang, and Wei-Chung Chiang. Galectin-3 directs mitophagy in response to parkin-/proteasome-dependent rupture of mitochondrial outer membrane. Biology Direct, Nov 2025. URL: https://doi.org/10.1186/s13062-025-00692-1, doi:10.1186/s13062-025-00692-1. This article has 1 citations and is from a peer-reviewed journal.

12. (zaborska2023theroleof pages 1-3): Beata Zaborska, Małgorzata Sikora-Frąc, Krzysztof Smarż, Ewa Pilichowska-Paszkiet, Andrzej Budaj, Dariusz Sitkiewicz, and Grażyna Sygitowicz. The role of galectin-3 in heart failure—the diagnostic, prognostic and therapeutic potential—where do we stand? International Journal of Molecular Sciences, 24:13111, Aug 2023. URL: https://doi.org/10.3390/ijms241713111, doi:10.3390/ijms241713111. This article has 103 citations.

13. (zhang2020atranslocationpathway pages 1-4): Min Zhang, Lei Liu, Xubo Lin, Yang-Ping Wang, Ying Li, Qing Guo, Shulin Li, Yuxin Sun, Xuan Tao, Di Zhang, Xiachen Lv, Li Zheng, and Liang Ge. A translocation pathway for vesicle-mediated unconventional protein secretion. Cell, 181:637-652.e15, Apr 2020. URL: https://doi.org/10.1016/j.cell.2020.03.031, doi:10.1016/j.cell.2020.03.031. This article has 297 citations and is from a highest quality peer-reviewed journal.

14. (wang2023periplocinsuppressesthe pages 1-2): Kui Wang, Shuyue Fu, Lixia Dong, Dingyue Zhang, Mao Wang, Xingyun Wu, Enhao Shen, Li Luo, Changlong Li, Edouard Collins Nice, Canhua Huang, and Bingwen Zou. Periplocin suppresses the growth of colorectal cancer cells by triggering lgals3 (galectin 3)-mediated lysophagy. Autophagy, 19:3132-3150, Jul 2023. URL: https://doi.org/10.1080/15548627.2023.2239042, doi:10.1080/15548627.2023.2239042. This article has 49 citations and is from a domain leading peer-reviewed journal.

15. (zhang2025multifacetedrolesof pages 10-11): Nan Zhang, Qiao Liu, Daihan Wang, Xiaoyun Wang, Zhaoping Pan, Bo Han, and Gu He. Multifaceted roles of galectins: from carbohydrate binding to targeted cancer therapy. Biomarker Research, Mar 2025. URL: https://doi.org/10.1186/s40364-025-00759-1, doi:10.1186/s40364-025-00759-1. This article has 39 citations and is from a peer-reviewed journal.

Asta Literature Retrieval: Literature evidence for LGALS3 (Homo sapiens): LGALS3 has immunological synapse (GO:0001772). Gene/protein: LGALS3. O...

This report is retrieval-only and is generated directly from Asta results.

• Papers retrieved: 11
• Snippets retrieved: 19

Relevant Papers

[1] High LGALS3 expression induced by HCP5/hsa-miR-27b-3p correlates with poor prognosis and tumor immune infiltration in hepatocellular carcinoma

• Authors: Yinghui Ren, Yongmei Qian, Qicheng Zhang, Xiaoping Li, Mingjiang Li et al.
• Year: 2024
• Venue: Cancer Cell International
• URL: https://www.semanticscholar.org/paper/552bd37c67dea75d0c33a9a0de2acdafcf0dcf6e
• DOI: 10.1186/s12935-024-03309-1
• PMID: 38643145
• PMCID: 11031979
• Citations: 13
• Summary: It is hypothesized that the HCP5/hsa-miR-27b-3p axis could serve as the most promising LGALS3 regulation mechanism in HCC and the upregulation of LGALS3 via the HCP5/hsa-miR-27b-3p axis is associated with unfavorable prognosis and increased tumor immune infiltration in HCC.
• Evidence snippets:
• Snippet 1 (score: 0.759)
  > Hepatocellular carcinoma (HCC) is widely recognized for its unfavorable prognosis. Increasing evidence has revealed that LGALS3 has an essential function in initiating and developing several malignancies in humans. Nevertheless, thorough analysis of the expression profile, clinical prognosis, pathway prediction, and immune infiltration of LGALS3 has not been fully explored in HCC. In this study, an initial pan-cancer analysis was conducted to investigate the expression and prognosis of LGALS3. Following a comprehensive analysis, which included expression analysis and correlation analysis, noncoding RNAs that contribute to the overexpression of LGALS3 were subsequently identified. This identification was further validated using HCC clinical tissue samples. TIMER2 and GEPIA2 were employed to examine the correlation between LGALS3 and HCP5 with immunological checkpoints, cell chemotaxis, and immune infiltration in HCC. The R program was applied to analyze the expression distribution of immune score in in HCC patients with high and low LGALS3 expression. The expression profiles of immune checkpoints were also analyzed. Use R to perform GSVA analysis in order to explore potential signaling pathways. First, we conducted pan-cancer analysis for LGALS3 expression level through an in-depth analysis of public databases and found that HCC has a high LGALS3 gene and protein expression level, which were then verified in clinical HCC specimens. Meanwhile, high LGALS3 gene expression is related to malignant progression and poor prognosis of HCC. Univariate and multivariate analyses confirmed that LGALS3 could serve as an independent prognostic marker for HCC. Next, by combining comprehensive analysis and validation on HCC clinical tissue samples, we hypothesize that the HCP5/hsa-miR-27b-3p axis could serve as the most promising LGALS3 regulation mechanism in HCC. KEGG and GO analyses highlighted that the LGALS3-related genes were involved in tumor immunity. Furthermore, we detected a significant positive association between LGALS3 and HCP5 with immunological checkpoints, cell chemotaxis, and immune infiltration. In addition, high LGALS3 expression groups had significantly
• Snippet 2 (score: 0.737)
  > analyses highlighted that the LGALS3-related genes were involved in tumor immunity. Furthermore, we detected a significant positive association between LGALS3 and HCP5 with immunological checkpoints, cell chemotaxis, and immune infiltration. In addition, high LGALS3 expression groups had significantly higher immune cell scores and immune checkpoint expression levels. Finally, GSVA analysis was performed to predict potential signaling pathways linked to LGALS3 and HCP5 in immune evasion and metabolic reprogramming of HCC. Our findings indicated that the upregulation of LGALS3 via the HCP5/hsa-miR-27b-3p axis is associated with unfavorable prognosis and increased tumor immune infiltration in HCC.
• Snippet 3 (score: 0.737)
  > The immune checkpoint molecules have a vital function in immune surveillance, immune escape, as well as immune editing [19].To further determine the possible oncogenic function of LGALS3 in HCC, the association between LGALS3 and several immunological checkpoints was evaluated.LGALS3 expression showed a significant positive association with CD274, TIGIT, PDCD1, HAVCR2, CTLA4, LAG3, as well as PDCD1LG2 after adjustment for tumor purity in HCC (Fig. 6A-B).Moreover, based on GEPIA2, the same positive association was identified between LGALS3 and these immune checkpoints (Fig. 6C-D).Furthermore, we found that the expression of these immune checkpoints was significantly upregulated in the high LGALS3 expression groups, as shown in Fig. 6E.These findings imply that tumor immune escape may have a role in LGALS3-mediated HCC carcinogenesis.
• Snippet 4 (score: 0.727)
  > LGALS3 has a crucial function in mediating cell adhesion as well as cell-cell interaction by recognizing complex carbohydrates on the surface of cells [22,23], as well as regulates cell apoptosis, autophagy, and inflammation [24,25].Interestingly, recent studies suggested that LGALS3 involves in essential cancer-related mechanisms, including cellular metabolism, carcinogenesis, metastasis, neoplasia, angiogenesis, as well as immune escape [26][27][28].In addition, LGALS3 is highly expressed and implicated in different cancer types progression such as HCC, gastric, colorectal, pancreatic carcinomas, melanomas or glioblastomas and breast cancer [29,30].Indeed, LGALS3 has been considered a potential marker for these malignancies.Interestingly, LGALS3, which is differentially expressed in different cancers, has been shown to exhibit tumor suppressor activity in certain cancer types.The different roles of LGALS3 may be attributed to different potential mechanisms that appear cancer-type dependent.The different locations and mutations of LGALS3 also contribute to its various functions.However, LGALS3 remains inadequately understood in HCC and requires further investigation.First, we conducted an extensive investigation of the expression profile, clinical prognosis, and pathologic stage of LGALS3 in HCC through an in-depth analysis of the public database.On the basis of TCGA and CPTAC datasets, we found that LGALS3 gene and protein expression was elevated in HCC tissues.Moreover, the OS and DSS were lesser in patients with HCC having higher expression levels of LGALS3 contrasted to those with low expression levels of LGALS3 based on GEPIA2 and Kaplan-Meier plotter datasets.Meanwhile, the expression of LGALS3 within HCC was significantly associated with the advanced tumor stage and grade, indicating that elevated LGALS3 expression could increase tumor progression.Song et al. [31] indicated that galectin-3 promoted HCC tumorigenesis and metastasis via β-catenin signalling in vitro and in vivo.
• Snippet 5 (score: 0.691)
  > To delineate the driving mechanism of LGALS3 for the malignant progression of HCC, the KEGG and GO analysis was conducted.The volcano plot and heatmap showed significantly differentially expressed genes between LGALS3 high-and low-expression groups (Figure S3A-B).The KEGG pathway analysis revealed that these LGALS3-related genes were enriched in the IL-17 signaling pathway, ECM-receptor interaction pathway, central carbon metabolism in cancer pathway, leukocyte transendothelial migration pathway and PI3K-Akt signaling pathway.Meanwhile, the GO analysis revealed that these genes were strongly associated with cell chemotaxis, leukocyte chemotaxis, regulation of leukocyte migration, as well as regulation of chemotaxis (Fig. 5A).Accumulating evidence has proven the immune system has an essential role in malignancy pathogenesis [17], and LGALS3 is closely correlated with CD163 + tumor-associated macrophages (TAM) in glioma [10].Therefore, we studied the association between LGALS3 level and the immune infiltration level in HCC.There was no statistical difference in immune cell infiltration levels over a number of LGALS3 copy numbers (Fig. 5B).Meanwhile, immune infiltration analysis revealed that expression of LGALS3 showed a significant positive association with several immune cell populations, involving CD4 + T cell, CD8 + T cell, B cell, neutrophil, macrophage, dendritic cell, as well as cancer-associated fibroblasts (CAFs) within HCC (Fig. 5C-E).Based on these results, we further evaluated the immune score in HCC patients with high and low LGALS3 expression.The scores of immune cells, including CD4 + T cell, CD8 + T cell, B cell, neutrophil, macrophage, and dendritic cell, were significantly higher in the high LGALS3 expression groups, as shown in Fig. 5F.Chemokines are a group of molecules that are important for the chemotaxis of immune cells [18].
• Snippet 6 (score: 0.690)
  > Next, the prognostic value of LGALS3 expression in the 23 kinds of cancer patients was then determined.Correlations between LGALS3 expression with OS (overall survival) were evaluated using the GEPIA2 database.In the OS study, only elevated LGALS3 expression indicated poorer survival for HCC patients (Fig. 2A).LGALS3 was not statistically significant for OS of 22 other cancer types patients.Furthermore, DSS (disease-specific survival) LGALS3 in predicting 1-, 3-, and 5-year OS. (H) ROC curve for LGALS3 in predicting 1-, 3-, and 5-year DSS.The higher values of AUC corresponding to higher predictive power.p value < 0.05; **p value < 0.001 was lesser in patients suffering from HCC having higher levels of LGALS3 expression (Fig. 2B).Next, we validated the expression levels of LGALS3 protein in HCC tissues using IF staining.As expected, HCC tumor demonstrated strong LGALS3 expression (Fig. 2C).These findings were further validated by qRT-PCR assay of tumor and adjacent normal tissues from 5 HCC patients.Here, LGALS3 expression was also significantly increased in the HCC tissues (Fig. 2D).In addition, LGALS3 expression was shown to be linked with the pathological stage of HCC, as illustrated in Fig. 2E.High expression of LGALS3 gene is associated with high tumor grade in HCC (Fig. 2F).Moreover, LGALS3 expression was significantly associated with OS and DSS in both univariate and multivariate analyses (Figure S2A-H).Time-dependent ROC analysis showed that the area under the ROC curve was 0.672 at 5 years of OS, and 0.691 at 5 years of DSS (Fig. 2G-H).Taken together, LGALS3 might function as a prospective biomarker for the prognosis of patients suffering from HCC.
• Snippet 7 (score: 0.687)
  > Zhang et al. [14] suggested overexpression of LGALS3 promoted HCC bone metastasis and induced associated skeletal complications.Nevertheless, the expression, prognosis, epigenetic, and molecular regulatory mechanisms of LGALS3 in HCC have been incompletely studied.In addition, LGALS3 relation with immune infiltration in HCC TME has yet to be inadequately investigated.
  > This work began with a pan-cancer study of LGALS3 expression and its predictive value in a variety of human malignancies.We further explored the LGALS3 potential upstream regulatory noncoding RNAs (ncRNAs) involving microRNAs (miRNAs) as well as long noncoding RNAs (lncRNAs) throughout HCC.Subsequently, in HCC, a correlation analysis was investigated between LGALS3 and tumor immunity-related indicators involving cell chemotaxis, immune checkpoints, immune cell biomarkers, and infiltration.Eventually, the association between the expression of LGALS3 and signaling pathways was examined in HCC.Findings demonstrated that LGALS3 might have a role in the malignancy of HCC and immune cell infiltration via the HCP5/hsa-miR-27b-3p/ LGALS3 axis, suggesting that a novel HCP5/hsa-miR-27b-3p/LGALS3 axis could be a biomarker for prognosis and treatment target for HCC patients.

[2] Mutation of the galectin‐3 glycan‐binding domain ( Lgals3‐R200S) enhances cortical bone expansion in male mice and trabecular bone mass in female mice

• Authors: Kevin A. Maupin, Daniel T. Dick, Vari Vivarium, Transgenics Core, B. Williams
• Year: 2020
• Venue: FEBS Open Bio
• URL: https://www.semanticscholar.org/paper/6ab62ea9acc6fef617d0b1f237c1a477f45b05c7
• DOI: 10.1002/2211-5463.13483
• PMID: 36062328
• PMCID: 9527582
• Citations: 2
• Summary: The results suggest that the trabecular bone phenotype of Lgals3-KO mice was driven primarily by loss of extracellular galectin-3, while the cortical bone phenotypeof Lgal3- KO mice may have also been influenced by Loss of intracellular galECTin- 3.
• Evidence snippets:
• Snippet 1 (score: 0.725)
  > The study of galectin-3 is complicated by its ability to function both intracellularly and extracellularly. While the mechanism of galectin-3 secretion is unclear, studies have shown that the mutation of a highly conserved arginine to a serine in human galectin-3 (LGALS3-R186S) blocks glycan binding and secretion. To gain insight into the roles of extracellular and intracellular functions of galectin-3, we generated mice with the equivalent mutation (Lgals3-R200S) using CRISPR/Cas9-directed homologous recombination. Consistent with a reduction in galectin-3 secretion, we observed significantly reduced galectin-3 protein levels in the plasma of heterozygous and homozygous mutant mice. We observed a similar increased bone mass phenotype in Lgals3-R200S mutant mice at 36 weeks as we previously observed in Lgals3-KO mice with slight variation. Like Lgals3-KO mice, Lgals3-R200S females, but not males, had significantly increased trabecular bone mass. However, only male Lgals3-R200S mice showed increased cortical bone expansion, which we had previously observed in both male and female Lgals3-KO mice and only in female mice using a separate Lgals3 null allele (Lgals3). These results suggest that the trabecular bone phenotype of Lgals3-KO mice was driven primarily by loss of extracellular galectin-3. However, the cortical bone phenotype of Lgals3-KO mice may have also been influenced by loss of intracellular galectin-3. Future analyses of these mice will aid in identifying the cellular and molecular mechanisms that contribute to the Lgals3-deficient bone phenotype as well as aid in distinguishing the extracellular vs. intracellular roles of galectin-3 in various signaling pathways.

[3] Galectin-3 aggravates microglial activation and tau transmission in tauopathy

• Authors: Jian-Jing Siew, Hui-Mei Chen, Feng‐Lan Chiu, Chia-Wei Lee, Yao-Ming Chang et al.
• Year: 2023
• Venue: The Journal of Clinical Investigation
• URL: https://www.semanticscholar.org/paper/8c77eea796475aa4e26a4051432bc4d4c021d847
• DOI: 10.1172/JCI165523
• PMID: 37988169
• PMCID: 10786694
• Citations: 24
• Influential citations: 1
• Summary: It is shown that Gal3 was upregulated in the microglia of humans and mice with tauopathy, and is a potential therapeutic target for tauopathy.
• Evidence snippets:
• Snippet 1 (score: 0.700)
  > In particular, the knockout of Gal3 normalized 348 DEG genes between Tau22/Lgals3 +/+ and WT mice (Figure 6, A and B and Supplemental Table 7). Further GO enrichment analysis revealed that the upregulated DEGs of Tau22/Lgals3 +/+ versus WT mice were enriched in multiple processes, including metabolic processes, oxidative reduction processes, and immune system processes (Figure 6, C and D). Importantly, the downregulated DEGs by Lgals3 deletion within the context of Tau22 were primarily enriched in immune responses and the production of cytokines and chemokines (Figure 6E). Conversely, the downregulated DEGs in Tau22/Lgals3 -/-versus Tau22/Lgals3 +/+ mice were enriched in processes including nervous system development, protein phosphorylation, synapse assembly, and learning (Supplemental Figure 21, E and F). No specific enriched processes were identified for the upregulated DEGs in Tau22/Lgals3 -/- versus Tau22/Lgals3 +/+ mice. These findings are consistent with what were observed in human iMGLs, confirming that Gal3 plays a principal role in governing the microglia-mediated immune response in tauopathy.
  > We next categorized these DEGs by their enriched cell type based on the Tabula Muris Consortium database (39) (Supplemental Figure 21D), and, as predicted, we found that the largest population of DEGs identified between Tau22/Lgals3 -/-and Tau22/Lgals3 +/+ mice was enriched in microglia (21.3%; Supple-cells (Figure 8). When encountering pathological tau, microglia become active and release Gal3 into the extracellular space either directly or via EVs (Figure 3O). Under the tested conditions, we found that Gal3 directly facilitated the aggregation of pTau into β-pleated-sheet structures (Figure 3L). This interaction between pTau and Gal3 may occur in EVs and/or the extracellular space between microglia and neurons.
• Snippet 2 (score: 0.685)
  > Importantly, the loss of Gal3 also prevented the learning and memory deficits present in Tau22/Lgals3 +/+ mice (33) to a great extent, as assessed by the Morris water maze test (Figure 5, H and I). Consistent with the GAM gene analysis (Figure 4, H and I), the number and level of CD68-positive microglia in Tau22/Lgals3 -/-mice were indeed lower than those in Tau22/Lgals3 +/+ mice (Figure 5, J and K), suggesting a key role of Gal3 in microglial activation. Given that synaptic loss is a feature of tauopathy that is also presented in Tau22 mice (33), we performed immunofluorescence staining of synapses at the CA1 region using VGLUT1 and Homer1 as presynaptic and postsynaptic markers, respectively. Our data showed that Gal3 knockout rescued the number of synapses assessed by the colocalization of VGLUT1 and Homer1 (Figure 5, L and M and Supplemental Figure 20, A and B). This finding suggests that GAM mediates the loss of synapses in Tau22 mice.
  > To further delineate the protective role of Gal3 depletion in tauopathy, we analyzed the gene expression profiles of the hippocampi of Tau22/Lgals3 -/-mice and corresponding controls using bulk RNA-Seq. In total, 3,770 DEGs were identified between Tau22/Lgals3 +/+ and WT mice, and 868 DEGs were identified between Tau22/Lgals3 -/-and Tau22/Lgals3 +/+ mice (Supplemental Figure 21, A-D). In particular, the knockout of Gal3 normalized 348 DEG genes between Tau22/Lgals3 +/+ and WT mice (Figure 6, A and B and Supplemental Table 7).

[4] The deficiency of galectin-3 in stromal cells leads to enhanced tumor growth and bone marrow metastasis

• Authors: J. X. Pereira, Maria Carolina Braga Azeredo, Felipe Sá Martins, R. Chammas, F. L. Oliveira et al.
• Year: 2016
• Venue: BMC Cancer
• URL: https://www.semanticscholar.org/paper/5f5ef422f3c44fa24a457d97d0c915ae8188a279
• DOI: 10.1186/s12885-016-2679-1
• PMID: 27526676
• PMCID: 4986277
• Citations: 12
• Influential citations: 1
• Summary: It is demonstrated for the first time that the absence of galectin-3 in the host microenvironment favors the growth of the primary tumors, the metastatic spread to the inguinal lymph nodes and bone marrow colonization by metastatic 4T1 tumor cells.
• Evidence snippets:
• Snippet 1 (score: 0.699)
  > We next investigated whether galectin-3 could influence the development of metastasis to the lymph node. Therefore, 28 days post orthotopic injection (p.o.i) of 4T1 cells in Lgals3+/+ or Lgals3−/− mice, the lymph nodes were excised and the presence of CK-19 positive cells was analyzed by immunohistochemistry. We observed that 4T1 cells (CK-19+) were predominantly present in the capsule of the draining lymph node in Lgals3+/+ mice (Fig. 3a) whereas in Lgals3−/− mice, CK-19+ cells were organized as "sheets-like" within the lymph node parenchyma and also found in the capsule (Fig. 3b). Moreover, we evaluated the presence of lymph node metastasis in Lgals3+/+ and Lgals3−/− mice using the 6-thioguanine clonogenic assay and found significant fewer metastasis in Lgals3+/+ mice in comparison to Lgals3−/− mice, both 21 and 28 days p.o.i. (Fig. 3c, p < 0,05). Interestingly though, we also found an increased CK-19 mRNA levels in Lgals3−/− mice at an earlier stage (15 days) p.o.i. (Fig. 3d, p < 0,05). These results suggest that Lgals3−/− mice are more permissive for 4T1 tumor cells dissemination to the inguinal lymph nodes.
  > Galectin-3-deficient bone marrow microenvironment supports more efficiently the growth of metastatic 4T1
  > We have previously described that Lgals3−/− mice presented structural and functional differences in the bone marrow [17]. Likewise, in this study we confirmed differences in terms of cellularity and projections of bone tissue inside the cavity between Balb/c Lgals3+/+ and Lgals3 −/− mice (Fig. 4a and b).

[5] LGALS3 is connected to CD74 in a previously unknown protein network that is associated with poor survival in patients with AML

• Authors: P. Ruvolo, Chenyue W. Hu, Y. Qiu, V. Ruvolo, Robin L. Go et al.
• Year: 2019
• Venue: EBioMedicine
• URL: https://www.semanticscholar.org/paper/46bbdbcb4660389e13acba24499cc415d75f18e0
• DOI: 10.1016/j.ebiom.2019.05.025
• PMID: 31105032
• PMCID: 6604360
• Citations: 25
• Influential citations: 2
• Summary: The data suggest that the LGALS3 network and the CD74 network each support AML cell survival and the two networks may cooperate in a novel high risk AML population.
• Evidence snippets:
• Snippet 1 (score: 0.697)
  > LGALS3 is associated with active Fig. 7. Suppression of LGALS3 does not alter gene expression of LGALS3 network protein genes or CD74 in THP-1 cells. RNA from THP-1 transductant cells with either LKO vector control shRNA or LGALS3 shRNA was isolated, cDNA produced, and mRNA levels of ATG7, LGALS3, ITGAL, CCND3, PRKCA, PARP1, CD74, MYC, CD44, SSBP2, PPP2R2A, CLPP, and B2M were determined by qRT-PCR and levels normalized to ABL-1 as described in "Materials and methods".
  > AKT and MAPK signaling. The protein with the strongest positive correlation with LGALS3 is with ATG7, an autophagy protein that has recently been implicated in maintaining hematopoietic stem cells and serving as a survival factor in AML [46,47]. Recent studies implicate LGALS3 in regulation of autophagy via autophagasome formation, though whether the mechanism involves ATG7 is not clear [48]. Interestingly, phosphorylated PKC delta was positively correlated with LGALS3. PKC delta is viewed as a pro-stress kinase but recent studies suggest that the enzyme has pro-survival properties [49][50][51]. Kinehara and colleagues suggest that PKC delta may act in human pluripotent stem cells as part of a mechanism to regulate stem cell renewal [52]. The data also suggest a novel relationship between LGALS3 and PP2A. The negative correlation of LGALS3 expression with PPP2R2A/B/C/D could reflect LGALS3 suppression of PP2A. The PP2A isoform containing PPP2R2A dephosphorylates both AKT and PKC alpha [53]. Thus, potential suppression of the PP2A subunit by LGALS3 could account for elevated AKT and PKC alpha phosphorylation in samples where LGALS3 expression is elevated.

[6] Periplocin suppresses the growth of colorectal cancer cells by triggering LGALS3 (galectin 3)-mediated lysophagy

• Authors: Kui Wang, Shuyue Fu, Lixia Dong, Dingyue Zhang, Mao Wang et al.
• Year: 2023
• Venue: Autophagy
• URL: https://www.semanticscholar.org/paper/3dadfc351823c4e325e65c171ab3765871189c80
• DOI: 10.1080/15548627.2023.2239042
• PMID: 37471054
• Citations: 35
• Influential citations: 2
• Summary: It is shown that periplocin exhibits promising anticancer activity against CRC both in vitro and in vivo, and is indicated as a potential therapeutic option for the treatment of CRC.
• Evidence snippets:
• Snippet 1 (score: 0.695)
  > We next investigated the mechanism underlying periplocinmediated lysophagy. The expression of LGALS3, a key lysophagy marker [46], was found to be upregulated following periplocin treatment as evidenced by immunofluorescent staining (Figure 2M). To this end, we presumed that periplocin-induced lysophagy might be attributable to the upregulation of LGALS3. Indeed, periplocin treatment prominently elevated the protein level of LGALS3 as evidence by immunoblotting analysis (Figure 6A). The increased protein level of LGALS3 was further confirmed in tumor xenografts from periplocin-treated mice (Figure 6B,C). However, no obvious change was observed on the mRNA level of LGALS3 in periplocin-treated cells compared with controls (Figure S6A), suggesting that transcriptional regulation was not involved in increased LGALS3 expression following periplocin treatment. Therefore, we postulated that periplocin might elevate LGALS3 by regulating protein stability. Of note, cycloheximide (CHX, a translational inhibitor) treatment led to an obvious decrease in LGALS3 protein level in control cells, but had no obvious effect on the upregulated protein level of LGALS3 in periplocin-treated cells, suggesting periplocin maintains LGALS3 stability (Figure 6D,E). In support of this, treatment with MG132 (a proteasome inhibitor) failed to further enhance the protein level of LGALS3 in response to periplocin treatment (Figure 6F,G). These data suggest that periplocin may prevent proteasomal degradation of LGALS3.
  > We therefore measured the effect of periplocin on LGALS3 ubiquitination. As shown in Figure 6H, periplocin markedly decreased the ubiquitin-conjugated level of LGALS3.
• Snippet 2 (score: 0.693)
  > Scale bar: 10 μm. (I) Immunofluorescent analysis of the colocalization of LGALS3 with ubiquitin in CRC cells treated with or without 0.50 μM periplocin for 24 h. Scale bar: 10 μm. (J) Representative fluorescent images of CRC cells transiently expressing Mrfp-GFP-tandem fluorescent-tagged LGALS3 (tfGal3) followed by 0.50 μM periplocin treatment for 24 h. Scale bar: 10 μm. (K) Quantitative analysis of the GFP + RFP + or GFP − RFP + LGALS3 puncta in (J). (L) the relative decreased ratio of Magic Red intensity, relative increased ratio of LysoSensor Blue intensity, relative increased ratio of the interaction between LGALS3 and TRIM16, and relative increased ratio of LC3B-II protein level in DLD-1 cells following 0.50 μM periplocin treatment at different time periods. Results are representative of three independent experiments. Data are presented as mean ± SD. P < 0.05, P < 0.01, **P < 0.001. for LGALS3 degradation, we generated lysine to arginine mutants of LGALS3 at K196 or Lys210 (LGALS3 K196R or LGALS3 K210R ). As shown in Figure 6I, the ubiquitinconjugated level of LGALS3 K196R mutant was comparable to the wild type (WT), whereas K210 mutation significantly decreased LGALS3 ubiquitination. These results suggest that periplocin elevates LGALS3 level by preventing K210 ubiquitination and proteasomal degradation. In addition, periplocin was found to stabilize the protein level of LGALS3 against thermal changes using a cellular thermal shift assay (CETSA) (Figure 6J,K), implying the binding of periplocin with LGALS3.

[7] In-depth quantitative proteomics analysis revealed C1GALT1 depletion in ECC-1 cells mimics an aggressive endometrial cancer phenotype observed in cancer patients with low C1GALT1 expression

• Authors: A. Montero‐Calle, Á. López-Janeiro, Marta L. Mendes, Daniel Perez-Hernandez, Irene Echevarría et al.
• Year: 2023
• Venue: Cellular Oncology
• URL: https://www.semanticscholar.org/paper/92b64e01bcb30f7457ddb8cc4be26de8b0c7cf69
• DOI: 10.1007/s13402-023-00778-w
• PMID: 36745330
• PMCID: 10205863
• Citations: 19
• Summary: C1GALT1 stably depleted ECC-1 cells mimic an EC aggressive phenotype observed in patients and might be useful for the identification and validation of EC markers of progression.
• Evidence snippets:
• Snippet 1 (score: 0.694)
  > Finally, since LGALS3 (Galectin-3) has been shown to interact with O-glycans in the mucosal epithelium [30], and considering its overexpression observed by proteomics and further confirmed by PCR and WB analyses upon depletion of C1GALT1, we focused on the role of LGALS3 in EC by IHC.
  > A total of 151 out of 178 cores from 79 EC patients were considered adequate for LGALS3 expression assessment by IHC. Morphologic assessment of LGALS3 IHC staining characteristics revealed different staining patterns (Fig. 5 A). Out of the 151 evaluable cores, 45 (29.8%) showed absent LGALS3 expression. LGALS3 positive samples showed variable and low intensity protein expression (mean positive tumor cells per sample = 35.4%). A small subset of cores (13/151, 8.6%) demonstrated diffuse (> 90% positive tumor cells per sample) staining. LGALS3 score varied across histologic types, with serous and undifferentiated tumors displaying the highest protein expression (median IHC LGALS3 score = 10, 20, 50 and 55 for endometrioid, clear cell, serous and undifferentiated tumor types, respectively) (Fig. 5B). Interestingly, the aggressive histologic variants (clear cell, serous and undifferentiated) showed higher LGALS3 IHC scores than endometrioid variants (p value < 0.001). In addition, LGALS3 expression positively correlated with tumor grade. High grade tumors (G3) displayed higher protein expression (median LGALS3 IHC score = 30) compared to low grade tumors (median LGALS3 IHC score for G1/G2 tumors = 10). This finding was independent of histologic type, as similar results were observed when analyzing endometrioid tumors.
  > Finally, we interrogated the correlation between the expression levels of LGALS3 and C1GALT1.

[8] Mice lacking galectin-3 (Lgals3) function have decreased home cage movement

• Authors: Tammy R. Chaudoin, S. Bonasera
• Year: 2018
• Venue: BMC Neuroscience
• URL: https://www.semanticscholar.org/paper/26255eafb963932be62ecb55d4943930217cb63f
• DOI: 10.1186/s12868-018-0428-x
• PMID: 29716523
• PMCID: 5930520
• Citations: 7
• Influential citations: 1
• Summary: P perturbation of behavioral circadian rhythms in Lgals3−/− mice is noted, with mice at both ages demonstrating greater variability in day-to-day performance of feeding, drinking, and movement compared to wildtype.
• Evidence snippets:
• Snippet 1 (score: 0.692)
  > atlases suggest that Lgals3 expression (at low-to-moderate levels) occurs in both pre-and post-natal brain, and has been localized to regions involved in motor behavior generation, including the cortex, striatum, cerebellum, and spinal cord. We thus argue that Lgals3 loss alters mouse motor function, either through its impact on motor development or through altered neuronal signaling in CNS regions that regulate or produce motor behavior. Further studies examining the consequences of Lgals3 loss at synaptic, neuronal, ensemble, and tissue levels of organization will be required to determine the precise mechanisms underlying this functional loss. Grey bands depict periods where mouse cohorts were tested in the home cage monitoring system. Note that neither axis begins at 0. Sampling interval for x-axis is 7 days except where noted by breakpoints
  > As mentioned earlier, Lgals3 has been implicated in a large number of physiological tasks at both a cellular and organwide level of organization. It is thus notable that mice with complete loss of Lgals3 function demonstrate relatively few behavioral differences when compared to wildtype C57BL/6J mice. This finding suggests that, at least in the mouse, there is some genetic redundancy regarding Lgals3 function. Studies of galectin evolution focusing on intron/exon organization as well as sequence identity suggest that duplication of ancestral galectin genes in animal lineages preceding the first teleost fish [62] provided the precursors for what has become a large vertebrate protein family [63]. There is also data suggesting that galectins may be able to substitute for one another in specific circumstances. For example, Lgals1 may compensate for Lgals3 loss at the spliceosome [64]. Extracellular Lgals1 also regulates T cell apoptosis in a manner similar to that of extracellular Lgals3 [65]. The behavioral phenotype arising from Lgals3 functional loss thus identifies neuronal loci and processes where there is no compensation for gene loss.

[9] Mice lacking galectin-3 (Lgals3) function have decreased home cage movement

• Authors: Tammy R. Chaudoin, S. Bonasera
• Year: 2018
• Venue: BMC Neuroscience
• URL: https://www.semanticscholar.org/paper/613a09b176431cdca195e6b3c439b4edbe4f92af
• DOI: 10.1186/s12868-018-0428-x
• Summary: P perturbation of behavioral circadian rhythms in Lgals3−/− mice is noted, with mice at both ages demonstrating greater variability in day-to-day performance of feeding, drinking, and movement compared to wildtype.
• Evidence snippets:
• Snippet 1 (score: 0.691)
  > atlases suggest that Lgals3 expression (at low-to-moderate levels) occurs in both pre-and post-natal brain, and has been localized to regions involved in motor behavior generation, including the cortex, striatum, cerebellum, and spinal cord. We thus argue that Lgals3 loss alters mouse motor function, either through its impact on motor development or through altered neuronal signaling in CNS regions that regulate or produce motor behavior. Further studies examining the consequences of Lgals3 loss at synaptic, neuronal, ensemble, and tissue levels of organization will be required to determine the precise mechanisms underlying this functional loss. Grey bands depict periods where mouse cohorts were tested in the home cage monitoring system. Note that neither axis begins at 0. Sampling interval for x-axis is 7 days except where noted by breakpoints
  > As mentioned earlier, Lgals3 has been implicated in a large number of physiological tasks at both a cellular and organwide level of organization. It is thus notable that mice with complete loss of Lgals3 function demonstrate relatively few behavioral differences when compared to wildtype C57BL/6J mice. This finding suggests that, at least in the mouse, there is some genetic redundancy regarding Lgals3 function. Studies of galectin evolution focusing on intron/exon organization as well as sequence identity suggest that duplication of ancestral galectin genes in animal lineages preceding the first teleost fish [62] provided the precursors for what has become a large vertebrate protein family [63]. There is also data suggesting that galectins may be able to substitute for one another in specific circumstances. For example, Lgals1 may compensate for Lgals3 loss at the spliceosome [64]. Extracellular Lgals1 also regulates T cell apoptosis in a manner similar to that of extracellular Lgals3 [65]. The behavioral phenotype arising from Lgals3 functional loss thus identifies neuronal loci and processes where there is no compensation for gene loss.

[10] Thyroid malignant neoplasm-associated biomarkers as targets for oncolytic virotherapy

• Authors: Mi Guan, Yanping Ma, S. Shah, G. Romano
• Year: 2016
• Venue: Oncolytic Virotherapy
• URL: https://www.semanticscholar.org/paper/9f79d851e32ad25e83c0a2d64e12919bf81a89f8
• DOI: 10.2147/OV.S99856
• PMID: 27579295
• PMCID: 4996252
• Citations: 4
• Summary: This review focuses on the strategy of biomarkers for the production of novel TMN oncolytic therapeutics, which may improve the specificity of targeting of tumor cells and limit adverse effects in patients.
• Evidence snippets:
• Snippet 1 (score: 0.690)
  > The Galectin-3 (LGALS3) is a protein that is encoded by a single gene, LGALS3, located on chromosome 14, locus q21-q22. 63 The molecular weight of this protein is ∼30 kDa, and it contains a carbohydrate-recognition-binding domain of ∼130 amino acids that enable the specific binding of β-galactosides. This protein localizes to the extracellular matrix, the cytoplasm, and the nucleus. It plays a role in numerous cellular functions including cell adhesion, cell activation and chemoattraction, cell growth, differentiation, cell cycle, apoptosis, innate immunity, cell adhesion, and T-cell regulation. 63,64 It has been known that LGALS3 is distributed widely around the tissues but in a low level.
  > To date, LGALS3 has been extensively studied as an IHC marker of thyroid malignancy, and a high diagnostic accuracy has been reported even for difficult pathological diagnoses. 64 Feilchenfeldt et al reported that the mRNA levels of LGALS3 and thyroglobulin in 28 benign and 31 malignant thyroid samples were quantified by real-time PCR. The LGALS3 expression at the mRNA was 60% (12/20) and the protein level was 100% (8/8), respectively. 65 The positive rate was 84% (41/49) when combined with the LGALS3 and HBME-1 in PTC specimens. 66 Two groups of researchers have detected the LGALS3 by IHC in PTC specimens. Saleh et al have shown that the sensitivity and the specificity for LGALS3 were 92.3% and 77.3%, respectively. 67 Song et al reported that positive expression of LGALS3 was 97% (427/441) in PTC group and 51% (77/151) in the benign thyroid lesions group. 68 These results may further support the notion that the high level of LGALS3 antigen expression occurs in patients with PTC. There are a number of different types of oncolytic viruses that have been altered from natural viruses in the laboratory such as adenovirus, reovirus, measles virus, herpes simplex

[11] SMURF1 controls the PPP3/calcineurin complex and TFEB at a regulatory node for lysosomal biogenesis

• Authors: Qin Xia, Hanfei Zheng, Yang Li, Wanting Xu, Chengwei Wu et al.
• Year: 2023
• Venue: Autophagy
• URL: https://www.semanticscholar.org/paper/7ab13fe72fa12a55aa9304ce52199d1494c8974a
• DOI: 10.1080/15548627.2023.2267413
• PMID: 37909662
• PMCID: 11062382
• Citations: 20
• Summary: This study showed that SMURF1 affected lysosomal biogenesis in response to lysosomal damage by preventing TFEB nuclear translocation, and determined that LLOMe-mediated TFEB nuclear import is dependent on SMURF1 under the condition of MTORC1 inhibition.
• Evidence snippets:
• Snippet 1 (score: 0.685)
  > Immunofluorescence assay showed that PPP3R1 was also recruited to lysosomes upon LLOMe treatment in a LGALS3-dependent manner (Figure S4A).To identify the role of PPP3R1 in the formation of complex, as expected, we first found that PPP3CB directly binds with PPP3R1 in a LLOMe-enhanced manner (Figure 6A, B).Considering that PPP3CB was directly associated with LGALS3, we also checked the interaction between PPP3R1 and LGALS3.The results showed that PPP3R1 indirectly binds with LGALS3 (Figure 6C).Similarly, LLOMe treatment also promoted the binding affinity between PPP3R1 and LGALS3 (Figure 6D).We next mapped the key interaction domain of LGALS3 with PPP3R1, and showed the NT domain of LGALS3 was essential for the association with PPP3R1 (Figure 6E, F).Furthermore, overexpression of PPP3CB increased, suppression of PPP3CB abolished, the interactions of PPP3R1 and LGALS3 (Figure 6G, H), suggesting PPP3CB is also the bridge for the interaction between LGALS3 and PPP3R1.Interestingly, we also detected that SMURF1 indirectly interacted with PPP3R1, but not MCOLN1, in a LLOMe-enhanced manner (Figure S4B-E).Given that both SMURF1 and PPP3R1 were indirectly bound with the NT domain of LGALS3, we asked whether SMURF1 affected the interactions between PPP3R1 and LGALS3.Our data indicated that suppression of SMURF1 decreased, overexpression of SMURF1 increased, the interactions of PPP3R1 and LGALS3 (Figure 6I, J), suggesting SMURF1 promotes the recruitment of PPP3R1 by LGALS3.We next mapped the key HECT domain of SMURF1 which was essential for interaction with PPP3R1 (Figure 6K, L).

Notes

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Asta Literature Retrieval: Literature evidence for LGALS3 (Homo sapiens): LGALS3 has monocyte chemotaxis (GO:0002548). Gene/protein: LGALS3. Org...

This report is retrieval-only and is generated directly from Asta results.

• Papers retrieved: 12
• Snippets retrieved: 20

Relevant Papers

[1] High LGALS3 expression induced by HCP5/hsa-miR-27b-3p correlates with poor prognosis and tumor immune infiltration in hepatocellular carcinoma

• Authors: Yinghui Ren, Yongmei Qian, Qicheng Zhang, Xiaoping Li, Mingjiang Li et al.
• Year: 2024
• Venue: Cancer Cell International
• URL: https://www.semanticscholar.org/paper/552bd37c67dea75d0c33a9a0de2acdafcf0dcf6e
• DOI: 10.1186/s12935-024-03309-1
• PMID: 38643145
• PMCID: 11031979
• Citations: 13
• Summary: It is hypothesized that the HCP5/hsa-miR-27b-3p axis could serve as the most promising LGALS3 regulation mechanism in HCC and the upregulation of LGALS3 via the HCP5/hsa-miR-27b-3p axis is associated with unfavorable prognosis and increased tumor immune infiltration in HCC.
• Evidence snippets:
• Snippet 1 (score: 0.933)
  > Chemokines are a group of molecules that are important for the chemotaxis of immune cells [18].According to Table S1, the expression of LGALS3 was statistically positively correlated with several chemokines of immune cells, involving monocytes/macrophages (CCL2, CCL3, CCL5, CCL7, CCL13, CCL17, and CCL22), T lymphocytes (CCL2, CCL1, CCL17, and CCL22), eosinophils (CCL11, CCL26, CCL5, CCL7, CCL13, and CCL3), mast cells (CCR1, CCR2, CCR3, CCR4, CCR5, CXCR2, and CXCR4), and neutrophils (CXCL8).Taken together, these outcomes indicate that LGALS3 is positively associated with immune cell infiltration and cell chemotaxis and could have a crucial function in HCC tumor immune microenvironment.
  > LGALS3 expression correlation and immune cell biomarkers in HCC Next, we wanted to investigate the LGALS3 function in HCC tumor immunity further.Utilizing GEPIA databases, we studied the correlation between LGALS3 expression and immune cell biomarkers within HCC.
• Snippet 2 (score: 0.902)
  > To delineate the driving mechanism of LGALS3 for the malignant progression of HCC, the KEGG and GO analysis was conducted.The volcano plot and heatmap showed significantly differentially expressed genes between LGALS3 high-and low-expression groups (Figure S3A-B).The KEGG pathway analysis revealed that these LGALS3-related genes were enriched in the IL-17 signaling pathway, ECM-receptor interaction pathway, central carbon metabolism in cancer pathway, leukocyte transendothelial migration pathway and PI3K-Akt signaling pathway.Meanwhile, the GO analysis revealed that these genes were strongly associated with cell chemotaxis, leukocyte chemotaxis, regulation of leukocyte migration, as well as regulation of chemotaxis (Fig. 5A).Accumulating evidence has proven the immune system has an essential role in malignancy pathogenesis [17], and LGALS3 is closely correlated with CD163 + tumor-associated macrophages (TAM) in glioma [10].Therefore, we studied the association between LGALS3 level and the immune infiltration level in HCC.There was no statistical difference in immune cell infiltration levels over a number of LGALS3 copy numbers (Fig. 5B).Meanwhile, immune infiltration analysis revealed that expression of LGALS3 showed a significant positive association with several immune cell populations, involving CD4 + T cell, CD8 + T cell, B cell, neutrophil, macrophage, dendritic cell, as well as cancer-associated fibroblasts (CAFs) within HCC (Fig. 5C-E).Based on these results, we further evaluated the immune score in HCC patients with high and low LGALS3 expression.The scores of immune cells, including CD4 + T cell, CD8 + T cell, B cell, neutrophil, macrophage, and dendritic cell, were significantly higher in the high LGALS3 expression groups, as shown in Fig. 5F.Chemokines are a group of molecules that are important for the chemotaxis of immune cells [18].
• Snippet 3 (score: 0.804)
  > Hepatocellular carcinoma (HCC) is widely recognized for its unfavorable prognosis. Increasing evidence has revealed that LGALS3 has an essential function in initiating and developing several malignancies in humans. Nevertheless, thorough analysis of the expression profile, clinical prognosis, pathway prediction, and immune infiltration of LGALS3 has not been fully explored in HCC. In this study, an initial pan-cancer analysis was conducted to investigate the expression and prognosis of LGALS3. Following a comprehensive analysis, which included expression analysis and correlation analysis, noncoding RNAs that contribute to the overexpression of LGALS3 were subsequently identified. This identification was further validated using HCC clinical tissue samples. TIMER2 and GEPIA2 were employed to examine the correlation between LGALS3 and HCP5 with immunological checkpoints, cell chemotaxis, and immune infiltration in HCC. The R program was applied to analyze the expression distribution of immune score in in HCC patients with high and low LGALS3 expression. The expression profiles of immune checkpoints were also analyzed. Use R to perform GSVA analysis in order to explore potential signaling pathways. First, we conducted pan-cancer analysis for LGALS3 expression level through an in-depth analysis of public databases and found that HCC has a high LGALS3 gene and protein expression level, which were then verified in clinical HCC specimens. Meanwhile, high LGALS3 gene expression is related to malignant progression and poor prognosis of HCC. Univariate and multivariate analyses confirmed that LGALS3 could serve as an independent prognostic marker for HCC. Next, by combining comprehensive analysis and validation on HCC clinical tissue samples, we hypothesize that the HCP5/hsa-miR-27b-3p axis could serve as the most promising LGALS3 regulation mechanism in HCC. KEGG and GO analyses highlighted that the LGALS3-related genes were involved in tumor immunity. Furthermore, we detected a significant positive association between LGALS3 and HCP5 with immunological checkpoints, cell chemotaxis, and immune infiltration. In addition, high LGALS3 expression groups had significantly
• Snippet 4 (score: 0.798)
  > analyses highlighted that the LGALS3-related genes were involved in tumor immunity. Furthermore, we detected a significant positive association between LGALS3 and HCP5 with immunological checkpoints, cell chemotaxis, and immune infiltration. In addition, high LGALS3 expression groups had significantly higher immune cell scores and immune checkpoint expression levels. Finally, GSVA analysis was performed to predict potential signaling pathways linked to LGALS3 and HCP5 in immune evasion and metabolic reprogramming of HCC. Our findings indicated that the upregulation of LGALS3 via the HCP5/hsa-miR-27b-3p axis is associated with unfavorable prognosis and increased tumor immune infiltration in HCC.
• Snippet 5 (score: 0.771)
  > Zhang et al. [14] suggested overexpression of LGALS3 promoted HCC bone metastasis and induced associated skeletal complications.Nevertheless, the expression, prognosis, epigenetic, and molecular regulatory mechanisms of LGALS3 in HCC have been incompletely studied.In addition, LGALS3 relation with immune infiltration in HCC TME has yet to be inadequately investigated.
  > This work began with a pan-cancer study of LGALS3 expression and its predictive value in a variety of human malignancies.We further explored the LGALS3 potential upstream regulatory noncoding RNAs (ncRNAs) involving microRNAs (miRNAs) as well as long noncoding RNAs (lncRNAs) throughout HCC.Subsequently, in HCC, a correlation analysis was investigated between LGALS3 and tumor immunity-related indicators involving cell chemotaxis, immune checkpoints, immune cell biomarkers, and infiltration.Eventually, the association between the expression of LGALS3 and signaling pathways was examined in HCC.Findings demonstrated that LGALS3 might have a role in the malignancy of HCC and immune cell infiltration via the HCP5/hsa-miR-27b-3p/ LGALS3 axis, suggesting that a novel HCP5/hsa-miR-27b-3p/LGALS3 axis could be a biomarker for prognosis and treatment target for HCC patients.

[2] Combined High—Throughput Proteomics and Random Forest Machine-Learning Approach Differentiates and Classifies Metabolic, Immune, Signaling and ECM Intra-Tumor Heterogeneity of Colorectal Cancer

• Authors: C. Contini, B. Manconi, A. Olianas, Giulia Guadalupi, Alessandra Schirru et al.
• Year: 2024
• Venue: Cells
• URL: https://www.semanticscholar.org/paper/b7d8516d42c8108cbdf59e6865a8fb424c450946
• DOI: 10.3390/cells13161311
• PMID: 39195201
• PMCID: 11352245
• Citations: 6
• Summary: Different metabolic strategies appeared to be adopted by the two CRC regions to uncouple the Krebs cycle and cytosolic glucose metabolism, promote lipogenesis, promote amino acid synthesis, down-regulate bioenergetics in mitochondria, and up-regulate oxidative stress.
• Evidence snippets:
• Snippet 1 (score: 0.871)
  > The regulatory activity on the cytoskeleton carried out by N-WASP is fundamental for the motility of leukocytes. CgA and Gal-3 are associated with GO annotations concerning the chemotaxis of immune cells, including GO:0002551 "mast cell chemotaxis", GO:0002548 "monocyte chemotaxis", and GO:0030593 "neutrophil chemotaxis".

[3] Phenotypic Switching of Vascular Smooth Muscle Cells in Atherosclerosis

• Authors: Runji Chen, D. McVey, D. Shen, Xiaoxin Huang, Shu Ye
• Year: 2023
• Venue: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
• URL: https://www.semanticscholar.org/paper/472c313e2214a97757712ab0a8b39b133bd6a6bc
• DOI: 10.1161/JAHA.123.031121
• PMID: 37815057
• PMCID: 10757534
• Citations: 133
• Influential citations: 2
• Summary: This review article discusses the 9 VSMC phenotypes that have been reported in atherosclerotic lesions and classifies them into differentiated VSMCs, intermediately dedifferentiated VSMCs, and dedifferentiated VSMCs.
• Evidence snippets:
• Snippet 1 (score: 0.844)
  > Lgals3 (also referred to as galectin-3) is considered a marker of macrophage-like cells. 13,31 Rong et al detected a population of VSMCs that expressed Lgals3 following cholesterol loading in vitro. 31 Recently, Alencar et al found that Lgals3 activation is not a specific marker of the differentiation of VSMCs to a macrophage-like state but rather it is a marker of VSMCs entering a transitional state, with increased expression of genes associated with stem cells that are capable of extracellular matrix remodeling. 16 Of note, similar to SEM-like cells, Lgals3 + cells also have increased expression of lymphocyte antigen 6 family member A and vascular cell adhesion molecule 1. Further studies to investigate if SEM-like cells are derived from Lgals3 + cells are warranted.
  > Using mouse, rat, and human models of cholesterolloading in VSMCs, Li et al found that SREBP1 (sterol regulatory-element binding protein-1) and Krüppel-like factor-15 induced up-and downregulation of Lgals3, respectively, via binding to the Lgals3 gene promoter (albeit at different sites). 45 Likewise, Lgals3 promoted SREBP1 gene expression, producing a feedforward loop upregulated by cholesterol loading. 45 Moreover, Lgals3 and SREBP1 downregulated myocardin-related transcription factor A expression in VSMCs. 45 In another study, Owsiany et al used a dual lineage tracing model and found that Lgals3 + VSMCs produce monocyte chemoattractant protein 1, a proinflammatory chemokine. 15 Knockout of monocyte chemoattractant protein 1 specifically in Lgals3 + VSMCs resulted in the formation of atherosclerotic lesions with a greater ACTA2 content in the fibrous cap and decreased Lgals3 + cell content, a feature of stable plaque. 15
• Snippet 2 (score: 0.785)
  > Knockout of monocyte chemoattractant protein 1 specifically in Lgals3 + VSMCs resulted in the formation of atherosclerotic lesions with a greater ACTA2 content in the fibrous cap and decreased Lgals3 + cell content, a feature of stable plaque. 15 Another study showed that deletion of the Has3 (smooth muscle cell hyaluronan synthase 3) gene in mouse promoted VSMC transition to a Lgals3 + state. 46

[4] Activation of CD14+ Monocytes via the IFN-γ Signaling Pathway Is Associated with Immune-Related Adverse Events in Hepatocellular Carcinoma Patients Receiving PD-1 Inhibition Combination Therapy

• Authors: Yaoru Song, S.-W. Pan, Jiahe Tian, Yingying Yu, Siyu Wang et al.
• Year: 2024
• Venue: Biomedicines
• URL: https://www.semanticscholar.org/paper/b05a3ac750e4ab33f0d31bc2708c804f3502f743
• DOI: 10.3390/biomedicines12061140
• PMID: 38927347
• PMCID: 11201226
• Citations: 5
• Summary: The activation of monocytes induced by the IFN-γ signaling pathway is an important mechanism underlying the occurrence of irAEs in HCC patients receiving PD-1 inhibition combination therapy.
• Evidence snippets:
• Snippet 1 (score: 0.835)
  > We used the AUCell-R package to score the target gene sets.With reference to the relevant literature, we used MONOCYTE CHEMOTAXIS (GO:0002548) for the monocyte chemotaxis score and TYPE II INTERFERON-MEDIATED SIGNALING PATHWAY (GO:0060333) for the IFN-γ signaling pathway score.

[5] Macrophage-derived Spp1 promotes intramuscular fat in dystrophic muscle

• Authors: Philip K Farahat, Chino Kumagai-Cresse, Raquel L. Aragón, Feiyang Ma, Justin K. Amakor et al.
• Year: 2025
• Venue: JCI Insight
• URL: https://www.semanticscholar.org/paper/25c265aed44730ce4b23491cd7ac24d8c3fcf94b
• DOI: 10.1172/jci.insight.181946
• PMID: 40626359
• PMCID: 12288893
• Citations: 7
• Summary: A role for myeloid-derived Spp1 in the differentiation of stromal cells towards an adipogenic fate, leading to accumulation of intramuscular fat in dystrophic muscles is suggested.
• Evidence snippets:
• Snippet 1 (score: 0.795)
  > Lgals3 clusters 2 and 3 expressed the highest Spp1. All Spp1-expressing clusters showed a drastic reduction in Spp1 in the cKO (Figure 2B, compare blue and green) (8). Lgals3-2 cells also expressed Arg1 while Lgals3-3 expressed Igf1 (11). The proportion of different monocyte/macrophage subtypes was evaluated in the 2 genotypes (Figure 2, C and D). While the proportion of Lgals3-3 and Lgals3-2 remained similar in the 2 genotypes, a mild increase in Lgals3-1 was observed in the cKO, while both monocyte subclusters slightly decreased in the cKO (Figure 2C). Although the overall number of macrophages increased in the cKO (mdx:969 vs cKO 4,028), cKO macrophages did not show large changes in the cellular frequency of subtypes (Figure 2D). Inflammatory genes were either unchanged or slightly reduced in the cKO, including the chemokines Ccl3 and Ccl4 (Figure 2F) and Tgfb1 (Supplemental Figure 2B). However, IFN genes such as Ifi207, Ifi204, and Isg15 were slightly increased in cKO monocytes (Figure 2F).

[6] Secreted Factors and Extracellular Vesicles Account for the Immunomodulatory and Tissue Regenerative Properties of Bone-Marrow-Derived Mesenchymal Stromal Cells for Osteoarthritis

• Authors: E. Ragni, C. Perucca Orfei, L. de Girolamo
• Year: 2022
• Venue: Cells
• URL: https://www.semanticscholar.org/paper/b4611c0ee0053b5bd745e5c412143451f2f14a97
• DOI: 10.3390/cells11213501
• PMID: 36359897
• PMCID: 9658264
• Citations: 12
• Influential citations: 1
• Summary: The majority of identified molecules repress the activation of immune cells and the production of OA-related inflammatory mediators, as well as promote cartilage protection by acting on both chondrocytes homeostasis and extracellular matrix-degrading enzymes.
• Evidence snippets:
• Snippet 1 (score: 0.790)
  > These were mainly associated with cluster 1 (Figure 4), which included leukocytes (30 overall factors, GO:0030595) and their subtypes: granulocytes (23, GO:0071621), lymphocytes (19, GO:0048247) and monocytes (17, GO:0002548) (Supplementary Figure S1 and Supplementary Table S1B for all analyzed factors). Interestingly, the leukocyte activation term was defined by several players (31, GO:0045321) without the identification of a specific cluster (Supplementary Figure S2 and Supplementary Table S1C for all analyzed factors). In this frame, lymphocytes (18, GO:0046649) and the subcategory T cells (12, GO:0042110) were the most present terms, followed by neutrophils (10, GO:0042119) and macrophages (4, GO:0042116). Using the online tool STRING, protein-protein interaction levels for 24 proteins of the BMSCs Cluster 1 related to the GO term "chemotaxis" for leukocytes, lymphocytes, monocytes and granulocytes were mined. The different colors represent the immune cell type the "chemotaxis" term is associated with. The blue connections are for proteins with known interactions based on curated databases; violet connections for proteins with experimentally determined interactions. Colorless nodes for proteins not related to the GO terms: leukocytes chemotaxis, lymphocytes chemotaxis, monocytes chemotaxis and granulocytes chemotaxis in the STRING database v 11.5. Empty nodes, proteins of unknown 3D structure; filled nodes, known or predicted 3D structure.

[7] Pregnancy Galectinology: Insights Into a Complex Network of Glycan Binding Proteins

• Authors: S. Blois, G. Dveksler, G. Vasta, N. Freitag, V. Blanchard et al.
• Year: 2019
• Venue: Frontiers in Immunology
• URL: https://www.semanticscholar.org/paper/68fad2b87411701fa708a1f49f8b918370486857
• DOI: 10.3389/fimmu.2019.01166
• PMID: 31231368
• PMCID: 6558399
• Citations: 56
• Influential citations: 7
• Summary: The relevance of galectin-glycan interactions as potential therapeutic targets in pregnancy disorders is discussed and the importance of angiogenesis during decidualization and in placenta formation is discussed.
• Evidence snippets:
• Snippet 1 (score: 0.755)
  > Lgals3 has been implicated in the regulation of innate and adaptive immune responses, where it participates in the activation or differentiation of immune cells and contributes to phagocytic clearance of microorganisms and apoptotic cells by macrophages (117,118). Lgals3 has been reported to promote but also to inhibit T-cell apoptosis depending on whether it binds to glycoproteins on the cell surface (CD45 and CD71) or to intracellular ligands (Bcl-2) (119, 120). In the placenta, Lgals3 was detected in all trophoblastic lineages including villous cytotrophoblasts (CTB) and EVT with a reduction of Lgals3 expression observed from the VT to the trophoblastic cell columns (121). This pattern of Lgals3 expression correlates with the switch from a proliferative to a migratory trophoblast phenotype and while placental Lgals3 dysregulation has been associated with some obstetric complications including spontaneous or recurrent miscarriages, further studies are needed to understand its contribution to trophoblast biology (81,122). In addition to trophoblasts, Lgals3 is expressed by maternal decidual cells (73). While showing a different expression pattern, both Lgals1 and Lgals3 have been proposed to play a role in cell-cell and cell-matrix interactions of trophoblast during placentation (121). Studies of the importance of Lgals3 in murine pregnancy by Yang et al. indicate that Lgals3 is expressed in the luminal and glandular epithelium and that an increase in Lgals3 is required for proper embryo implantation (123). In addition, Lgals3 affects chemotaxis and morphology of endothelial cells and stimulates capillary tube formation and angiogenesis in vivo (124). Therefore, besides its proposed roles in embryo implantation, immune regulation and trophoblast-matrix interactions, Lgals3 has a potential role in placental angiogenesis.

[8] Periplocin suppresses the growth of colorectal cancer cells by triggering LGALS3 (galectin 3)-mediated lysophagy

• Authors: Kui Wang, Shuyue Fu, Lixia Dong, Dingyue Zhang, Mao Wang et al.
• Year: 2023
• Venue: Autophagy
• URL: https://www.semanticscholar.org/paper/3dadfc351823c4e325e65c171ab3765871189c80
• DOI: 10.1080/15548627.2023.2239042
• PMID: 37471054
• Citations: 35
• Influential citations: 2
• Summary: It is shown that periplocin exhibits promising anticancer activity against CRC both in vitro and in vivo, and is indicated as a potential therapeutic option for the treatment of CRC.
• Evidence snippets:
• Snippet 1 (score: 0.750)
  > Scale bar: 10 μm. (I) Immunofluorescent analysis of the colocalization of LGALS3 with ubiquitin in CRC cells treated with or without 0.50 μM periplocin for 24 h. Scale bar: 10 μm. (J) Representative fluorescent images of CRC cells transiently expressing Mrfp-GFP-tandem fluorescent-tagged LGALS3 (tfGal3) followed by 0.50 μM periplocin treatment for 24 h. Scale bar: 10 μm. (K) Quantitative analysis of the GFP + RFP + or GFP − RFP + LGALS3 puncta in (J). (L) the relative decreased ratio of Magic Red intensity, relative increased ratio of LysoSensor Blue intensity, relative increased ratio of the interaction between LGALS3 and TRIM16, and relative increased ratio of LC3B-II protein level in DLD-1 cells following 0.50 μM periplocin treatment at different time periods. Results are representative of three independent experiments. Data are presented as mean ± SD. P < 0.05, P < 0.01, **P < 0.001. for LGALS3 degradation, we generated lysine to arginine mutants of LGALS3 at K196 or Lys210 (LGALS3 K196R or LGALS3 K210R ). As shown in Figure 6I, the ubiquitinconjugated level of LGALS3 K196R mutant was comparable to the wild type (WT), whereas K210 mutation significantly decreased LGALS3 ubiquitination. These results suggest that periplocin elevates LGALS3 level by preventing K210 ubiquitination and proteasomal degradation. In addition, periplocin was found to stabilize the protein level of LGALS3 against thermal changes using a cellular thermal shift assay (CETSA) (Figure 6J,K), implying the binding of periplocin with LGALS3.
• Snippet 2 (score: 0.733)
  > We next investigated the mechanism underlying periplocinmediated lysophagy. The expression of LGALS3, a key lysophagy marker [46], was found to be upregulated following periplocin treatment as evidenced by immunofluorescent staining (Figure 2M). To this end, we presumed that periplocin-induced lysophagy might be attributable to the upregulation of LGALS3. Indeed, periplocin treatment prominently elevated the protein level of LGALS3 as evidence by immunoblotting analysis (Figure 6A). The increased protein level of LGALS3 was further confirmed in tumor xenografts from periplocin-treated mice (Figure 6B,C). However, no obvious change was observed on the mRNA level of LGALS3 in periplocin-treated cells compared with controls (Figure S6A), suggesting that transcriptional regulation was not involved in increased LGALS3 expression following periplocin treatment. Therefore, we postulated that periplocin might elevate LGALS3 by regulating protein stability. Of note, cycloheximide (CHX, a translational inhibitor) treatment led to an obvious decrease in LGALS3 protein level in control cells, but had no obvious effect on the upregulated protein level of LGALS3 in periplocin-treated cells, suggesting periplocin maintains LGALS3 stability (Figure 6D,E). In support of this, treatment with MG132 (a proteasome inhibitor) failed to further enhance the protein level of LGALS3 in response to periplocin treatment (Figure 6F,G). These data suggest that periplocin may prevent proteasomal degradation of LGALS3.
  > We therefore measured the effect of periplocin on LGALS3 ubiquitination. As shown in Figure 6H, periplocin markedly decreased the ubiquitin-conjugated level of LGALS3.

[9] LGALS3 Is a Poor Prognostic Factor in Diffusely Infiltrating Gliomas and Is Closely Correlated With CD163+ Tumor-Associated Macrophages

• Authors: Wan-Ming Hu, Yuan-Zhong Yang, Tian Zhang, Changling Qin, Xuenong Li
• Year: 2020
• Venue: Frontiers in Medicine
• URL: https://www.semanticscholar.org/paper/53b083f91a08aefebb5f9edaaa95625e2dc98f2b
• DOI: 10.3389/fmed.2020.00182
• PMID: 32528967
• PMCID: 7254797
• Citations: 18
• Influential citations: 1
• Summary: LGALS3 was an independent poor prognostic marker in diffusely infiltrating gliomas and was positively correlated with immune cell infiltration, particularly CD163+ tumor-associated macrophages in the TCGA dataset, Rembrandt dataset, and the SYSUCC cohort.
• Evidence snippets:
• Snippet 1 (score: 0.743)
  > Background: Glioma, the most common brain tumor, is a heterogeneous group of glia-derived tumors, the majority of which have characteristics of diffuse infiltration and immunosuppression. The LGALS protein family is a large class of sugar-binding proteins. Among them, LGALS3 has been reported to promote tumor development and progression in some cancers. However, the clinical significance and biological functions of LGALS3 in glioma remain virtually unknown. The purpose of our research is to detect LGALS3 expression and its prognostic value in glioma and reveal the relationship between its expression and the clinico/molecular-pathological features of patients and immune cell infiltration. Methods: LGALS3 protein expression was examined by immunohistochemistry. The mRNA expression data of LGALS3 was downloaded and analyzed from TCGA and Rembrandt datasets. The association between LGALS3 and glioma clinically relevant diagnostic/molecular markers (IDH, 1p19q, ATRX, MGMT, and TERT) was examined using the Chi-Squared (χ2) test. The correlation between LGALS3 expression and the infiltration of multiple intra-tumoral immune cell types, including B cells (CD20), T cells (CD4 and CD8), macrophages (CD68), and M2 tumor-associated macrophages (CD163), was evaluated by Spearman correlation analysis. Kaplan-Meier analysis and the Cox regression analysis were applied to evaluate the prognostic value of LGALS3 in glioma. The log-rank test was used to evaluate Kaplan-Meier results for significance. Results: Out of all 304 glioma cases, LGALS3 protein was expressed in 125 glioma cases (41.1%, 125/304), with 69.2% (9/13) in WHO I, 9.8% (8/82) in WHO II, 34.2% (26/76) in WHO III, and 61.7% (82/133) in WHO IV. The expression of LGALS3 was correlated with patient age, WHO grade, PHH3 (mitosis), Ki67 index,
• Snippet 2 (score: 0.738)
  > This may explain why LGALS3 positive glioma patients have a significantly shorter OS than LGALS3 negative patients, suggesting that LGALS3 may play a role in malignant progression in glioma through changing the immune microenvironment in glioma. Some studies have also confirmed that LGALS3 played a key role in glioma development through increasing cell motility and invasion (21,22). Vladimirova et al. (23) found that LGALS3 expression was mediated by Runx-2 transcription factors, which contributed to the malignant progression of glial tumors. Conversely, only Gordower et al. (24) reported that LGALS3 expression decreased as the WHO level increased in astrocytic tumors. We think the reason for this difference may be partially due to the small number of patient samples in their study. Moreover, online database analysis also verified our results. Patients with high expression of LGALS3 mRNA had a poor prognosis.
  > LGALS3 was closely related to IDH status, CD163+ TAMs and was mainly expressed in IDH wild-type glioma. It is worth noting that LGALS3 mRNA was highly expressed in the mesenchymal subtype, a more malignant TCGA GBM subtype with a higher tendency for recurrence, metastasis, and increased vascularity.
  > Most importantly, we found that LGALS3 was involved in the regulation of the glioma immune microenvironment, particularly CD163+ TAMs. There is growing evidence that complex tumor microenvironments contribute to the malignant progression of gliomas (25,26). Among the components of the tumor microenvironment, tumor-associated macrophages (TAMs) are considered to provide important support for tumor growth. Macrophages are divided into M1 and M2 subtypes according to their functions. Typically, CD68 is a general marker for macrophages, while CD163 is considered to be a highly specific marker for M2 type macrophages.
• Snippet 3 (score: 0.733)
  > In the LGALS family, LGALS3 has a special domain that recognizes and binds to β-galactosides on cellular glycoproteins and glycolipids (5).
  > LGALS3 may be observed in the cytoplasm and in the nucleus as well as the extracellular matrix (6). It serves different biological functions, such as cell growth, cell adhesion, angiogenesis, and apoptosis (7).
  > LGALS3 can be expressed in different types of tumors, and accumulating evidence has proved that LGALS3 plays a vital role in tumorigenesis and development (6,(8)(9)(10)(11)(12)(13)(14)(15)(16). Recently, a study indicated that LGALS3 can promote the therapeutic resistance of glioblastoma and is related to tumor risk and prognosis (17). However, its prognostic significance needs to be further confirmed in large glioma samples, and, hitherto, no studies have explored the role of LGALS3 in the glioma immune microenvironment and its correlation with key molecular markers, including isocitrate dehydrogenase 1 (IDH1), alpha-thalassemia/mental retardation X-linked (ATRX), O-6methylguanine-DNA methyltransferase (MGMT), telomerase reverse transcriptase (TERT), and 1p19q.

[10] Impairment of lysosomal quality control in Huntington disease

• Authors: P. Rusmini, F. Mina, M. Valenza, Martina Vitali, V. Ferrari et al.
• Year: 2025
• Venue: Cell Death & Disease
• URL: https://www.semanticscholar.org/paper/c874bbb3c9e6aa0a3f74519c022f3fa822daf4a8
• DOI: 10.1038/s41419-025-08103-z
• PMID: 41145409
• PMCID: 12559425
• Citations: 4
• Influential citations: 1
• Summary: TFEB and TFE3 are sequestered in muHTT aggregates, and muHTT proteins associates with LMP triggering the translocation of LGALS3 to the lumen of lysosomes, with a close relation between polyQ size and severity of these events.
• Evidence snippets:
• Snippet 1 (score: 0.739)
  > In HD, high levels of LGALS3 have been found in plasma and brain of patients and mice. LGALS3 upregulation was observed in HD mice before the motor symptoms, in the microglia LGALS3 was found associated to damaged lysosomes and its suppression in microglia ameliorated the HD mice phenotype [36].
  > LGALS3 is emerging as a key factor for NDs for its intracellular role in lysosomal damage, but also for its functions linked to its secretion in the extracellular space. Many pieces of evidence suggest its detrimental role in neurodegeneration, even if a protective role of LGALS3 has been reported (reviewed in ref. [75]). LGALS3 mechanisms of action need further investigation but its pharmacological modulation might represent a valuable target for intervention for NDs. LGALS3 inhibitors have already been tested in metabolic and fibrotic diseases, and these approaches might be applied to NDs. 3′-bis-(4aryltriazol-1-yl) thiodigalactoside (GB039, formerly named TD139), a synthetic small molecule that antagonizes LGALS3 activity by binding to the carbohydrate recognition domain, was effective in idiopathic pulmonary fibrosis and retinal degeneration [76,77]. Pectins, plant cell wall polysaccharides, mostly obtained from citrus and apples, represent natural LGALS3 inhibitors [78,79].
  > In summary, our experiments suggest that LQC impairment might contribute to HD. Indeed, the LGALS3 accumulation observed in HD cellular models due to TFEB and TFE3 sequestration by muHTT inclusions causes LMP and lysophagy impairment, in turn, influences LQC.
  > Fig. 8 TFEB and TFE3 sequestration affects the LQC. A, B NSC-34 cells were transfected with wt or muHTT.

[11] Citrus pectin modulates chicken peripheral blood mononuclear cell proteome in vitro

• Authors: G. Ávila, M. Bonnet, D. Viala, S. Déjean, G. Grilli et al.
• Year: 2024
• Venue: Poultry Science
• URL: https://www.semanticscholar.org/paper/6755550163f80e4863389b3402bd6ac0b5ac8aa0
• DOI: 10.1016/j.psj.2024.104293
• PMID: 39288719
• PMCID: 11421475
• Citations: 1
• Summary: The results provide a proteomics background to the anti-inflammatory activity of CP, demonstrating that the in vitro downregulation of phagocytosis and chemotaxis is related to changes in proteins related to the cytoskeleton.
• Evidence snippets:
• Snippet 1 (score: 0.738)
  > Specifically, MARCKS has been shown to promote murine macrophage migration (Green et al., 2012), phagocytosis (Carballo et al., 1999), and proinflammatory cytokines production (Lee et al., 2015), confirming its involvement in modulating inflammation. Some proteins were also less abundant in the CP group. Galectin-3 (LGALS3) and galectin-8 (LGALS8) are ubiquitous carbohydrate-binding proteins (Brinchmann et al., 2018) that participate in several cellular processes, such as inflammation, immune responses, cell migration, autophagy, and cell signaling. In chickens, 5 members have been identified (Kaltner et al., 2011): LGALS3 and LGALS. LGALS3 is highly expressed in monocytes and macrophages and is a potent regulator of cell-extracellular matrix (ECM) and cell-cell interactions, migration, and phagocytosis (Lu et al., 2017). The decreased abundance of LGALS3 in the CP group is also remarkable, as mouse LGALS3 was downregulated by modified citrus pectin (MCP)-a derivative of citrus pectin (Kolatsi-Joannou et al., 2011). MCP also directly inhibits LGALS3, decreasing the adhesion of monocytes and macrophages (Lu et al., 2017). LGALS8 is involved in cytoskeleton reorganization processes, cell adhesion, and cell migration, as well as in autophagy and cytokines and chemokines expression (Gentilini et al., 2017;Johannes et al., 2018). Finally, we also identified proteins involved in the positive regulation of T and B cell proliferation (TFRC) (Ned et al., 2003) and human mononuclear cell migration (AHNAK2) (Zheng et al., 2021), further supporting the CP immune-modulatory function.

[12] Mutation of the galectin‐3 glycan‐binding domain ( Lgals3‐R200S) enhances cortical bone expansion in male mice and trabecular bone mass in female mice

• Authors: Kevin A. Maupin, Daniel T. Dick, Vari Vivarium, Transgenics Core, B. Williams
• Year: 2020
• Venue: FEBS Open Bio
• URL: https://www.semanticscholar.org/paper/6ab62ea9acc6fef617d0b1f237c1a477f45b05c7
• DOI: 10.1002/2211-5463.13483
• PMID: 36062328
• PMCID: 9527582
• Citations: 2
• Summary: The results suggest that the trabecular bone phenotype of Lgals3-KO mice was driven primarily by loss of extracellular galectin-3, while the cortical bone phenotypeof Lgal3- KO mice may have also been influenced by Loss of intracellular galECTin- 3.
• Evidence snippets:
• Snippet 1 (score: 0.733)
  > The study of galectin-3 is complicated by its ability to function both intracellularly and extracellularly. While the mechanism of galectin-3 secretion is unclear, studies have shown that the mutation of a highly conserved arginine to a serine in human galectin-3 (LGALS3-R186S) blocks glycan binding and secretion. To gain insight into the roles of extracellular and intracellular functions of galectin-3, we generated mice with the equivalent mutation (Lgals3-R200S) using CRISPR/Cas9-directed homologous recombination. Consistent with a reduction in galectin-3 secretion, we observed significantly reduced galectin-3 protein levels in the plasma of heterozygous and homozygous mutant mice. We observed a similar increased bone mass phenotype in Lgals3-R200S mutant mice at 36 weeks as we previously observed in Lgals3-KO mice with slight variation. Like Lgals3-KO mice, Lgals3-R200S females, but not males, had significantly increased trabecular bone mass. However, only male Lgals3-R200S mice showed increased cortical bone expansion, which we had previously observed in both male and female Lgals3-KO mice and only in female mice using a separate Lgals3 null allele (Lgals3). These results suggest that the trabecular bone phenotype of Lgals3-KO mice was driven primarily by loss of extracellular galectin-3. However, the cortical bone phenotype of Lgals3-KO mice may have also been influenced by loss of intracellular galectin-3. Future analyses of these mice will aid in identifying the cellular and molecular mechanisms that contribute to the Lgals3-deficient bone phenotype as well as aid in distinguishing the extracellular vs. intracellular roles of galectin-3 in various signaling pathways.

Notes

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Asta Literature Retrieval: Literature evidence for LGALS3 (Homo sapiens): LGALS3 has nucleus (GO:0005634). Gene/protein: LGALS3. Organism: Homo...

This report is retrieval-only and is generated directly from Asta results.

• Papers retrieved: 12
• Snippets retrieved: 20

Relevant Papers

[1] Periplocin suppresses the growth of colorectal cancer cells by triggering LGALS3 (galectin 3)-mediated lysophagy

• Authors: Kui Wang, Shuyue Fu, Lixia Dong, Dingyue Zhang, Mao Wang et al.
• Year: 2023
• Venue: Autophagy
• URL: https://www.semanticscholar.org/paper/3dadfc351823c4e325e65c171ab3765871189c80
• DOI: 10.1080/15548627.2023.2239042
• PMID: 37471054
• Citations: 35
• Influential citations: 2
• Summary: It is shown that periplocin exhibits promising anticancer activity against CRC both in vitro and in vivo, and is indicated as a potential therapeutic option for the treatment of CRC.
• Evidence snippets:
• Snippet 1 (score: 0.779)
  > We next investigated the mechanism underlying periplocinmediated lysophagy. The expression of LGALS3, a key lysophagy marker [46], was found to be upregulated following periplocin treatment as evidenced by immunofluorescent staining (Figure 2M). To this end, we presumed that periplocin-induced lysophagy might be attributable to the upregulation of LGALS3. Indeed, periplocin treatment prominently elevated the protein level of LGALS3 as evidence by immunoblotting analysis (Figure 6A). The increased protein level of LGALS3 was further confirmed in tumor xenografts from periplocin-treated mice (Figure 6B,C). However, no obvious change was observed on the mRNA level of LGALS3 in periplocin-treated cells compared with controls (Figure S6A), suggesting that transcriptional regulation was not involved in increased LGALS3 expression following periplocin treatment. Therefore, we postulated that periplocin might elevate LGALS3 by regulating protein stability. Of note, cycloheximide (CHX, a translational inhibitor) treatment led to an obvious decrease in LGALS3 protein level in control cells, but had no obvious effect on the upregulated protein level of LGALS3 in periplocin-treated cells, suggesting periplocin maintains LGALS3 stability (Figure 6D,E). In support of this, treatment with MG132 (a proteasome inhibitor) failed to further enhance the protein level of LGALS3 in response to periplocin treatment (Figure 6F,G). These data suggest that periplocin may prevent proteasomal degradation of LGALS3.
  > We therefore measured the effect of periplocin on LGALS3 ubiquitination. As shown in Figure 6H, periplocin markedly decreased the ubiquitin-conjugated level of LGALS3.
• Snippet 2 (score: 0.764)
  > Scale bar: 10 μm. (I) Immunofluorescent analysis of the colocalization of LGALS3 with ubiquitin in CRC cells treated with or without 0.50 μM periplocin for 24 h. Scale bar: 10 μm. (J) Representative fluorescent images of CRC cells transiently expressing Mrfp-GFP-tandem fluorescent-tagged LGALS3 (tfGal3) followed by 0.50 μM periplocin treatment for 24 h. Scale bar: 10 μm. (K) Quantitative analysis of the GFP + RFP + or GFP − RFP + LGALS3 puncta in (J). (L) the relative decreased ratio of Magic Red intensity, relative increased ratio of LysoSensor Blue intensity, relative increased ratio of the interaction between LGALS3 and TRIM16, and relative increased ratio of LC3B-II protein level in DLD-1 cells following 0.50 μM periplocin treatment at different time periods. Results are representative of three independent experiments. Data are presented as mean ± SD. P < 0.05, P < 0.01, **P < 0.001. for LGALS3 degradation, we generated lysine to arginine mutants of LGALS3 at K196 or Lys210 (LGALS3 K196R or LGALS3 K210R ). As shown in Figure 6I, the ubiquitinconjugated level of LGALS3 K196R mutant was comparable to the wild type (WT), whereas K210 mutation significantly decreased LGALS3 ubiquitination. These results suggest that periplocin elevates LGALS3 level by preventing K210 ubiquitination and proteasomal degradation. In addition, periplocin was found to stabilize the protein level of LGALS3 against thermal changes using a cellular thermal shift assay (CETSA) (Figure 6J,K), implying the binding of periplocin with LGALS3.
• Snippet 3 (score: 0.738)
  > Therefore, periplocininduced lysophagy-mediated clearance of damaged lysosomes can nonspecifically engulf vicinal functional lysosomes when lysosome fusion occurs, leading to excessive lysophagy and subsequent cell death. Our findings thus demonstrate a cytotoxic mechanism of lysophagy, and suggest a contextdependent manner for lysophagy-mediated cell fate decision. In addition, we found that periplocin treatment promoted the translocation of TFEB (transcription factor EB) into the nucleus (Figure S7A,B). Interestingly, periplocin treatment led to increased TFEB nuclear translocation and LGALS3 expression both in a time-dependent manner. While the protein level of LGALS3 increased at 1 h of periplocin treatment, the level of nuclear TFEB increased at 3-6 h after periplocin treatment (Figure S7C,D). These data imply that TFEB nuclear translocation and activation in periplocin-treated CRC cells may represent a compensate mechanism for lysosomal damage through promoting the lysosomal biogenesis.
  > Target identification is the initial and critical step for understanding the mechanism of action and development of novel natural products [50,56]. In this study, we found periplocin physically engaged LGALS3 in living CRC cells, suggesting LGALS3 is a binding target of periplocin. Further studies are needed to confirm the direct binding using recombinant LGALS3 protein. The binding of periplocin inhibited ubiquitin-mediated degradation of LGALS3, leading to elevated protein level of LGALS3. Periplocin binding might affect the conformational change of LGALS3 and decrease its binding with related E3 ligase, thereby preventing ubiquitin-mediated degradation of LGALS3, which also requires further investigation. Upregulated LGALS3 was then recruited to the lysosomes following periplocin treatment to initiate excessive lysophagy machinery.
• Snippet 4 (score: 0.725)
  > In addition, periplocin was found to stabilize the protein level of LGALS3 against thermal changes using a cellular thermal shift assay (CETSA) (Figure 6J,K), implying the binding of periplocin with LGALS3. The interaction between periplocin and LGALS3 was further confirmed by drug affinity responsive target stability (DARTS) analysis, as evidenced by a more stable property of LGALS3 protein against pronase digestion in response to periplocin treatment (Figure 6L,M). Moreover, using semiflexible docking analysis, we found that LGALS3 showed a good binding activity for periplocin, with a binding energy of −6.689 kcal/mol. Glu165, Arg162, Gly152, Gln150, Arg144, and Asn143 of LGALS3 were identified as possible sites for periplocin binding (Figure 6N,O), which required further experimental investigation. Together, these data suggest that periplocin binds and prevents ubiquitin-mediated degradation of LGALS3 in CRC cells.
• Snippet 5 (score: 0.705)
  > As shown in Figure 6H, periplocin markedly decreased the ubiquitin-conjugated level of LGALS3. In addition, periplocin did not affect the ubiquitination of other proteins, such as PHGDH (phosphoglycerate dehydrogenase) and PRMT1 (protein arginine methyltransferase 1) (Figure S6B,C), and had no obvious effect on the expression of several essential proteasome components (Figure S6D,E). These data suggest that periplocin specifically prevents LGALS3 from ubiquitin-mediated degradation, regardless of the general ubiquitylation status of the proteasome. A previous study of systematic ubiquitination profiling identified Lys196 (K196) and Lys210 (K210) as the potential ubiquitination sites of LGALS3 [47]. To determine the ubiquitination site required without 0.50 μM periplocin for 24 h. (D) Immunoblotting analysis of PRKAA, p-PRKAA (Thr172), ACACA, p-ACACA (Ser79), MTOR, and p-MTOR (Ser2448) in cells treated with periplocin for 24 h at the indicated concentrations. (E and F) Reciprocal co-immunoprecipitation analysis of the interaction between endogenous LGALS3 and TRIM16 in cells treated with or without 0.50 μM periplocin for 24 h. (G) Co-immunoprecipitation analysis of the interaction between endogenous LGALS3 with PDCD6IP/Alix, CHMP4B, and TRIM16 in DLD-1 cells treated with 0.50 μM periplocin at different time periods. (H) Immunofluorescent analysis of the colocalization of LC3B with LGALS3 in CRC cells treated with or without 0.50 μM periplocin for 24 h. Scale bar: 10 μm.

[2] Thyroid malignant neoplasm-associated biomarkers as targets for oncolytic virotherapy

• Authors: Mi Guan, Yanping Ma, S. Shah, G. Romano
• Year: 2016
• Venue: Oncolytic Virotherapy
• URL: https://www.semanticscholar.org/paper/9f79d851e32ad25e83c0a2d64e12919bf81a89f8
• DOI: 10.2147/OV.S99856
• PMID: 27579295
• PMCID: 4996252
• Citations: 4
• Summary: This review focuses on the strategy of biomarkers for the production of novel TMN oncolytic therapeutics, which may improve the specificity of targeting of tumor cells and limit adverse effects in patients.
• Evidence snippets:
• Snippet 1 (score: 0.767)
  > The Galectin-3 (LGALS3) is a protein that is encoded by a single gene, LGALS3, located on chromosome 14, locus q21-q22. 63 The molecular weight of this protein is ∼30 kDa, and it contains a carbohydrate-recognition-binding domain of ∼130 amino acids that enable the specific binding of β-galactosides. This protein localizes to the extracellular matrix, the cytoplasm, and the nucleus. It plays a role in numerous cellular functions including cell adhesion, cell activation and chemoattraction, cell growth, differentiation, cell cycle, apoptosis, innate immunity, cell adhesion, and T-cell regulation. 63,64 It has been known that LGALS3 is distributed widely around the tissues but in a low level.
  > To date, LGALS3 has been extensively studied as an IHC marker of thyroid malignancy, and a high diagnostic accuracy has been reported even for difficult pathological diagnoses. 64 Feilchenfeldt et al reported that the mRNA levels of LGALS3 and thyroglobulin in 28 benign and 31 malignant thyroid samples were quantified by real-time PCR. The LGALS3 expression at the mRNA was 60% (12/20) and the protein level was 100% (8/8), respectively. 65 The positive rate was 84% (41/49) when combined with the LGALS3 and HBME-1 in PTC specimens. 66 Two groups of researchers have detected the LGALS3 by IHC in PTC specimens. Saleh et al have shown that the sensitivity and the specificity for LGALS3 were 92.3% and 77.3%, respectively. 67 Song et al reported that positive expression of LGALS3 was 97% (427/441) in PTC group and 51% (77/151) in the benign thyroid lesions group. 68 These results may further support the notion that the high level of LGALS3 antigen expression occurs in patients with PTC. There are a number of different types of oncolytic viruses that have been altered from natural viruses in the laboratory such as adenovirus, reovirus, measles virus, herpes simplex

[3] Impairment of lysosomal quality control in Huntington disease

• Authors: P. Rusmini, F. Mina, M. Valenza, Martina Vitali, V. Ferrari et al.
• Year: 2025
• Venue: Cell Death & Disease
• URL: https://www.semanticscholar.org/paper/c874bbb3c9e6aa0a3f74519c022f3fa822daf4a8
• DOI: 10.1038/s41419-025-08103-z
• PMID: 41145409
• PMCID: 12559425
• Citations: 4
• Influential citations: 1
• Summary: TFEB and TFE3 are sequestered in muHTT aggregates, and muHTT proteins associates with LMP triggering the translocation of LGALS3 to the lumen of lysosomes, with a close relation between polyQ size and severity of these events.
• Evidence snippets:
• Snippet 1 (score: 0.748)
  > In HD, high levels of LGALS3 have been found in plasma and brain of patients and mice. LGALS3 upregulation was observed in HD mice before the motor symptoms, in the microglia LGALS3 was found associated to damaged lysosomes and its suppression in microglia ameliorated the HD mice phenotype [36].
  > LGALS3 is emerging as a key factor for NDs for its intracellular role in lysosomal damage, but also for its functions linked to its secretion in the extracellular space. Many pieces of evidence suggest its detrimental role in neurodegeneration, even if a protective role of LGALS3 has been reported (reviewed in ref. [75]). LGALS3 mechanisms of action need further investigation but its pharmacological modulation might represent a valuable target for intervention for NDs. LGALS3 inhibitors have already been tested in metabolic and fibrotic diseases, and these approaches might be applied to NDs. 3′-bis-(4aryltriazol-1-yl) thiodigalactoside (GB039, formerly named TD139), a synthetic small molecule that antagonizes LGALS3 activity by binding to the carbohydrate recognition domain, was effective in idiopathic pulmonary fibrosis and retinal degeneration [76,77]. Pectins, plant cell wall polysaccharides, mostly obtained from citrus and apples, represent natural LGALS3 inhibitors [78,79].
  > In summary, our experiments suggest that LQC impairment might contribute to HD. Indeed, the LGALS3 accumulation observed in HD cellular models due to TFEB and TFE3 sequestration by muHTT inclusions causes LMP and lysophagy impairment, in turn, influences LQC.
  > Fig. 8 TFEB and TFE3 sequestration affects the LQC. A, B NSC-34 cells were transfected with wt or muHTT.

[4] LGALS3 is connected to CD74 in a previously unknown protein network that is associated with poor survival in patients with AML

• Authors: P. Ruvolo, Chenyue W. Hu, Y. Qiu, V. Ruvolo, Robin L. Go et al.
• Year: 2019
• Venue: EBioMedicine
• URL: https://www.semanticscholar.org/paper/46bbdbcb4660389e13acba24499cc415d75f18e0
• DOI: 10.1016/j.ebiom.2019.05.025
• PMID: 31105032
• PMCID: 6604360
• Citations: 25
• Influential citations: 2
• Summary: The data suggest that the LGALS3 network and the CD74 network each support AML cell survival and the two networks may cooperate in a novel high risk AML population.
• Evidence snippets:
• Snippet 1 (score: 0.747)
  > Thus, potential suppression of the PP2A subunit by LGALS3 could account for elevated AKT and PKC alpha phosphorylation in samples where LGALS3 expression is elevated. Induction of PPP2R2A protein (Fig. 5) but not gene expression (Fig. 7) in THP-1 cells expressing LGALS3 shRNA suggests that LGALS3 acts directly on the PP2A subunits via a post-transcriptional mechanism in these cells. The TCGA data (Table 3) however suggests that there is a positive correlation between gene expression of LGALS3 and PPP2R2A suggesting that a common pathway may regulate the two genes. Fig. 8. Progeny clustering identified an optimal number of 4 distinct protein clusters for this ProFnGrp. Protein networks were generated and showed interactions between "core-proteins" (large nodes) and other probed proteins (small nodes) from the data set. Clustering method has been described in our previous publication (ref. [37]) and further information on these protein networks can be found on our website "Leukemia Profile Atlases", available at https://www.leukemiaatlas.org/. Progeny clustering identified one protein cluster with expression similar to that of the normal CD34+ samples which was designated as "normal-state" while three "leukemia-specific" protein patterns characterized by high expression individually of CD74, LGAL3, and a fourth state with both on. PPP2RA/B/C/D was the only LGALS3 network protein demonstrated to be directly regulated by LGALS3 in the THP-1 cells (Fig. 5). In our previous study we saw potent suppression of AKT signaling by LGALS3 inhibition, so perhaps the mechanism involves LGALS3 suppression of the AKT phosphatase [15]. However, we did not see suppression of LGALS3 affect other network proteins in the THP-1 cells (data not shown). The role of other galectins such as LGALS1 in AML biology is not clear.
• Snippet 2 (score: 0.742)
  > LGALS3 is associated with active Fig. 7. Suppression of LGALS3 does not alter gene expression of LGALS3 network protein genes or CD74 in THP-1 cells. RNA from THP-1 transductant cells with either LKO vector control shRNA or LGALS3 shRNA was isolated, cDNA produced, and mRNA levels of ATG7, LGALS3, ITGAL, CCND3, PRKCA, PARP1, CD74, MYC, CD44, SSBP2, PPP2R2A, CLPP, and B2M were determined by qRT-PCR and levels normalized to ABL-1 as described in "Materials and methods".
  > AKT and MAPK signaling. The protein with the strongest positive correlation with LGALS3 is with ATG7, an autophagy protein that has recently been implicated in maintaining hematopoietic stem cells and serving as a survival factor in AML [46,47]. Recent studies implicate LGALS3 in regulation of autophagy via autophagasome formation, though whether the mechanism involves ATG7 is not clear [48]. Interestingly, phosphorylated PKC delta was positively correlated with LGALS3. PKC delta is viewed as a pro-stress kinase but recent studies suggest that the enzyme has pro-survival properties [49][50][51]. Kinehara and colleagues suggest that PKC delta may act in human pluripotent stem cells as part of a mechanism to regulate stem cell renewal [52]. The data also suggest a novel relationship between LGALS3 and PP2A. The negative correlation of LGALS3 expression with PPP2R2A/B/C/D could reflect LGALS3 suppression of PP2A. The PP2A isoform containing PPP2R2A dephosphorylates both AKT and PKC alpha [53]. Thus, potential suppression of the PP2A subunit by LGALS3 could account for elevated AKT and PKC alpha phosphorylation in samples where LGALS3 expression is elevated.

[5] LGALS3 Is a Poor Prognostic Factor in Diffusely Infiltrating Gliomas and Is Closely Correlated With CD163+ Tumor-Associated Macrophages

• Authors: Wan-Ming Hu, Yuan-Zhong Yang, Tian Zhang, Changling Qin, Xuenong Li
• Year: 2020
• Venue: Frontiers in Medicine
• URL: https://www.semanticscholar.org/paper/53b083f91a08aefebb5f9edaaa95625e2dc98f2b
• DOI: 10.3389/fmed.2020.00182
• PMID: 32528967
• PMCID: 7254797
• Citations: 18
• Influential citations: 1
• Summary: LGALS3 was an independent poor prognostic marker in diffusely infiltrating gliomas and was positively correlated with immune cell infiltration, particularly CD163+ tumor-associated macrophages in the TCGA dataset, Rembrandt dataset, and the SYSUCC cohort.
• Evidence snippets:
• Snippet 1 (score: 0.732)
  > In the LGALS family, LGALS3 has a special domain that recognizes and binds to β-galactosides on cellular glycoproteins and glycolipids (5).
  > LGALS3 may be observed in the cytoplasm and in the nucleus as well as the extracellular matrix (6). It serves different biological functions, such as cell growth, cell adhesion, angiogenesis, and apoptosis (7).
  > LGALS3 can be expressed in different types of tumors, and accumulating evidence has proved that LGALS3 plays a vital role in tumorigenesis and development (6,(8)(9)(10)(11)(12)(13)(14)(15)(16). Recently, a study indicated that LGALS3 can promote the therapeutic resistance of glioblastoma and is related to tumor risk and prognosis (17). However, its prognostic significance needs to be further confirmed in large glioma samples, and, hitherto, no studies have explored the role of LGALS3 in the glioma immune microenvironment and its correlation with key molecular markers, including isocitrate dehydrogenase 1 (IDH1), alpha-thalassemia/mental retardation X-linked (ATRX), O-6methylguanine-DNA methyltransferase (MGMT), telomerase reverse transcriptase (TERT), and 1p19q.

[6] Lgals3 Promotes Calcium Oxalate Crystal Formation and Kidney Injury Through Histone Lactylation‐Mediated FGFR4 Activation

• Authors: Zehua Ye, Yushi Sun, Songyuan Yang, Lei Li, Bojun Li et al.
• Year: 2025
• Venue: Advanced Science
• URL: https://www.semanticscholar.org/paper/adbfa30b5832407d200a5eade9196d41be08050e
• DOI: 10.1002/advs.202413937
• PMID: 39903812
• PMCID: 11947994
• Citations: 18
• Summary: Findings suggest that Lgals3 may play a key role in CaOx stone formation and kidney injury by interacting with PKM2 and promoting both H3K18la‐mediated gene transcription and activation.
• Evidence snippets:
• Snippet 1 (score: 0.729)
  > Furthermore, this study investigated whether Lgals3 deficiency reduced H3K18la during CaOx deposition. Western blot and immunofluorescence staining showed that Lgals3 knockdown in vitro decreased the levels of global lactylation and H3K18la levels (Figure 9E-G). Similarly, Lgals3 −/− mice exhibited significant decreases in global lactylation and H3K18la levels compared with the WT mice through Western blot and immunofluorescence staining (Figure 9H-J). Meanwhile, we also tested the level of acetylation of histone H3 and histone H4 and the results showed that Lgals3 deficiency have no impact on the expression of acetylation of histone H3 and histone H4 (Figure S9, Supporting Information)

[7] High LGALS3 expression induced by HCP5/hsa-miR-27b-3p correlates with poor prognosis and tumor immune infiltration in hepatocellular carcinoma

• Authors: Yinghui Ren, Yongmei Qian, Qicheng Zhang, Xiaoping Li, Mingjiang Li et al.
• Year: 2024
• Venue: Cancer Cell International
• URL: https://www.semanticscholar.org/paper/552bd37c67dea75d0c33a9a0de2acdafcf0dcf6e
• DOI: 10.1186/s12935-024-03309-1
• PMID: 38643145
• PMCID: 11031979
• Citations: 13
• Summary: It is hypothesized that the HCP5/hsa-miR-27b-3p axis could serve as the most promising LGALS3 regulation mechanism in HCC and the upregulation of LGALS3 via the HCP5/hsa-miR-27b-3p axis is associated with unfavorable prognosis and increased tumor immune infiltration in HCC.
• Evidence snippets:
• Snippet 1 (score: 0.726)
  > Hepatocellular carcinoma (HCC) is widely recognized for its unfavorable prognosis. Increasing evidence has revealed that LGALS3 has an essential function in initiating and developing several malignancies in humans. Nevertheless, thorough analysis of the expression profile, clinical prognosis, pathway prediction, and immune infiltration of LGALS3 has not been fully explored in HCC. In this study, an initial pan-cancer analysis was conducted to investigate the expression and prognosis of LGALS3. Following a comprehensive analysis, which included expression analysis and correlation analysis, noncoding RNAs that contribute to the overexpression of LGALS3 were subsequently identified. This identification was further validated using HCC clinical tissue samples. TIMER2 and GEPIA2 were employed to examine the correlation between LGALS3 and HCP5 with immunological checkpoints, cell chemotaxis, and immune infiltration in HCC. The R program was applied to analyze the expression distribution of immune score in in HCC patients with high and low LGALS3 expression. The expression profiles of immune checkpoints were also analyzed. Use R to perform GSVA analysis in order to explore potential signaling pathways. First, we conducted pan-cancer analysis for LGALS3 expression level through an in-depth analysis of public databases and found that HCC has a high LGALS3 gene and protein expression level, which were then verified in clinical HCC specimens. Meanwhile, high LGALS3 gene expression is related to malignant progression and poor prognosis of HCC. Univariate and multivariate analyses confirmed that LGALS3 could serve as an independent prognostic marker for HCC. Next, by combining comprehensive analysis and validation on HCC clinical tissue samples, we hypothesize that the HCP5/hsa-miR-27b-3p axis could serve as the most promising LGALS3 regulation mechanism in HCC. KEGG and GO analyses highlighted that the LGALS3-related genes were involved in tumor immunity. Furthermore, we detected a significant positive association between LGALS3 and HCP5 with immunological checkpoints, cell chemotaxis, and immune infiltration. In addition, high LGALS3 expression groups had significantly
• Snippet 2 (score: 0.724)
  > Next, the prognostic value of LGALS3 expression in the 23 kinds of cancer patients was then determined.Correlations between LGALS3 expression with OS (overall survival) were evaluated using the GEPIA2 database.In the OS study, only elevated LGALS3 expression indicated poorer survival for HCC patients (Fig. 2A).LGALS3 was not statistically significant for OS of 22 other cancer types patients.Furthermore, DSS (disease-specific survival) LGALS3 in predicting 1-, 3-, and 5-year OS. (H) ROC curve for LGALS3 in predicting 1-, 3-, and 5-year DSS.The higher values of AUC corresponding to higher predictive power.p value < 0.05; **p value < 0.001 was lesser in patients suffering from HCC having higher levels of LGALS3 expression (Fig. 2B).Next, we validated the expression levels of LGALS3 protein in HCC tissues using IF staining.As expected, HCC tumor demonstrated strong LGALS3 expression (Fig. 2C).These findings were further validated by qRT-PCR assay of tumor and adjacent normal tissues from 5 HCC patients.Here, LGALS3 expression was also significantly increased in the HCC tissues (Fig. 2D).In addition, LGALS3 expression was shown to be linked with the pathological stage of HCC, as illustrated in Fig. 2E.High expression of LGALS3 gene is associated with high tumor grade in HCC (Fig. 2F).Moreover, LGALS3 expression was significantly associated with OS and DSS in both univariate and multivariate analyses (Figure S2A-H).Time-dependent ROC analysis showed that the area under the ROC curve was 0.672 at 5 years of OS, and 0.691 at 5 years of DSS (Fig. 2G-H).Taken together, LGALS3 might function as a prospective biomarker for the prognosis of patients suffering from HCC.
• Snippet 3 (score: 0.710)
  > LGALS3 has a crucial function in mediating cell adhesion as well as cell-cell interaction by recognizing complex carbohydrates on the surface of cells [22,23], as well as regulates cell apoptosis, autophagy, and inflammation [24,25].Interestingly, recent studies suggested that LGALS3 involves in essential cancer-related mechanisms, including cellular metabolism, carcinogenesis, metastasis, neoplasia, angiogenesis, as well as immune escape [26][27][28].In addition, LGALS3 is highly expressed and implicated in different cancer types progression such as HCC, gastric, colorectal, pancreatic carcinomas, melanomas or glioblastomas and breast cancer [29,30].Indeed, LGALS3 has been considered a potential marker for these malignancies.Interestingly, LGALS3, which is differentially expressed in different cancers, has been shown to exhibit tumor suppressor activity in certain cancer types.The different roles of LGALS3 may be attributed to different potential mechanisms that appear cancer-type dependent.The different locations and mutations of LGALS3 also contribute to its various functions.However, LGALS3 remains inadequately understood in HCC and requires further investigation.First, we conducted an extensive investigation of the expression profile, clinical prognosis, and pathologic stage of LGALS3 in HCC through an in-depth analysis of the public database.On the basis of TCGA and CPTAC datasets, we found that LGALS3 gene and protein expression was elevated in HCC tissues.Moreover, the OS and DSS were lesser in patients with HCC having higher expression levels of LGALS3 contrasted to those with low expression levels of LGALS3 based on GEPIA2 and Kaplan-Meier plotter datasets.Meanwhile, the expression of LGALS3 within HCC was significantly associated with the advanced tumor stage and grade, indicating that elevated LGALS3 expression could increase tumor progression.Song et al. [31] indicated that galectin-3 promoted HCC tumorigenesis and metastasis via β-catenin signalling in vitro and in vivo.

[8] Mutation of the galectin‐3 glycan‐binding domain ( Lgals3‐R200S) enhances cortical bone expansion in male mice and trabecular bone mass in female mice

• Authors: Kevin A. Maupin, Daniel T. Dick, Vari Vivarium, Transgenics Core, B. Williams
• Year: 2020
• Venue: FEBS Open Bio
• URL: https://www.semanticscholar.org/paper/6ab62ea9acc6fef617d0b1f237c1a477f45b05c7
• DOI: 10.1002/2211-5463.13483
• PMID: 36062328
• PMCID: 9527582
• Citations: 2
• Summary: The results suggest that the trabecular bone phenotype of Lgals3-KO mice was driven primarily by loss of extracellular galectin-3, while the cortical bone phenotypeof Lgal3- KO mice may have also been influenced by Loss of intracellular galECTin- 3.
• Evidence snippets:
• Snippet 1 (score: 0.723)
  > s3 +/+ ), heterozygous (Lgals3-R200S KI/+ ), and homozygous (Lgals3-R200S KI/KI ) mutant mice (Fig. 1C). Consistent with a reduction in Gal-3 secretion, we observed significantly reduced Gal-3 protein levels in the plasma of adult heterozygous and homozygous mutant mice (Fig. 1D).
  > We generated mouse embryonic fibroblasts (MEFs) to look at cell-surface proteins, to confirm reduction of extracellular Gal-3 protein in Lgals3-R200S cells. Cell surface proteins were biotinylated and captured with NeutrAvidin Agarose. Western blot analysis showed cell surface Gal-3 levels were decreased in Lgals3-R200S KI/+ and Lgals3-R200S KI/KI cells compared to wild-type (Fig. 1E). The absence of the cytoplasmic protein, vinculin, from the pull-down lanes confirmed that the experiments worked to preferentially pull-down biotinylated cell surface proteins. Immunocytochemistry of MEFs from Lgals3-R200S KI/KI mice confirmed that Gal-3 is present in the cytosol and nucleus (Fig. 1F). Quantification of the mean and median amount of fluorescence per unit area indicated that Galectin-3 both on the cell surface and inside the cell was reduced, by approximately 30% and 26% respectively, in Lgals3-R200S KI/KI MEFs (P = 0.024). From these studies, we conclude that the R200S mutation in mice reduced cell surface Gal-3 and may have contributed to lower intracellular Gal-3 levels. Further studies will be necessary to determine if the 25-30% reduction in intracellular Gal-3 is biologically significant.
• Snippet 2 (score: 0.720)
  > The study of galectin-3 is complicated by its ability to function both intracellularly and extracellularly. While the mechanism of galectin-3 secretion is unclear, studies have shown that the mutation of a highly conserved arginine to a serine in human galectin-3 (LGALS3-R186S) blocks glycan binding and secretion. To gain insight into the roles of extracellular and intracellular functions of galectin-3, we generated mice with the equivalent mutation (Lgals3-R200S) using CRISPR/Cas9-directed homologous recombination. Consistent with a reduction in galectin-3 secretion, we observed significantly reduced galectin-3 protein levels in the plasma of heterozygous and homozygous mutant mice. We observed a similar increased bone mass phenotype in Lgals3-R200S mutant mice at 36 weeks as we previously observed in Lgals3-KO mice with slight variation. Like Lgals3-KO mice, Lgals3-R200S females, but not males, had significantly increased trabecular bone mass. However, only male Lgals3-R200S mice showed increased cortical bone expansion, which we had previously observed in both male and female Lgals3-KO mice and only in female mice using a separate Lgals3 null allele (Lgals3). These results suggest that the trabecular bone phenotype of Lgals3-KO mice was driven primarily by loss of extracellular galectin-3. However, the cortical bone phenotype of Lgals3-KO mice may have also been influenced by loss of intracellular galectin-3. Future analyses of these mice will aid in identifying the cellular and molecular mechanisms that contribute to the Lgals3-deficient bone phenotype as well as aid in distinguishing the extracellular vs. intracellular roles of galectin-3 in various signaling pathways.

[9] In-depth quantitative proteomics analysis revealed C1GALT1 depletion in ECC-1 cells mimics an aggressive endometrial cancer phenotype observed in cancer patients with low C1GALT1 expression

• Authors: A. Montero‐Calle, Á. López-Janeiro, Marta L. Mendes, Daniel Perez-Hernandez, Irene Echevarría et al.
• Year: 2023
• Venue: Cellular Oncology
• URL: https://www.semanticscholar.org/paper/92b64e01bcb30f7457ddb8cc4be26de8b0c7cf69
• DOI: 10.1007/s13402-023-00778-w
• PMID: 36745330
• PMCID: 10205863
• Citations: 19
• Summary: C1GALT1 stably depleted ECC-1 cells mimic an EC aggressive phenotype observed in patients and might be useful for the identification and validation of EC markers of progression.
• Evidence snippets:
• Snippet 1 (score: 0.711)
  > Finally, since LGALS3 (Galectin-3) has been shown to interact with O-glycans in the mucosal epithelium [30], and considering its overexpression observed by proteomics and further confirmed by PCR and WB analyses upon depletion of C1GALT1, we focused on the role of LGALS3 in EC by IHC.
  > A total of 151 out of 178 cores from 79 EC patients were considered adequate for LGALS3 expression assessment by IHC. Morphologic assessment of LGALS3 IHC staining characteristics revealed different staining patterns (Fig. 5 A). Out of the 151 evaluable cores, 45 (29.8%) showed absent LGALS3 expression. LGALS3 positive samples showed variable and low intensity protein expression (mean positive tumor cells per sample = 35.4%). A small subset of cores (13/151, 8.6%) demonstrated diffuse (> 90% positive tumor cells per sample) staining. LGALS3 score varied across histologic types, with serous and undifferentiated tumors displaying the highest protein expression (median IHC LGALS3 score = 10, 20, 50 and 55 for endometrioid, clear cell, serous and undifferentiated tumor types, respectively) (Fig. 5B). Interestingly, the aggressive histologic variants (clear cell, serous and undifferentiated) showed higher LGALS3 IHC scores than endometrioid variants (p value < 0.001). In addition, LGALS3 expression positively correlated with tumor grade. High grade tumors (G3) displayed higher protein expression (median LGALS3 IHC score = 30) compared to low grade tumors (median LGALS3 IHC score for G1/G2 tumors = 10). This finding was independent of histologic type, as similar results were observed when analyzing endometrioid tumors.
  > Finally, we interrogated the correlation between the expression levels of LGALS3 and C1GALT1.

[10] Galectin-3 aggravates microglial activation and tau transmission in tauopathy

• Authors: Jian-Jing Siew, Hui-Mei Chen, Feng‐Lan Chiu, Chia-Wei Lee, Yao-Ming Chang et al.
• Year: 2023
• Venue: The Journal of Clinical Investigation
• URL: https://www.semanticscholar.org/paper/8c77eea796475aa4e26a4051432bc4d4c021d847
• DOI: 10.1172/JCI165523
• PMID: 37988169
• PMCID: 10786694
• Citations: 24
• Influential citations: 1
• Summary: It is shown that Gal3 was upregulated in the microglia of humans and mice with tauopathy, and is a potential therapeutic target for tauopathy.
• Evidence snippets:
• Snippet 1 (score: 0.710)
  > In particular, the knockout of Gal3 normalized 348 DEG genes between Tau22/Lgals3 +/+ and WT mice (Figure 6, A and B and Supplemental Table 7). Further GO enrichment analysis revealed that the upregulated DEGs of Tau22/Lgals3 +/+ versus WT mice were enriched in multiple processes, including metabolic processes, oxidative reduction processes, and immune system processes (Figure 6, C and D). Importantly, the downregulated DEGs by Lgals3 deletion within the context of Tau22 were primarily enriched in immune responses and the production of cytokines and chemokines (Figure 6E). Conversely, the downregulated DEGs in Tau22/Lgals3 -/-versus Tau22/Lgals3 +/+ mice were enriched in processes including nervous system development, protein phosphorylation, synapse assembly, and learning (Supplemental Figure 21, E and F). No specific enriched processes were identified for the upregulated DEGs in Tau22/Lgals3 -/- versus Tau22/Lgals3 +/+ mice. These findings are consistent with what were observed in human iMGLs, confirming that Gal3 plays a principal role in governing the microglia-mediated immune response in tauopathy.
  > We next categorized these DEGs by their enriched cell type based on the Tabula Muris Consortium database (39) (Supplemental Figure 21D), and, as predicted, we found that the largest population of DEGs identified between Tau22/Lgals3 -/-and Tau22/Lgals3 +/+ mice was enriched in microglia (21.3%; Supple-cells (Figure 8). When encountering pathological tau, microglia become active and release Gal3 into the extracellular space either directly or via EVs (Figure 3O). Under the tested conditions, we found that Gal3 directly facilitated the aggregation of pTau into β-pleated-sheet structures (Figure 3L). This interaction between pTau and Gal3 may occur in EVs and/or the extracellular space between microglia and neurons.

[11] Enhanced cortical bone expansion in Lgals3-deficient mice during aging

• Authors: Kevin A. Maupin, Kevin Weaver, Alexis Bergsma, Cheryl Christie, Z. Zhong et al.
• Year: 2018
• Venue: Bone Research
• URL: https://www.semanticscholar.org/paper/186b9fa98d1dd1342931f3b02765fa78aecd0100
• DOI: 10.1038/s41413-017-0003-6
• PMID: 30886760
• PMCID: 6416267
• Citations: 15
• Summary: Investigation of bone cells showed the increase was probably due to increased bone formation, rather than decreased bone resorption, and the researchers conclude that disrupting galectin-3 may help to prevent aging-related bone loss.
• Evidence snippets:
• Snippet 1 (score: 0.706)
  > Mice from this cross were then crossed to mice homozygous for the Crerecombinase transgene under control of the CMV enhancer [BALB/ c-Tg(CMV-cre)1Cgn/J] to remove exon 4 which was flanked with loxP sites. These mice were then crossed to a wild-type C57BL/6J mouse to remove the Cre transgene to obtain Lgals3 Δ/+ heterozygous mice. These heterozygotes were set up into breeding pairs to generate litters containing wild type (Lgals3 +/ + ), heterozygous (Lgals3 Δ/+ ) and homozygous mutant (Lgals3 Δ/Δ ) offspring.
  > We verified loss of galectin-3 protein in these mice by western blot of lung lysates using a Mac-2/galectin-3 rat monoclonal antibody 59 (gift from John Wang, MSU, E. Lansing, MI) which recognizes an that is N-terminal of the region encoded by exon 4. 60 No protein product corresponding to full-length or truncated galectin-3 was detected from lung lysates of Lgals3 Δ/Δ mice. The additional benefits of using Lgals3 Δ/Δ mice is that they avoid potential transcriptional effects on neighboring genes by a neomycin resistance cassette 61 ; also, the genomic deletion is downstream from the galectin-3 internal gene, Galig, which utilizes a promoter in intron 2 and encodes a small protein via an alternative open reading frame of exon 3 of Lgals3. 62,63 Figure 2 shows the null alleles utilized in this study. Genomic DNA was isolated from tail clips at weaning and necropsy by proteinase K digestion and ethanol precipitation. Genotypes were assigned by allele specific PCR.

[12] SREBP1 regulates Lgals3 activation in response to cholesterol loading

• Authors: Jing Li, Hongtao Shen, G. Owens, Lian‐Wang Guo
• Year: 2022
• Venue: Molecular Therapy. Nucleic Acids
• URL: https://www.semanticscholar.org/paper/6c55d666855233ff0e7035d46075997924da854c
• DOI: 10.1016/j.omtn.2022.05.028
• PMID: 35694209
• PMCID: 9168384
• Citations: 13
• Summary: Results identify a previously uncharacterized cholesterol-responsive dyad—SREBP1 and LGALS3, constituting a feedforward circuit that can be blocked by BETs inhibition in SMC phenotypic transition and potential interventional targets.
• Evidence snippets:
• Snippet 1 (score: 0.706)
  > Beyond this knowledge, our data contributed new information showing that LGALS3 decreased expression of MRTF-A protein, a well-established transcription co-activator of SMC contractile genes. Collectively, our results and existing reports suggest that rather than merely a cell-type marker, LGALS3 is a key effector that promotes cholesterol-induced SMC phenotypic states, including migration, inflammation, dedifferentiation, lipid storage, and resistance to apoptosis (Figure S3). Moreover, we identified it as an atypical target gene of both SREBP1 and KLF15. In addition, we observed that LGALS3 promotes SREBP1 expression but represses KLF15 production. Our coIP experiments did not show an obvious LGALS3/ SREBP1 physical association, although it has been reported that
  > LGALS3 participates in nuclear function, such as forming an early splicing machinery. 29 However, it will be important that future studies determine how LGALS3 regulates SREBP1 and KLF15 expression.
  > In view of the SREBP1/LGALS3/SREBP1 feedforward circuit identified herein, and previous evidence that SMCs with activated Lgals3 preferentially give rise to atherosclerotic lesion cells, 4 it is interesting to consider LGALS3 as a potential interventional target for breaking this vicious cycle. However, the effectiveness of using an
  > 6][47] In contrast, BETs inhibition with JQ1 abrogated cholesterol-induced increases of
  > LGALS3 and SREBP1 protein levels, in rodent SMCs and also in human primary SMCs. This potent effect implicates an alternative strategy to inhibit this SREBP1/LGALS3 pathway. BETs inhibitors have shown anti-atherogenic efficacy in preclinical models. 35,40 In a phase II clinical trial, the pan-BETs inhibitor RVX208, which is known to increase apolipoprotein A-I, 48 has exhibited a favorable profile of safety and efficacy in amelioration of major adverse cardiovascular events. 49

Notes

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Asta Literature Retrieval: Literature evidence for LGALS3 (Homo sapiens): LGALS3 has cytoplasm (GO:0005737). Gene/protein: LGALS3. Organism: Hom...

This report is retrieval-only and is generated directly from Asta results.

• Papers retrieved: 14
• Snippets retrieved: 20

Relevant Papers

[1] Physical Activity Attenuates the Obesity-Induced Dysregulated Expression of Brown Adipokines in Murine Interscapular Brown Adipose Tissue

• Authors: T. Sakurai, Toshiyuki Fukutomi, Sachiko Yamamoto, Eriko Nozaki, T. Kizaki
• Year: 2021
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/c62f909c1038a72ef7c427bfa9914983c22b5422
• DOI: 10.3390/ijms221910391
• PMID: 34638731
• PMCID: 8508858
• Citations: 2
• Summary: Results indicate that PA attenuates the obesity-induced dysregulated expression of brown adipokines and suggests that Lgals3 and Lgal3bp are involved in brown adipocyte differentiation.
• Evidence snippets:
• Snippet 1 (score: 0.790)
  > In addition, although the Flag-tagged Lgals3 protein was secreted at each stage of brown adipocyte differentiation, most of this protein was uniformly present in the cytoplasm (Figure 1D). Furthermore, the expression of Flag-tagged Lgals3bp in the cytoplasm was heterogeneous compared with that of the Flag-tagged Lgals3 protein (Figure 1D).
• Snippet 2 (score: 0.723)
  > Enhanced expression of Lgals3 gene is found in the WAT and the BAT of obese mice, and the insulin signal was reported to be altered in the WAT of Lgals3 knock out (KO) mice, but the influence of Lgals3 on brown adipocytes remains unknown [41,42]. Lgals3bp was identified as a protein that binds to Lgals3 and Lgals1, but its effect on brown adipocytes is also unknown [43]. As shown in Table 3, the expressions of genes for Lgals3 and Lgals3bp are thought to be greatly influenced by HFD intake and PA. Therefore, we attempted to establish an overexpression of Flag-tagged Lgals3 and Lgals3bp in HB2 cells. Real-time PCR analysis showed a significant increase in the expressions of Lgals3 and Lgals3bp mRNAs in Flag-tagged Lgals3 (HB2-L3 cells), Lgals3bp (HB2-L3bp cells), or both (HB2-L3-L3bp cells) when compared with that in control cells (HB2-C cells) (Figure 1A). Moreover, expression of exogenous Flag-tagged proteins in cell lysate and Flag-Lgals3 or Lgals3bp protein secretion into cell culture medium were confirmed in HB2-L3, -L3bp, and -L3-L3bp cells (Figure 1B). As shown in Figure 1B,C, in the differentiation process of HB2 cells into brown adipocytes, Flag-tagged Lgals3 protein was secreted the most during the early stages of differentiation, while the secretion from mature brown adipocytes was decreased by comparison. In contrast, the secretion of the Flag-tagged Lgals3bp protein from mature brown adipocytes was the most prominent. In addition, although the Flag-tagged Lgals3 protein was secreted at each stage of brown adipocyte differentiation, most of this protein was uniformly present in the cytoplasm (Figure 1D).

[2] Selection signature analysis reveals genes underlying sheep milking performance

• Authors: Zehu Yuan, Wanhong Li, Fadi Li, X. Yue
• Year: 2019
• Venue: Archives Animal Breeding
• URL: https://www.semanticscholar.org/paper/fd4b15d018bfa94628954941797606d5d92cecb8
• DOI: 10.5194/aab-62-501-2019
• PMID: 31807661
• PMCID: 6859915
• Citations: 7
• Summary: SUCNR1 and PPARGC1A (PPARG coactivator 1 alpha) may be the most significant genes that affect sheep milking performance, which supply a significant indication for future studies to investigate candidate genes that play an important role in milk production and quality.
• Evidence snippets:
• Snippet 1 (score: 0.783)
  > The most significant GO term of CC is cytoplasm (GO: 0005737, P =6.93E10-8, FDR = 2.98 × 10 −5 ). The most significant GO term of MF was the G-protein coupled nucleotide receptor activity (GO: 0001608, P = 6.37007×10 −5 , FDR = 6.37007×10 −5 ) and G-protein coupled purinergic nucleotide receptor activity (GO: 0045028, P = 6.37007 × 10 −5 , FDR = 6.37007 × 10 −5 ). The finding that the cytoplasm GO term (GO: 0005737) was enriched in our gene set is interesting. Previous studies have reported that candidate genes associated with milk protein composition traits in a Chinese Holstein population were significantly (FDR = 0.0247) enriched in cytoplasm (GO: 0005737) (Zhou et al., 2019). Apart from GO analysis, KEGG analysis showed that candidate genes could be annotated to 36 KEGG classes (Fig. S1) and could participate in 173 pathways. The highest number of genes of KEGG categories was signal transduction (29 genes). However, no significant pathways were found.

[3] Mutation of the galectin‐3 glycan‐binding domain ( Lgals3‐R200S) enhances cortical bone expansion in male mice and trabecular bone mass in female mice

• Authors: Kevin A. Maupin, Daniel T. Dick, Vari Vivarium, Transgenics Core, B. Williams
• Year: 2020
• Venue: FEBS Open Bio
• URL: https://www.semanticscholar.org/paper/6ab62ea9acc6fef617d0b1f237c1a477f45b05c7
• DOI: 10.1002/2211-5463.13483
• PMID: 36062328
• PMCID: 9527582
• Citations: 2
• Summary: The results suggest that the trabecular bone phenotype of Lgals3-KO mice was driven primarily by loss of extracellular galectin-3, while the cortical bone phenotypeof Lgal3- KO mice may have also been influenced by Loss of intracellular galECTin- 3.
• Evidence snippets:
• Snippet 1 (score: 0.756)
  > The study of galectin-3 is complicated by its ability to function both intracellularly and extracellularly. While the mechanism of galectin-3 secretion is unclear, studies have shown that the mutation of a highly conserved arginine to a serine in human galectin-3 (LGALS3-R186S) blocks glycan binding and secretion. To gain insight into the roles of extracellular and intracellular functions of galectin-3, we generated mice with the equivalent mutation (Lgals3-R200S) using CRISPR/Cas9-directed homologous recombination. Consistent with a reduction in galectin-3 secretion, we observed significantly reduced galectin-3 protein levels in the plasma of heterozygous and homozygous mutant mice. We observed a similar increased bone mass phenotype in Lgals3-R200S mutant mice at 36 weeks as we previously observed in Lgals3-KO mice with slight variation. Like Lgals3-KO mice, Lgals3-R200S females, but not males, had significantly increased trabecular bone mass. However, only male Lgals3-R200S mice showed increased cortical bone expansion, which we had previously observed in both male and female Lgals3-KO mice and only in female mice using a separate Lgals3 null allele (Lgals3). These results suggest that the trabecular bone phenotype of Lgals3-KO mice was driven primarily by loss of extracellular galectin-3. However, the cortical bone phenotype of Lgals3-KO mice may have also been influenced by loss of intracellular galectin-3. Future analyses of these mice will aid in identifying the cellular and molecular mechanisms that contribute to the Lgals3-deficient bone phenotype as well as aid in distinguishing the extracellular vs. intracellular roles of galectin-3 in various signaling pathways.
• Snippet 2 (score: 0.701)
  > s3 +/+ ), heterozygous (Lgals3-R200S KI/+ ), and homozygous (Lgals3-R200S KI/KI ) mutant mice (Fig. 1C). Consistent with a reduction in Gal-3 secretion, we observed significantly reduced Gal-3 protein levels in the plasma of adult heterozygous and homozygous mutant mice (Fig. 1D).
  > We generated mouse embryonic fibroblasts (MEFs) to look at cell-surface proteins, to confirm reduction of extracellular Gal-3 protein in Lgals3-R200S cells. Cell surface proteins were biotinylated and captured with NeutrAvidin Agarose. Western blot analysis showed cell surface Gal-3 levels were decreased in Lgals3-R200S KI/+ and Lgals3-R200S KI/KI cells compared to wild-type (Fig. 1E). The absence of the cytoplasmic protein, vinculin, from the pull-down lanes confirmed that the experiments worked to preferentially pull-down biotinylated cell surface proteins. Immunocytochemistry of MEFs from Lgals3-R200S KI/KI mice confirmed that Gal-3 is present in the cytosol and nucleus (Fig. 1F). Quantification of the mean and median amount of fluorescence per unit area indicated that Galectin-3 both on the cell surface and inside the cell was reduced, by approximately 30% and 26% respectively, in Lgals3-R200S KI/KI MEFs (P = 0.024). From these studies, we conclude that the R200S mutation in mice reduced cell surface Gal-3 and may have contributed to lower intracellular Gal-3 levels. Further studies will be necessary to determine if the 25-30% reduction in intracellular Gal-3 is biologically significant.

[4] Thyroid malignant neoplasm-associated biomarkers as targets for oncolytic virotherapy

• Authors: Mi Guan, Yanping Ma, S. Shah, G. Romano
• Year: 2016
• Venue: Oncolytic Virotherapy
• URL: https://www.semanticscholar.org/paper/9f79d851e32ad25e83c0a2d64e12919bf81a89f8
• DOI: 10.2147/OV.S99856
• PMID: 27579295
• PMCID: 4996252
• Citations: 4
• Summary: This review focuses on the strategy of biomarkers for the production of novel TMN oncolytic therapeutics, which may improve the specificity of targeting of tumor cells and limit adverse effects in patients.
• Evidence snippets:
• Snippet 1 (score: 0.738)
  > The Galectin-3 (LGALS3) is a protein that is encoded by a single gene, LGALS3, located on chromosome 14, locus q21-q22. 63 The molecular weight of this protein is ∼30 kDa, and it contains a carbohydrate-recognition-binding domain of ∼130 amino acids that enable the specific binding of β-galactosides. This protein localizes to the extracellular matrix, the cytoplasm, and the nucleus. It plays a role in numerous cellular functions including cell adhesion, cell activation and chemoattraction, cell growth, differentiation, cell cycle, apoptosis, innate immunity, cell adhesion, and T-cell regulation. 63,64 It has been known that LGALS3 is distributed widely around the tissues but in a low level.
  > To date, LGALS3 has been extensively studied as an IHC marker of thyroid malignancy, and a high diagnostic accuracy has been reported even for difficult pathological diagnoses. 64 Feilchenfeldt et al reported that the mRNA levels of LGALS3 and thyroglobulin in 28 benign and 31 malignant thyroid samples were quantified by real-time PCR. The LGALS3 expression at the mRNA was 60% (12/20) and the protein level was 100% (8/8), respectively. 65 The positive rate was 84% (41/49) when combined with the LGALS3 and HBME-1 in PTC specimens. 66 Two groups of researchers have detected the LGALS3 by IHC in PTC specimens. Saleh et al have shown that the sensitivity and the specificity for LGALS3 were 92.3% and 77.3%, respectively. 67 Song et al reported that positive expression of LGALS3 was 97% (427/441) in PTC group and 51% (77/151) in the benign thyroid lesions group. 68 These results may further support the notion that the high level of LGALS3 antigen expression occurs in patients with PTC. There are a number of different types of oncolytic viruses that have been altered from natural viruses in the laboratory such as adenovirus, reovirus, measles virus, herpes simplex

[5] Periplocin suppresses the growth of colorectal cancer cells by triggering LGALS3 (galectin 3)-mediated lysophagy

• Authors: Kui Wang, Shuyue Fu, Lixia Dong, Dingyue Zhang, Mao Wang et al.
• Year: 2023
• Venue: Autophagy
• URL: https://www.semanticscholar.org/paper/3dadfc351823c4e325e65c171ab3765871189c80
• DOI: 10.1080/15548627.2023.2239042
• PMID: 37471054
• Citations: 35
• Influential citations: 2
• Summary: It is shown that periplocin exhibits promising anticancer activity against CRC both in vitro and in vivo, and is indicated as a potential therapeutic option for the treatment of CRC.
• Evidence snippets:
• Snippet 1 (score: 0.734)
  > Scale bar: 10 μm. (I) Immunofluorescent analysis of the colocalization of LGALS3 with ubiquitin in CRC cells treated with or without 0.50 μM periplocin for 24 h. Scale bar: 10 μm. (J) Representative fluorescent images of CRC cells transiently expressing Mrfp-GFP-tandem fluorescent-tagged LGALS3 (tfGal3) followed by 0.50 μM periplocin treatment for 24 h. Scale bar: 10 μm. (K) Quantitative analysis of the GFP + RFP + or GFP − RFP + LGALS3 puncta in (J). (L) the relative decreased ratio of Magic Red intensity, relative increased ratio of LysoSensor Blue intensity, relative increased ratio of the interaction between LGALS3 and TRIM16, and relative increased ratio of LC3B-II protein level in DLD-1 cells following 0.50 μM periplocin treatment at different time periods. Results are representative of three independent experiments. Data are presented as mean ± SD. P < 0.05, P < 0.01, **P < 0.001. for LGALS3 degradation, we generated lysine to arginine mutants of LGALS3 at K196 or Lys210 (LGALS3 K196R or LGALS3 K210R ). As shown in Figure 6I, the ubiquitinconjugated level of LGALS3 K196R mutant was comparable to the wild type (WT), whereas K210 mutation significantly decreased LGALS3 ubiquitination. These results suggest that periplocin elevates LGALS3 level by preventing K210 ubiquitination and proteasomal degradation. In addition, periplocin was found to stabilize the protein level of LGALS3 against thermal changes using a cellular thermal shift assay (CETSA) (Figure 6J,K), implying the binding of periplocin with LGALS3.
• Snippet 2 (score: 0.728)
  > We next investigated the mechanism underlying periplocinmediated lysophagy. The expression of LGALS3, a key lysophagy marker [46], was found to be upregulated following periplocin treatment as evidenced by immunofluorescent staining (Figure 2M). To this end, we presumed that periplocin-induced lysophagy might be attributable to the upregulation of LGALS3. Indeed, periplocin treatment prominently elevated the protein level of LGALS3 as evidence by immunoblotting analysis (Figure 6A). The increased protein level of LGALS3 was further confirmed in tumor xenografts from periplocin-treated mice (Figure 6B,C). However, no obvious change was observed on the mRNA level of LGALS3 in periplocin-treated cells compared with controls (Figure S6A), suggesting that transcriptional regulation was not involved in increased LGALS3 expression following periplocin treatment. Therefore, we postulated that periplocin might elevate LGALS3 by regulating protein stability. Of note, cycloheximide (CHX, a translational inhibitor) treatment led to an obvious decrease in LGALS3 protein level in control cells, but had no obvious effect on the upregulated protein level of LGALS3 in periplocin-treated cells, suggesting periplocin maintains LGALS3 stability (Figure 6D,E). In support of this, treatment with MG132 (a proteasome inhibitor) failed to further enhance the protein level of LGALS3 in response to periplocin treatment (Figure 6F,G). These data suggest that periplocin may prevent proteasomal degradation of LGALS3.
  > We therefore measured the effect of periplocin on LGALS3 ubiquitination. As shown in Figure 6H, periplocin markedly decreased the ubiquitin-conjugated level of LGALS3.
• Snippet 3 (score: 0.716)
  > In addition, periplocin was found to stabilize the protein level of LGALS3 against thermal changes using a cellular thermal shift assay (CETSA) (Figure 6J,K), implying the binding of periplocin with LGALS3. The interaction between periplocin and LGALS3 was further confirmed by drug affinity responsive target stability (DARTS) analysis, as evidenced by a more stable property of LGALS3 protein against pronase digestion in response to periplocin treatment (Figure 6L,M). Moreover, using semiflexible docking analysis, we found that LGALS3 showed a good binding activity for periplocin, with a binding energy of −6.689 kcal/mol. Glu165, Arg162, Gly152, Gln150, Arg144, and Asn143 of LGALS3 were identified as possible sites for periplocin binding (Figure 6N,O), which required further experimental investigation. Together, these data suggest that periplocin binds and prevents ubiquitin-mediated degradation of LGALS3 in CRC cells.

[6] Impairment of lysosomal quality control in Huntington disease

• Authors: P. Rusmini, F. Mina, M. Valenza, Martina Vitali, V. Ferrari et al.
• Year: 2025
• Venue: Cell Death & Disease
• URL: https://www.semanticscholar.org/paper/c874bbb3c9e6aa0a3f74519c022f3fa822daf4a8
• DOI: 10.1038/s41419-025-08103-z
• PMID: 41145409
• PMCID: 12559425
• Citations: 4
• Influential citations: 1
• Summary: TFEB and TFE3 are sequestered in muHTT aggregates, and muHTT proteins associates with LMP triggering the translocation of LGALS3 to the lumen of lysosomes, with a close relation between polyQ size and severity of these events.
• Evidence snippets:
• Snippet 1 (score: 0.732)
  > In HD, high levels of LGALS3 have been found in plasma and brain of patients and mice. LGALS3 upregulation was observed in HD mice before the motor symptoms, in the microglia LGALS3 was found associated to damaged lysosomes and its suppression in microglia ameliorated the HD mice phenotype [36].
  > LGALS3 is emerging as a key factor for NDs for its intracellular role in lysosomal damage, but also for its functions linked to its secretion in the extracellular space. Many pieces of evidence suggest its detrimental role in neurodegeneration, even if a protective role of LGALS3 has been reported (reviewed in ref. [75]). LGALS3 mechanisms of action need further investigation but its pharmacological modulation might represent a valuable target for intervention for NDs. LGALS3 inhibitors have already been tested in metabolic and fibrotic diseases, and these approaches might be applied to NDs. 3′-bis-(4aryltriazol-1-yl) thiodigalactoside (GB039, formerly named TD139), a synthetic small molecule that antagonizes LGALS3 activity by binding to the carbohydrate recognition domain, was effective in idiopathic pulmonary fibrosis and retinal degeneration [76,77]. Pectins, plant cell wall polysaccharides, mostly obtained from citrus and apples, represent natural LGALS3 inhibitors [78,79].
  > In summary, our experiments suggest that LQC impairment might contribute to HD. Indeed, the LGALS3 accumulation observed in HD cellular models due to TFEB and TFE3 sequestration by muHTT inclusions causes LMP and lysophagy impairment, in turn, influences LQC.
  > Fig. 8 TFEB and TFE3 sequestration affects the LQC. A, B NSC-34 cells were transfected with wt or muHTT.
• Snippet 2 (score: 0.689)
  > A, B NSC-34 cells were transfected with wt or muHTT. (A) Representative images by confocal microscopy of double immunostaining with anti-LAMP1 (green) and anti-HTT antibody (red), nuclei were stained with DAPI (blue) (63X magnification). Scale bar: 10 μm. B the scatter dot blot represents the quantification of lysosome volume. The fields were randomly selected and at least 100 cells for each sample were analyzed (p < 0.001, one-way ANOVA with Tukey's test). C, D NSC-34 cells were cotransfected with wt or mutant HTT and EGFP-LGALS3. C Representative images by confocal microscopy of EGFP-LGALS3 (green) and IF staining with anti-HTT antibody (red), nuclei were stained with DAPI (blue) (63X magnification). Scale bar: 10 μm. D LGALS3 puncta assay. The bar graph represents the quantification of percentage of cells with >3 GFP-LGALS3 puncta. (* p < 0.005, p < 0.0001, one-way ANOVA with Tukey's test). NSC-34 cells were co-transfected with EGFP-LGALS3, FLAG-TFEB (E), FLAG-TFE3 (F), or EV, and wt or muHTT. LGALS3 puncta assay was performed. The graphs with individual values represent the quantification of percentage of cells with >3 GFP-LGALS3 puncta (p < 0.005, ****p < 0.0001, two-way ANOVA with Bonferroni's test).

[7] LGALS3 Is a Poor Prognostic Factor in Diffusely Infiltrating Gliomas and Is Closely Correlated With CD163+ Tumor-Associated Macrophages

• Authors: Wan-Ming Hu, Yuan-Zhong Yang, Tian Zhang, Changling Qin, Xuenong Li
• Year: 2020
• Venue: Frontiers in Medicine
• URL: https://www.semanticscholar.org/paper/53b083f91a08aefebb5f9edaaa95625e2dc98f2b
• DOI: 10.3389/fmed.2020.00182
• PMID: 32528967
• PMCID: 7254797
• Citations: 18
• Influential citations: 1
• Summary: LGALS3 was an independent poor prognostic marker in diffusely infiltrating gliomas and was positively correlated with immune cell infiltration, particularly CD163+ tumor-associated macrophages in the TCGA dataset, Rembrandt dataset, and the SYSUCC cohort.
• Evidence snippets:
• Snippet 1 (score: 0.723)
  > In the LGALS family, LGALS3 has a special domain that recognizes and binds to β-galactosides on cellular glycoproteins and glycolipids (5).
  > LGALS3 may be observed in the cytoplasm and in the nucleus as well as the extracellular matrix (6). It serves different biological functions, such as cell growth, cell adhesion, angiogenesis, and apoptosis (7).
  > LGALS3 can be expressed in different types of tumors, and accumulating evidence has proved that LGALS3 plays a vital role in tumorigenesis and development (6,(8)(9)(10)(11)(12)(13)(14)(15)(16). Recently, a study indicated that LGALS3 can promote the therapeutic resistance of glioblastoma and is related to tumor risk and prognosis (17). However, its prognostic significance needs to be further confirmed in large glioma samples, and, hitherto, no studies have explored the role of LGALS3 in the glioma immune microenvironment and its correlation with key molecular markers, including isocitrate dehydrogenase 1 (IDH1), alpha-thalassemia/mental retardation X-linked (ATRX), O-6methylguanine-DNA methyltransferase (MGMT), telomerase reverse transcriptase (TERT), and 1p19q.
• Snippet 2 (score: 0.702)
  > LGALS3 was Mainly Expressed in Pilocytic Astrocytoma, GBM, and IDH Wild-Type LGG
  > LGALS3 was mainly expressed in cytoplasm, and weak expression in endothelial cells was used as an internal control in glioma. The typical positive and negative results of IHC staining for LGALS3 in glioma are presented in Figures 1A-D. Distinctly high expression of LGALS3 was observed in pilocytic astrocytoma and GBM, both with a diffuse pattern (Figures 1E-H). In total, out of all 304 glioma cases, LGALS3 protein expression was positive in 125 glioma cases (41.1%, 125/304), with 69.2% (9/13) in WHO I (pilocytic astrocytoma), 9.8% (8/82) in WHO II (diffuse astrocytoma and oligodendroglioma), 34.2% (26/76) in WHO III (anaplastic astrocytoma and oligodendroglioma), and 61.7% (82/133) in WHO IV (glioblastoma) (Figure S2A). Further analysis showed that LGALS3 was mainly expressed in IDH wildtype LGG compared with IDH mutated LGG (Figure S2B). LGALS3-positive patients presented with significantly shorter OS than those of negative patients in all the gliomas, LGG, GBM, AA, and IDH glioma but no statistical difference in PA. PA, pilocytic astrocytoma; LGG, lower grade glioma; GBM, glioblastoma; AA, anaplastic astrocytoma.
  > = 0.002). Kaplan-Meier plots revealed that LGALS3 expression was a significantly unfavorable prognostic marker in diffusely infiltrating gliomas (WHO II-IV) but not in pilocytic glioma (WHO I).

[8] Identification of an Internal Gene to the Human Galectin-3 Gene with Two Different Overlapping Reading Frames That Do Not Encode Galectin-3*

• Authors: M. Guittaut, Stéphane Charpentier, Thierry Normand, Martine Dubois, J. Raimond et al.
• Year: 2001
• Venue: The Journal of Biological Chemistry
• URL: https://www.semanticscholar.org/paper/75ca62f4b6eb66b3bcdac062664da410941fdcaa
• DOI: 10.1074/JBC.M002523200
• PMID: 11160123
• Citations: 37
• Influential citations: 6
• Summary: It is demonstrated that these transcripts arise from an internal gene embedded within LGALS3 and named galig (Galectin-3 internal gene), which appears to be tightly regulated and principally activated in leukocytes from peripheral blood.
• Evidence snippets:
• Snippet 1 (score: 0.719)
  > Human Rapid-Scan Gene Expression Panel was used to detect the alternative transcripts in various human tissues using RT-PCR. The primers used were designed to amplify a 923-or 629-bp fragment.
  > LGALS3 transcripts were detected as a 457-bp DNA and actin transcripts as a 640-bp DNA. PCR was performed using 0.25 ng or 2.5 ng (10ϫ) template cDNA.
  > average of other human proteins is 10 times lower. This rich content in tryptophans confers hydrophobic properties that may account for the membrane localization of the ORF2⅐EGFP protein (Fig. 6). Consistent with the mitochondrial localization of the ORF2⅐EGFP fusion protein, this sequence exhibits the common properties of mitochondrial-imported proteins such as the enrichment of arginine, leucine, and serine residues (36).
  > Tissue Specificity of galig Expression-Detection of galig transcripts in HOS cells and colon tumor cells revealed a low expression level. Based on this observation, the rationale that the appearance of galig transcripts may have resulted from a leaky transcription of a cryptic promoter rather than from an independently functioning promoter could not be excluded. Screening of several human tissues indicated clearly that galig is a tightly regulated gene whose expression is most efficient in leukocytes from peripheral blood. The low level of transcription in bone marrow indicates that galig is specifically expressed in mature forms of leukocytes. Whereas the precise quantification of galig mRNA has not been addressed in these experiments, it is clear that these transcripts are much less abundant than LGALS3 transcripts. This may not be surprising considering that LGALS3 is known to be highly expressed when activated (37,38). Indeed, the amount of LGALS3 transcripts appeared as abundant as those from actin genes. This shows a different type of regulation by the galig and LGALS3 promoters. In particular, muscle, stomach, and uterus, although expressing low levels of galig transcripts, revealed no LGALS3 transcripts, thus indicating an independent functioning of the two promoters.

[9] LGALS3 is connected to CD74 in a previously unknown protein network that is associated with poor survival in patients with AML

• Authors: P. Ruvolo, Chenyue W. Hu, Y. Qiu, V. Ruvolo, Robin L. Go et al.
• Year: 2019
• Venue: EBioMedicine
• URL: https://www.semanticscholar.org/paper/46bbdbcb4660389e13acba24499cc415d75f18e0
• DOI: 10.1016/j.ebiom.2019.05.025
• PMID: 31105032
• PMCID: 6604360
• Citations: 25
• Influential citations: 2
• Summary: The data suggest that the LGALS3 network and the CD74 network each support AML cell survival and the two networks may cooperate in a novel high risk AML population.
• Evidence snippets:
• Snippet 1 (score: 0.717)
  > LGALS3 is associated with active Fig. 7. Suppression of LGALS3 does not alter gene expression of LGALS3 network protein genes or CD74 in THP-1 cells. RNA from THP-1 transductant cells with either LKO vector control shRNA or LGALS3 shRNA was isolated, cDNA produced, and mRNA levels of ATG7, LGALS3, ITGAL, CCND3, PRKCA, PARP1, CD74, MYC, CD44, SSBP2, PPP2R2A, CLPP, and B2M were determined by qRT-PCR and levels normalized to ABL-1 as described in "Materials and methods".
  > AKT and MAPK signaling. The protein with the strongest positive correlation with LGALS3 is with ATG7, an autophagy protein that has recently been implicated in maintaining hematopoietic stem cells and serving as a survival factor in AML [46,47]. Recent studies implicate LGALS3 in regulation of autophagy via autophagasome formation, though whether the mechanism involves ATG7 is not clear [48]. Interestingly, phosphorylated PKC delta was positively correlated with LGALS3. PKC delta is viewed as a pro-stress kinase but recent studies suggest that the enzyme has pro-survival properties [49][50][51]. Kinehara and colleagues suggest that PKC delta may act in human pluripotent stem cells as part of a mechanism to regulate stem cell renewal [52]. The data also suggest a novel relationship between LGALS3 and PP2A. The negative correlation of LGALS3 expression with PPP2R2A/B/C/D could reflect LGALS3 suppression of PP2A. The PP2A isoform containing PPP2R2A dephosphorylates both AKT and PKC alpha [53]. Thus, potential suppression of the PP2A subunit by LGALS3 could account for elevated AKT and PKC alpha phosphorylation in samples where LGALS3 expression is elevated.

[10] High LGALS3 expression induced by HCP5/hsa-miR-27b-3p correlates with poor prognosis and tumor immune infiltration in hepatocellular carcinoma

• Authors: Yinghui Ren, Yongmei Qian, Qicheng Zhang, Xiaoping Li, Mingjiang Li et al.
• Year: 2024
• Venue: Cancer Cell International
• URL: https://www.semanticscholar.org/paper/552bd37c67dea75d0c33a9a0de2acdafcf0dcf6e
• DOI: 10.1186/s12935-024-03309-1
• PMID: 38643145
• PMCID: 11031979
• Citations: 13
• Summary: It is hypothesized that the HCP5/hsa-miR-27b-3p axis could serve as the most promising LGALS3 regulation mechanism in HCC and the upregulation of LGALS3 via the HCP5/hsa-miR-27b-3p axis is associated with unfavorable prognosis and increased tumor immune infiltration in HCC.
• Evidence snippets:
• Snippet 1 (score: 0.705)
  > LGALS3 has a crucial function in mediating cell adhesion as well as cell-cell interaction by recognizing complex carbohydrates on the surface of cells [22,23], as well as regulates cell apoptosis, autophagy, and inflammation [24,25].Interestingly, recent studies suggested that LGALS3 involves in essential cancer-related mechanisms, including cellular metabolism, carcinogenesis, metastasis, neoplasia, angiogenesis, as well as immune escape [26][27][28].In addition, LGALS3 is highly expressed and implicated in different cancer types progression such as HCC, gastric, colorectal, pancreatic carcinomas, melanomas or glioblastomas and breast cancer [29,30].Indeed, LGALS3 has been considered a potential marker for these malignancies.Interestingly, LGALS3, which is differentially expressed in different cancers, has been shown to exhibit tumor suppressor activity in certain cancer types.The different roles of LGALS3 may be attributed to different potential mechanisms that appear cancer-type dependent.The different locations and mutations of LGALS3 also contribute to its various functions.However, LGALS3 remains inadequately understood in HCC and requires further investigation.First, we conducted an extensive investigation of the expression profile, clinical prognosis, and pathologic stage of LGALS3 in HCC through an in-depth analysis of the public database.On the basis of TCGA and CPTAC datasets, we found that LGALS3 gene and protein expression was elevated in HCC tissues.Moreover, the OS and DSS were lesser in patients with HCC having higher expression levels of LGALS3 contrasted to those with low expression levels of LGALS3 based on GEPIA2 and Kaplan-Meier plotter datasets.Meanwhile, the expression of LGALS3 within HCC was significantly associated with the advanced tumor stage and grade, indicating that elevated LGALS3 expression could increase tumor progression.Song et al. [31] indicated that galectin-3 promoted HCC tumorigenesis and metastasis via β-catenin signalling in vitro and in vivo.

[11] Mice lacking galectin-3 (Lgals3) function have decreased home cage movement

• Authors: Tammy R. Chaudoin, S. Bonasera
• Year: 2018
• Venue: BMC Neuroscience
• URL: https://www.semanticscholar.org/paper/26255eafb963932be62ecb55d4943930217cb63f
• DOI: 10.1186/s12868-018-0428-x
• PMID: 29716523
• PMCID: 5930520
• Citations: 7
• Influential citations: 1
• Summary: P perturbation of behavioral circadian rhythms in Lgals3−/− mice is noted, with mice at both ages demonstrating greater variability in day-to-day performance of feeding, drinking, and movement compared to wildtype.
• Evidence snippets:
• Snippet 1 (score: 0.697)
  > atlases suggest that Lgals3 expression (at low-to-moderate levels) occurs in both pre-and post-natal brain, and has been localized to regions involved in motor behavior generation, including the cortex, striatum, cerebellum, and spinal cord. We thus argue that Lgals3 loss alters mouse motor function, either through its impact on motor development or through altered neuronal signaling in CNS regions that regulate or produce motor behavior. Further studies examining the consequences of Lgals3 loss at synaptic, neuronal, ensemble, and tissue levels of organization will be required to determine the precise mechanisms underlying this functional loss. Grey bands depict periods where mouse cohorts were tested in the home cage monitoring system. Note that neither axis begins at 0. Sampling interval for x-axis is 7 days except where noted by breakpoints
  > As mentioned earlier, Lgals3 has been implicated in a large number of physiological tasks at both a cellular and organwide level of organization. It is thus notable that mice with complete loss of Lgals3 function demonstrate relatively few behavioral differences when compared to wildtype C57BL/6J mice. This finding suggests that, at least in the mouse, there is some genetic redundancy regarding Lgals3 function. Studies of galectin evolution focusing on intron/exon organization as well as sequence identity suggest that duplication of ancestral galectin genes in animal lineages preceding the first teleost fish [62] provided the precursors for what has become a large vertebrate protein family [63]. There is also data suggesting that galectins may be able to substitute for one another in specific circumstances. For example, Lgals1 may compensate for Lgals3 loss at the spliceosome [64]. Extracellular Lgals1 also regulates T cell apoptosis in a manner similar to that of extracellular Lgals3 [65]. The behavioral phenotype arising from Lgals3 functional loss thus identifies neuronal loci and processes where there is no compensation for gene loss.

[12] Mice lacking galectin-3 (Lgals3) function have decreased home cage movement

• Authors: Tammy R. Chaudoin, S. Bonasera
• Year: 2018
• Venue: BMC Neuroscience
• URL: https://www.semanticscholar.org/paper/613a09b176431cdca195e6b3c439b4edbe4f92af
• DOI: 10.1186/s12868-018-0428-x
• Summary: P perturbation of behavioral circadian rhythms in Lgals3−/− mice is noted, with mice at both ages demonstrating greater variability in day-to-day performance of feeding, drinking, and movement compared to wildtype.
• Evidence snippets:
• Snippet 1 (score: 0.696)
  > atlases suggest that Lgals3 expression (at low-to-moderate levels) occurs in both pre-and post-natal brain, and has been localized to regions involved in motor behavior generation, including the cortex, striatum, cerebellum, and spinal cord. We thus argue that Lgals3 loss alters mouse motor function, either through its impact on motor development or through altered neuronal signaling in CNS regions that regulate or produce motor behavior. Further studies examining the consequences of Lgals3 loss at synaptic, neuronal, ensemble, and tissue levels of organization will be required to determine the precise mechanisms underlying this functional loss. Grey bands depict periods where mouse cohorts were tested in the home cage monitoring system. Note that neither axis begins at 0. Sampling interval for x-axis is 7 days except where noted by breakpoints
  > As mentioned earlier, Lgals3 has been implicated in a large number of physiological tasks at both a cellular and organwide level of organization. It is thus notable that mice with complete loss of Lgals3 function demonstrate relatively few behavioral differences when compared to wildtype C57BL/6J mice. This finding suggests that, at least in the mouse, there is some genetic redundancy regarding Lgals3 function. Studies of galectin evolution focusing on intron/exon organization as well as sequence identity suggest that duplication of ancestral galectin genes in animal lineages preceding the first teleost fish [62] provided the precursors for what has become a large vertebrate protein family [63]. There is also data suggesting that galectins may be able to substitute for one another in specific circumstances. For example, Lgals1 may compensate for Lgals3 loss at the spliceosome [64]. Extracellular Lgals1 also regulates T cell apoptosis in a manner similar to that of extracellular Lgals3 [65]. The behavioral phenotype arising from Lgals3 functional loss thus identifies neuronal loci and processes where there is no compensation for gene loss.

[13] In-depth quantitative proteomics analysis revealed C1GALT1 depletion in ECC-1 cells mimics an aggressive endometrial cancer phenotype observed in cancer patients with low C1GALT1 expression

• Authors: A. Montero‐Calle, Á. López-Janeiro, Marta L. Mendes, Daniel Perez-Hernandez, Irene Echevarría et al.
• Year: 2023
• Venue: Cellular Oncology
• URL: https://www.semanticscholar.org/paper/92b64e01bcb30f7457ddb8cc4be26de8b0c7cf69
• DOI: 10.1007/s13402-023-00778-w
• PMID: 36745330
• PMCID: 10205863
• Citations: 19
• Summary: C1GALT1 stably depleted ECC-1 cells mimic an EC aggressive phenotype observed in patients and might be useful for the identification and validation of EC markers of progression.
• Evidence snippets:
• Snippet 1 (score: 0.696)
  > Finally, since LGALS3 (Galectin-3) has been shown to interact with O-glycans in the mucosal epithelium [30], and considering its overexpression observed by proteomics and further confirmed by PCR and WB analyses upon depletion of C1GALT1, we focused on the role of LGALS3 in EC by IHC.
  > A total of 151 out of 178 cores from 79 EC patients were considered adequate for LGALS3 expression assessment by IHC. Morphologic assessment of LGALS3 IHC staining characteristics revealed different staining patterns (Fig. 5 A). Out of the 151 evaluable cores, 45 (29.8%) showed absent LGALS3 expression. LGALS3 positive samples showed variable and low intensity protein expression (mean positive tumor cells per sample = 35.4%). A small subset of cores (13/151, 8.6%) demonstrated diffuse (> 90% positive tumor cells per sample) staining. LGALS3 score varied across histologic types, with serous and undifferentiated tumors displaying the highest protein expression (median IHC LGALS3 score = 10, 20, 50 and 55 for endometrioid, clear cell, serous and undifferentiated tumor types, respectively) (Fig. 5B). Interestingly, the aggressive histologic variants (clear cell, serous and undifferentiated) showed higher LGALS3 IHC scores than endometrioid variants (p value < 0.001). In addition, LGALS3 expression positively correlated with tumor grade. High grade tumors (G3) displayed higher protein expression (median LGALS3 IHC score = 30) compared to low grade tumors (median LGALS3 IHC score for G1/G2 tumors = 10). This finding was independent of histologic type, as similar results were observed when analyzing endometrioid tumors.
  > Finally, we interrogated the correlation between the expression levels of LGALS3 and C1GALT1.

[14] Lysosomal damage is a therapeutic target in Duchenne muscular dystrophy

• Authors: Abbass Jaber, Laura Palmieri, R. Bakour, N. Bourg, A. Hong et al.
• Year: 2025
• Venue: Science Advances
• URL: https://www.semanticscholar.org/paper/3265a29ad8c2d48b294017fd50b6df9188b55ecb
• DOI: 10.1126/sciadv.adv6805
• PMID: 41124255
• PMCID: 12542950
• Citations: 7
• Summary: Lysosomal perturbations in myofibers of patients with DMD and animal models are identified, highlighting lysosomal damage as an important pathomechanism in DMD and suggesting that combining trehalose with gene therapy could enhance therapeutic efficacy.
• Evidence snippets:
• Snippet 1 (score: 0.690)
  > To investigate whether cholesterol accumulation in dystrophic muscle is associated with the impaired lysosomal function, we sought a method to quantify lysosomal damage. Several studies have recently focused on lysosomal dysfunction, in which LMP plays a central role (18). However, very few studies have investigated lysosome damage in muscle. One identified marker of LMP is Gal-3 (or LGALS3), which is part of the galectins, a family of lectins that bind specifically to carbohydrates (19). These lectins are present in the cytosol, nucleus, and extracellular matrix and are translocated to the membrane of damaged lysosomes before their removal by the autophagy machinery (20). To analyze LGALS3 expression in a myogenic environment and its capacity to detect LMP, we differentiated healthy human immortalized myoblasts into elongated myotubes for 7 days and then performed immunostaining for LGALS3 and lysosome-associated membrane protein 2 (LAMP2), which is commonly used as a lysosome marker (21). A diffuse expression of LGALS3 was observed in the cells (fig. S1A). Treatment with l-leucyl-l-leucine methyl ester (LLOMe), a lysomotropic agent that induces lysosome-specific membrane damage (22), for 30 min at 2.5 mM triggered the formation of LGALS3-positive puncta, which colocalized with LAMP2, indicating typical damaged lysosomes. An up-regulation of LGALS3 was also detected by Western blotting after 30 min to 1 hour of LLOMe treatment (fig. S1, B and C). LGALS3 puncta were markedly reduced 3 hours after treatment, and LGALS3 expression was restored to the control level, demonstrating efficient lysosomal repair by the cells. This pattern correlated inversely with the amount of LGALS3 released in the media, detected by an enzyme-linked immunosorbent assay (ELISA) assay (fig.

Notes

• This provider combines search_papers_by_relevance with snippet_search.
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Asta Literature Retrieval: Literature evidence for LGALS3 (Homo sapiens): LGALS3 has IgE binding (GO:0019863). Gene/protein: LGALS3. Organism: H...

This report is retrieval-only and is generated directly from Asta results.

• Papers retrieved: 14
• Snippets retrieved: 20

Relevant Papers

[1] Galectins: regulators of acute and chronic inflammation

• Authors: Fu-Tong Liu, Gabriel A. Rabinovich
• Year: 2010
• Venue: Annals of the New York Academy of Sciences
• URL: https://www.semanticscholar.org/paper/83c612d18547a49a6e5a5966b75f7c2f75db351c
• DOI: 10.1111/j.1749-6632.2009.05131.x
• PMID: 20146714
• Citations: 411
• Influential citations: 8
• Summary: Current research indicates that galectins play important roles in the development of acute inflammation as well as chronic inflammation associated with allergies, autoimmune diseases, atherosclerosis, infectious processes, and cancer, and recombinant proteins or specific galectin inhibitors may be used as therapeutic agents for inflammatory diseases.
• Evidence snippets:
• Snippet 1 (score: 0.885)
  > optotic activity through binding to RAGE. 45 The function of endogenous galectin-3 in the mast cell response has been established by studying Lgals3 −/− mice. Lgals3 −/− mast cells exhibited lower degranulation and decreased cytokine production compared to wild-type cells when activated by cross-linkage of IgE receptor. The positive regulatory role of galectin-3 in mast cell response was supported by in vivo data: Lgals3 −/− mice exhibited diminished IgE-mediated passive cutaneous anaphylactic reactions. 48

[2] Periplocin suppresses the growth of colorectal cancer cells by triggering LGALS3 (galectin 3)-mediated lysophagy

• Authors: Kui Wang, Shuyue Fu, Lixia Dong, Dingyue Zhang, Mao Wang et al.
• Year: 2023
• Venue: Autophagy
• URL: https://www.semanticscholar.org/paper/3dadfc351823c4e325e65c171ab3765871189c80
• DOI: 10.1080/15548627.2023.2239042
• PMID: 37471054
• Citations: 35
• Influential citations: 2
• Summary: It is shown that periplocin exhibits promising anticancer activity against CRC both in vitro and in vivo, and is indicated as a potential therapeutic option for the treatment of CRC.
• Evidence snippets:
• Snippet 1 (score: 0.806)
  > In addition, periplocin was found to stabilize the protein level of LGALS3 against thermal changes using a cellular thermal shift assay (CETSA) (Figure 6J,K), implying the binding of periplocin with LGALS3. The interaction between periplocin and LGALS3 was further confirmed by drug affinity responsive target stability (DARTS) analysis, as evidenced by a more stable property of LGALS3 protein against pronase digestion in response to periplocin treatment (Figure 6L,M). Moreover, using semiflexible docking analysis, we found that LGALS3 showed a good binding activity for periplocin, with a binding energy of −6.689 kcal/mol. Glu165, Arg162, Gly152, Gln150, Arg144, and Asn143 of LGALS3 were identified as possible sites for periplocin binding (Figure 6N,O), which required further experimental investigation. Together, these data suggest that periplocin binds and prevents ubiquitin-mediated degradation of LGALS3 in CRC cells.
• Snippet 2 (score: 0.731)
  > Scale bar: 10 μm. (I) Immunofluorescent analysis of the colocalization of LGALS3 with ubiquitin in CRC cells treated with or without 0.50 μM periplocin for 24 h. Scale bar: 10 μm. (J) Representative fluorescent images of CRC cells transiently expressing Mrfp-GFP-tandem fluorescent-tagged LGALS3 (tfGal3) followed by 0.50 μM periplocin treatment for 24 h. Scale bar: 10 μm. (K) Quantitative analysis of the GFP + RFP + or GFP − RFP + LGALS3 puncta in (J). (L) the relative decreased ratio of Magic Red intensity, relative increased ratio of LysoSensor Blue intensity, relative increased ratio of the interaction between LGALS3 and TRIM16, and relative increased ratio of LC3B-II protein level in DLD-1 cells following 0.50 μM periplocin treatment at different time periods. Results are representative of three independent experiments. Data are presented as mean ± SD. P < 0.05, P < 0.01, **P < 0.001. for LGALS3 degradation, we generated lysine to arginine mutants of LGALS3 at K196 or Lys210 (LGALS3 K196R or LGALS3 K210R ). As shown in Figure 6I, the ubiquitinconjugated level of LGALS3 K196R mutant was comparable to the wild type (WT), whereas K210 mutation significantly decreased LGALS3 ubiquitination. These results suggest that periplocin elevates LGALS3 level by preventing K210 ubiquitination and proteasomal degradation. In addition, periplocin was found to stabilize the protein level of LGALS3 against thermal changes using a cellular thermal shift assay (CETSA) (Figure 6J,K), implying the binding of periplocin with LGALS3.

[3] Mutation of the galectin‐3 glycan‐binding domain ( Lgals3‐R200S) enhances cortical bone expansion in male mice and trabecular bone mass in female mice

• Authors: Kevin A. Maupin, Daniel T. Dick, Vari Vivarium, Transgenics Core, B. Williams
• Year: 2020
• Venue: FEBS Open Bio
• URL: https://www.semanticscholar.org/paper/6ab62ea9acc6fef617d0b1f237c1a477f45b05c7
• DOI: 10.1002/2211-5463.13483
• PMID: 36062328
• PMCID: 9527582
• Citations: 2
• Summary: The results suggest that the trabecular bone phenotype of Lgals3-KO mice was driven primarily by loss of extracellular galectin-3, while the cortical bone phenotypeof Lgal3- KO mice may have also been influenced by Loss of intracellular galECTin- 3.
• Evidence snippets:
• Snippet 1 (score: 0.773)
  > The study of galectin-3 is complicated by its ability to function both intracellularly and extracellularly. While the mechanism of galectin-3 secretion is unclear, studies have shown that the mutation of a highly conserved arginine to a serine in human galectin-3 (LGALS3-R186S) blocks glycan binding and secretion. To gain insight into the roles of extracellular and intracellular functions of galectin-3, we generated mice with the equivalent mutation (Lgals3-R200S) using CRISPR/Cas9-directed homologous recombination. Consistent with a reduction in galectin-3 secretion, we observed significantly reduced galectin-3 protein levels in the plasma of heterozygous and homozygous mutant mice. We observed a similar increased bone mass phenotype in Lgals3-R200S mutant mice at 36 weeks as we previously observed in Lgals3-KO mice with slight variation. Like Lgals3-KO mice, Lgals3-R200S females, but not males, had significantly increased trabecular bone mass. However, only male Lgals3-R200S mice showed increased cortical bone expansion, which we had previously observed in both male and female Lgals3-KO mice and only in female mice using a separate Lgals3 null allele (Lgals3). These results suggest that the trabecular bone phenotype of Lgals3-KO mice was driven primarily by loss of extracellular galectin-3. However, the cortical bone phenotype of Lgals3-KO mice may have also been influenced by loss of intracellular galectin-3. Future analyses of these mice will aid in identifying the cellular and molecular mechanisms that contribute to the Lgals3-deficient bone phenotype as well as aid in distinguishing the extracellular vs. intracellular roles of galectin-3 in various signaling pathways.
• Snippet 2 (score: 0.715)
  > In this study, we generated the Lgals3-R200S allele using CRISPR/Cas9 and a single-stranded DNA oligonucleotide as a template for homologous recombination. Mutation of the cognate arginine to serine in human Gal-3 (R186S) prevents Gal-3 secretion and glycan-binding [30,31,40]. Because mutation of the functionally equivalent arginine in galectin-7 also prevents glycan-binding [32,33], the R200S mutation in Gal-3 should be functionally equivalent. As confirmation, our surface biotinylation experiment demonstrated a dose-dependent reduction in surface Gal-3 in heterozygous and homozygous Lgals3-R200S mice. In our aged mouse bone studies, we observed a sexdependent increase in trabecular bone mass in female Lgals3-R200S mice. Yet only male Lgals3-R200S had significant increase in cortical bone expansion. The increased cortical bone expansion was coupled with reduced tissue quality (reduced max stress), and no change in tissue or whole bone stiffness values.
  > Similar to the findings presented here, we previously observed that female mice with genomic loss of Gal-3 (Lgals3-KO mice) had significant protection against age-related trabecular bone loss between 24 and 36 weeks of age [5]. But Lgals3-KO mice also had increased cortical bone expansion, whereas only male Lgals3-R200S did in this study. The effect size of the increases in cortical bone size was greater in Lgals3-KO females than males [5]. The similarities between Lgals3-R200S and Lgals3-KO mice (i.e., increased trabecular bone mass in female mice and increased cortical bone expansion in males) likely reflect the role of extracellular Gal-3 loss in increasing bone mass. Conversely, the differences between the two models (tissue stiffness and lack of female cortical bone expansion) could reflect the role of intracellular Gal-3.
  > The female dominance of the cortical bone expansion in
• Snippet 3 (score: 0.706)
  > We previously observed that genomic loss of galectin-3 (Gal-3; encoded by Lgals3) in mice has a significant protective effect on age-related bone loss. Gal-3 has both intracellular and extracellular functionality, and we wanted to assess whether the affect we observed in the Lgals3 knockout (KO) mice could be attributed to the ability of Gal-3 to bind glycoproteins. Mutation of a highly conserved arginine to a serine in human Gal-3 (LGALS3-R186S) blocks glycan binding and secretion. We generated mice with the equivalent mutation (Lgals3-R200S) and observed a subsequent reduction in Gal-3 secretion from mouse embryonic fibroblasts and in circulating blood. When examining bone structure in aged mice, we noticed some similarities to the Lgals3-KO mice and some differences. First, we observed greater bone mass in Lgals3-R200S mutant mice, as was previously observed in Lgals3-KO mice. Like Lgals3-KO mice, significantly increased trabecular bone mass was only observed in female Lgals3-R200S mice. These results suggest that the greater bone mass observed is driven by the loss of extracellular Gal-3 functionality. However, the results from our cortical bone expansion data showed a sex-dependent difference, with only male Lgals3-KO mice having an increased response, contrasting with our earlier study. These notable sex differences suggest a potential role for sex hormones, most likely androgen signaling, being involved. In summary, our results suggest that targeting extracellular Gal-3 function may be a suitable treatment for age-related loss of bone mass.
  > Galectin-3 (Gal-3; encoded by Lgals3) is a protein that functions outside the cell to regulate glycoprotein secretion and turnover [1,2] and intracellularly in protein chaperoning and mRNA splicing [3,4]. We previously found that genomic deletion of Gal-3 in mice (Lgals3-KO) protects the mice against age-related [5] or sex-hormone deprivation bone loss [6]. A better understanding of the

[4] Beyond Colonoscopy: Exploring New Cell Surface Biomarkers for Detection of Early, Heterogenous Colorectal Lesions

• Authors: Saleh M. Ramezani, Arianna Parkhideh, P. Bhattacharya, M. Farach-Carson, D. Harrington
• Year: 2021
• Venue: Frontiers in Oncology
• URL: https://www.semanticscholar.org/paper/4b48091d0ad86a2121491218707db23e88605000
• DOI: 10.3389/fonc.2021.657701
• PMID: 34290978
• PMCID: 8287259
• Citations: 13
• Summary: This review contextualizes existing and emergent CRC surface biomarkers and assess each’s potential as a candidate marker for early marker-based detection of CRC lesions and presents an overview of recent advances in imaging techniques useful for visual detection of surface biomarker detection.
• Evidence snippets:
• Snippet 1 (score: 0.749)
  > Galectin 3, or LGALS3, is a member of the galectin family, a group of carbohydrate-binding lectins characterized by their binding affinity for beta-galactosides (85).
  > LGALS3 is expressed at the cell surface, where it interacts with the extracellular matrix, especially with glycoproteins, and has the ability to affect intracellular signaling pathways (42). LGALS3-expressing cells also possess higher ALDH1 activity, which often correlates with a dedifferentiated cancer stem cell phenotype, than do their LGALS3-negative counterparts (86).
  > The correlation of LGALS3 expression in CRC with clinical pathological characteristics has been explored in several immunohistochemical and RT-PCR studies. In one study, the IHC staining of CRC tissue (n=61) and normal adjacent tissue (n=23) samples showed significantly higher LGALS3 expression in cancer tissue (62.5%) versus normal cancer-adjacent tissue (13.0%) (41). In another study, 75% of CRC tissue samples stain high for LGALS3, and ten CRC cell lines were shown to have increased LGALS3 protein levels compared to HeLa cells (42).
  > LGALS3 expression varies according to cancer staging and the degree of differentiation of the adenocarcinoma. LGALS3 mRNA levels were higher in early stage colorectal cancers (58% in stage I) compared to advanced cancers (50% in stage IV) (43). Protein analysis found higher LGALS3 levels in primary adenocarcinomas than in metastatic adenocarcinomas, and stronger LGALS3 staining in well-differentiated tumor areas compared to poorly differentiated tumor areas (43). Conversely, colorectal adenocarcinomas may display higher levels of LGALS3 than do colorectal adenomas; one study sets the rate of colorectal adenocarcinoma expression of LGALS3 at 95% while only 73% of adenomas were positive for LGALS3 (43).

[5] SMURF1 controls the PPP3/calcineurin complex and TFEB at a regulatory node for lysosomal biogenesis

• Authors: Qin Xia, Hanfei Zheng, Yang Li, Wanting Xu, Chengwei Wu et al.
• Year: 2023
• Venue: Autophagy
• URL: https://www.semanticscholar.org/paper/7ab13fe72fa12a55aa9304ce52199d1494c8974a
• DOI: 10.1080/15548627.2023.2267413
• PMID: 37909662
• PMCID: 11062382
• Citations: 20
• Summary: This study showed that SMURF1 affected lysosomal biogenesis in response to lysosomal damage by preventing TFEB nuclear translocation, and determined that LLOMe-mediated TFEB nuclear import is dependent on SMURF1 under the condition of MTORC1 inhibition.
• Evidence snippets:
• Snippet 1 (score: 0.743)
  > Consistently,
  > LGALS3 and PPP3R1 were required for binding of PPP3CB and TFEB evidenced by knocking down LGALS3 or PPP3R1 decreased, while overexpression of LGALS3 or PPP3R1 increased, the interaction of PPP3CB and TFEB (Figure 8K, L).Of note, we found that the enhanced PPP3CB and TFEB interaction mediated by SMURF1 overexpression was abolished by LGALS3 deletion (Figure 8M).Overall, these data strengthened our hypothesis that LGALS3 and SMURF1 contribute to PPP3CB from "close" to "open" form, which facilitates TFEB docking to the AID domain (Figure 8N).
• Snippet 2 (score: 0.737)
  > Immunofluorescence assay showed that PPP3R1 was also recruited to lysosomes upon LLOMe treatment in a LGALS3-dependent manner (Figure S4A).To identify the role of PPP3R1 in the formation of complex, as expected, we first found that PPP3CB directly binds with PPP3R1 in a LLOMe-enhanced manner (Figure 6A, B).Considering that PPP3CB was directly associated with LGALS3, we also checked the interaction between PPP3R1 and LGALS3.The results showed that PPP3R1 indirectly binds with LGALS3 (Figure 6C).Similarly, LLOMe treatment also promoted the binding affinity between PPP3R1 and LGALS3 (Figure 6D).We next mapped the key interaction domain of LGALS3 with PPP3R1, and showed the NT domain of LGALS3 was essential for the association with PPP3R1 (Figure 6E, F).Furthermore, overexpression of PPP3CB increased, suppression of PPP3CB abolished, the interactions of PPP3R1 and LGALS3 (Figure 6G, H), suggesting PPP3CB is also the bridge for the interaction between LGALS3 and PPP3R1.Interestingly, we also detected that SMURF1 indirectly interacted with PPP3R1, but not MCOLN1, in a LLOMe-enhanced manner (Figure S4B-E).Given that both SMURF1 and PPP3R1 were indirectly bound with the NT domain of LGALS3, we asked whether SMURF1 affected the interactions between PPP3R1 and LGALS3.Our data indicated that suppression of SMURF1 decreased, overexpression of SMURF1 increased, the interactions of PPP3R1 and LGALS3 (Figure 6I, J), suggesting SMURF1 promotes the recruitment of PPP3R1 by LGALS3.We next mapped the key HECT domain of SMURF1 which was essential for interaction with PPP3R1 (Figure 6K, L).

[6] Clusterin Seals the Ocular Surface Barrier in Mouse Dry Eye

• Authors: Aditi Bauskar, W. Mack, J. Mauris, P. Argüeso, M. Heur et al.
• Year: 2015
• Venue: PLoS ONE
• URL: https://www.semanticscholar.org/paper/ddc53237e6b4b7c325cb047e4eaf34098273148e
• DOI: 10.1371/journal.pone.0138958
• PMID: 26402857
• PMCID: 4581869
• Citations: 35
• Influential citations: 2
• Summary: It is shown that CLU prevents and ameliorates ocular surface barrier disruption by a remarkable sealing mechanism dependent on attainment of a critical all-or-none concentration, and suggests CLU as a biotherapeutic for dry eye.
• Evidence snippets:
• Snippet 1 (score: 0.740)
  > In other cases, CLU spots were clearly separate.
  > Next we considered what kinds of ocular surface molecules might bind CLU.
  > LGALS3, a key component of the ocular surface barrier, is a member of the galectin class of beta-galactosidebinding proteins. What is known about the glycosyl moiety of CLU is consistent with LGALS3 binding [25,27]. CLU applied to an LGALS3-sepharose affinity column bound to the beads and was not eluted 0.1 M sucrose, a disaccharide that does not compete with LGALS3 sugar binding, but was mostly eluted with a competitive inhibitor of LGALS3 sugar binding, 0.1 M beta-lactose (Fig 5C). This suggests that CLU binding to LGALS3 is specific for the beta-galactoside-binding function.

[7] High LGALS3 expression induced by HCP5/hsa-miR-27b-3p correlates with poor prognosis and tumor immune infiltration in hepatocellular carcinoma

• Authors: Yinghui Ren, Yongmei Qian, Qicheng Zhang, Xiaoping Li, Mingjiang Li et al.
• Year: 2024
• Venue: Cancer Cell International
• URL: https://www.semanticscholar.org/paper/552bd37c67dea75d0c33a9a0de2acdafcf0dcf6e
• DOI: 10.1186/s12935-024-03309-1
• PMID: 38643145
• PMCID: 11031979
• Citations: 13
• Summary: It is hypothesized that the HCP5/hsa-miR-27b-3p axis could serve as the most promising LGALS3 regulation mechanism in HCC and the upregulation of LGALS3 via the HCP5/hsa-miR-27b-3p axis is associated with unfavorable prognosis and increased tumor immune infiltration in HCC.
• Evidence snippets:
• Snippet 1 (score: 0.734)
  > LGALS3 has a crucial function in mediating cell adhesion as well as cell-cell interaction by recognizing complex carbohydrates on the surface of cells [22,23], as well as regulates cell apoptosis, autophagy, and inflammation [24,25].Interestingly, recent studies suggested that LGALS3 involves in essential cancer-related mechanisms, including cellular metabolism, carcinogenesis, metastasis, neoplasia, angiogenesis, as well as immune escape [26][27][28].In addition, LGALS3 is highly expressed and implicated in different cancer types progression such as HCC, gastric, colorectal, pancreatic carcinomas, melanomas or glioblastomas and breast cancer [29,30].Indeed, LGALS3 has been considered a potential marker for these malignancies.Interestingly, LGALS3, which is differentially expressed in different cancers, has been shown to exhibit tumor suppressor activity in certain cancer types.The different roles of LGALS3 may be attributed to different potential mechanisms that appear cancer-type dependent.The different locations and mutations of LGALS3 also contribute to its various functions.However, LGALS3 remains inadequately understood in HCC and requires further investigation.First, we conducted an extensive investigation of the expression profile, clinical prognosis, and pathologic stage of LGALS3 in HCC through an in-depth analysis of the public database.On the basis of TCGA and CPTAC datasets, we found that LGALS3 gene and protein expression was elevated in HCC tissues.Moreover, the OS and DSS were lesser in patients with HCC having higher expression levels of LGALS3 contrasted to those with low expression levels of LGALS3 based on GEPIA2 and Kaplan-Meier plotter datasets.Meanwhile, the expression of LGALS3 within HCC was significantly associated with the advanced tumor stage and grade, indicating that elevated LGALS3 expression could increase tumor progression.Song et al. [31] indicated that galectin-3 promoted HCC tumorigenesis and metastasis via β-catenin signalling in vitro and in vivo.

[8] In-depth quantitative proteomics analysis revealed C1GALT1 depletion in ECC-1 cells mimics an aggressive endometrial cancer phenotype observed in cancer patients with low C1GALT1 expression

• Authors: A. Montero‐Calle, Á. López-Janeiro, Marta L. Mendes, Daniel Perez-Hernandez, Irene Echevarría et al.
• Year: 2023
• Venue: Cellular Oncology
• URL: https://www.semanticscholar.org/paper/92b64e01bcb30f7457ddb8cc4be26de8b0c7cf69
• DOI: 10.1007/s13402-023-00778-w
• PMID: 36745330
• PMCID: 10205863
• Citations: 19
• Summary: C1GALT1 stably depleted ECC-1 cells mimic an EC aggressive phenotype observed in patients and might be useful for the identification and validation of EC markers of progression.
• Evidence snippets:
• Snippet 1 (score: 0.731)
  > Finally, since LGALS3 (Galectin-3) has been shown to interact with O-glycans in the mucosal epithelium [30], and considering its overexpression observed by proteomics and further confirmed by PCR and WB analyses upon depletion of C1GALT1, we focused on the role of LGALS3 in EC by IHC.
  > A total of 151 out of 178 cores from 79 EC patients were considered adequate for LGALS3 expression assessment by IHC. Morphologic assessment of LGALS3 IHC staining characteristics revealed different staining patterns (Fig. 5 A). Out of the 151 evaluable cores, 45 (29.8%) showed absent LGALS3 expression. LGALS3 positive samples showed variable and low intensity protein expression (mean positive tumor cells per sample = 35.4%). A small subset of cores (13/151, 8.6%) demonstrated diffuse (> 90% positive tumor cells per sample) staining. LGALS3 score varied across histologic types, with serous and undifferentiated tumors displaying the highest protein expression (median IHC LGALS3 score = 10, 20, 50 and 55 for endometrioid, clear cell, serous and undifferentiated tumor types, respectively) (Fig. 5B). Interestingly, the aggressive histologic variants (clear cell, serous and undifferentiated) showed higher LGALS3 IHC scores than endometrioid variants (p value < 0.001). In addition, LGALS3 expression positively correlated with tumor grade. High grade tumors (G3) displayed higher protein expression (median LGALS3 IHC score = 30) compared to low grade tumors (median LGALS3 IHC score for G1/G2 tumors = 10). This finding was independent of histologic type, as similar results were observed when analyzing endometrioid tumors.
  > Finally, we interrogated the correlation between the expression levels of LGALS3 and C1GALT1.

[9] Thyroid malignant neoplasm-associated biomarkers as targets for oncolytic virotherapy

• Authors: Mi Guan, Yanping Ma, S. Shah, G. Romano
• Year: 2016
• Venue: Oncolytic Virotherapy
• URL: https://www.semanticscholar.org/paper/9f79d851e32ad25e83c0a2d64e12919bf81a89f8
• DOI: 10.2147/OV.S99856
• PMID: 27579295
• PMCID: 4996252
• Citations: 4
• Summary: This review focuses on the strategy of biomarkers for the production of novel TMN oncolytic therapeutics, which may improve the specificity of targeting of tumor cells and limit adverse effects in patients.
• Evidence snippets:
• Snippet 1 (score: 0.726)
  > The Galectin-3 (LGALS3) is a protein that is encoded by a single gene, LGALS3, located on chromosome 14, locus q21-q22. 63 The molecular weight of this protein is ∼30 kDa, and it contains a carbohydrate-recognition-binding domain of ∼130 amino acids that enable the specific binding of β-galactosides. This protein localizes to the extracellular matrix, the cytoplasm, and the nucleus. It plays a role in numerous cellular functions including cell adhesion, cell activation and chemoattraction, cell growth, differentiation, cell cycle, apoptosis, innate immunity, cell adhesion, and T-cell regulation. 63,64 It has been known that LGALS3 is distributed widely around the tissues but in a low level.
  > To date, LGALS3 has been extensively studied as an IHC marker of thyroid malignancy, and a high diagnostic accuracy has been reported even for difficult pathological diagnoses. 64 Feilchenfeldt et al reported that the mRNA levels of LGALS3 and thyroglobulin in 28 benign and 31 malignant thyroid samples were quantified by real-time PCR. The LGALS3 expression at the mRNA was 60% (12/20) and the protein level was 100% (8/8), respectively. 65 The positive rate was 84% (41/49) when combined with the LGALS3 and HBME-1 in PTC specimens. 66 Two groups of researchers have detected the LGALS3 by IHC in PTC specimens. Saleh et al have shown that the sensitivity and the specificity for LGALS3 were 92.3% and 77.3%, respectively. 67 Song et al reported that positive expression of LGALS3 was 97% (427/441) in PTC group and 51% (77/151) in the benign thyroid lesions group. 68 These results may further support the notion that the high level of LGALS3 antigen expression occurs in patients with PTC. There are a number of different types of oncolytic viruses that have been altered from natural viruses in the laboratory such as adenovirus, reovirus, measles virus, herpes simplex

[10] Krüppel-like Factor 3 (KLF3/BKLF) Is Required for Widespread Repression of the Inflammatory Modulator Galectin-3 (Lgals3)*

• Authors: Alexander J. Knights, Jinfen. J. Yik, Hanapi Mat Jusoh, Laura J. Norton, Alister P. W. Funnell et al.
• Year: 2016
• Venue: The Journal of Biological Chemistry
• URL: https://www.semanticscholar.org/paper/dce84b7faec66ad9234b04f596d036ed32078971
• DOI: 10.1074/jbc.M116.715748
• PMID: 27226561
• Citations: 27
• Influential citations: 1
• Summary: It is shown that the zinc finger transcription factor Krüppel-like factor 3 (KLF3) directly represses galectin-3 transcription, and mechanistic insights into the regulation of Lgals3 are provided, demonstrating that C-terminal binding protein (CtBP) is required to drive optimal KLF3-mediated silencing.
• Evidence snippets:
• Snippet 1 (score: 0.725)
  > Despite the importance of galectin-3 in a host of biological settings, little is known about how its gene is activated (32)(33)(34), and to our knowledge, there is no published work on the repression of Lgals3. Here we have shown that galectin-3 expression is up-regulated in the absence of KLF3, and we have demonstrated that KLF3 directly binds and represses the Lgals3 promoter in vivo. Furthermore, we have provided mechanistic insights into KLF3 repression of Lgals3. In reporter assays, a KLF3 mutant that is unable to bind the co-repressor CtBP showed a reduced ability to repress Lgals3. Analysis of the expression levels of Lgals3 in Klf3 Ϫ/Ϫ MEFs rescued with KLF3 or a KLF3 mutant unable to bind to CtBP also showed that KLF3 recruitment of CtBP is necessary for optimal Lgals3 repression. These two lines of evidence suggest that recruitment of the co-repressor CtBP is important for KLF3 repression of Lgals3 but that CtBP-independent mechanisms also exist. We also assessed the contribution of the KLF3 functional domain to repression in Klf3 Ϫ/Ϫ MEF rescue experiments. KLF3 DNA-binding domain only showed only a modest ability to rescue Lgals3 repression when introduced into Klf3 Ϫ/Ϫ MEFs, suggesting that the functional domain (where CtBP binds) is important and also that direct competition for DNA binding to the Lgals3 promoter between KLF3 and the activating KLF1 is not likely to be a major feature of the mechanism of repression.
  > Galectin-3 has been identified as an important regulator of inflammation in metabolic tissues (27). Its deficiency in mice is associated with increased adiposity, systemic inflammation, and an accumulation of inflammatory cells in metabolic tissues (26,28). This phenotype poses a striking contrast to that seen in mice lacking KLF3, which display reduced fat mass and are protected from diet-induced obesity and glucose intolerance (23).

[11] LGALS3 is connected to CD74 in a previously unknown protein network that is associated with poor survival in patients with AML

• Authors: P. Ruvolo, Chenyue W. Hu, Y. Qiu, V. Ruvolo, Robin L. Go et al.
• Year: 2019
• Venue: EBioMedicine
• URL: https://www.semanticscholar.org/paper/46bbdbcb4660389e13acba24499cc415d75f18e0
• DOI: 10.1016/j.ebiom.2019.05.025
• PMID: 31105032
• PMCID: 6604360
• Citations: 25
• Influential citations: 2
• Summary: The data suggest that the LGALS3 network and the CD74 network each support AML cell survival and the two networks may cooperate in a novel high risk AML population.
• Evidence snippets:
• Snippet 1 (score: 0.724)
  > LGALS3 levels correlate with a variety of signaling molecules in blast cells from AML patients RPPA was used to examine correlations of LGALS3 with 230 other proteins. As shown in Fig. 3A, 68 of 231 proteins showed statistically significant (p b 0.0001, R N 0.25) correlation with LGALS3, with positive correlation for 27 total and 10 phospho-proteins and negative correlation for 24 total and 7 phospho-proteins. The strongest positive correlation was with the autophagy protein ATG7. The phospho-proteins positively correlated with LGALS3 included survival kinases such as p-ERK (pY202/pY204), p-AKT (pT308), three phospho-protein variants of PKC delta (i.e. pT507, pS645, and pS664), and p-PKC alpha (pS657) (Fig. 3). LGALS3 expression also positively correlated with phosphorylation of the tyrosine kinase SRC (i.e. pY416 and pY527). The most negatively correlated protein was Single Stranded DNA Binding Protein 2 (SSBP2) (Fig. 3). Among the other proteins negatively correlated with LGALS3 was the members of the PP2A B55 family (PPP2R2A, PPP2R2B, PPP2R2C, and PPP2R2D).
  > Protein network analysis was performed on the set of proteins associated with LGALS3 using String software (String 10.1; website: http:// string-db.org; ref. 38). The network of LGALS3 proteins identified by RPPA are highly associated with a protein:protein enrichment p value b1.0e−16 (Fig. 4) by String. Numerous biological pathways (N = 588) and KEGG pathways (N = 86) associated with LGALS3 network were identified using the String software. Data are presented in Supplemental Table 1 and Supplemental Table 2, respectively.
• Snippet 2 (score: 0.717)
  > However, CD44 is present and interestingly is most elevated in patients with active LGALS3 network and CD74 network (Fig. 8). LGALS3 has been shown to be critical for CD44 endocytosis so LGALS3 would be expected to promote CD44 surface expression [54]. In AML cells with LGALS3 supported CD44 surface expression, CD74 would be predicted to augment signaling mediated by CD44.
  > LGALS3 is well known as an immune regulatory molecule that suppresses host anti-tumor immune surveillance by diverse mechanisms [1,2,55].
  > LGALS3 blocks or at least dampens immune cell function by reducing surface expression of glycosylated T cell receptor in T cells and preventing NK cell receptor binding to antigen [1,2]. LGALS3 has emerged as a critical component in MSC in AML patients to impact response to therapy [56]. It is likely that LGALS3 secreted from MSC and other support cells in the AML microenvironment negatively impacts immune surveillance in AML patients. It is yet to be determined if LGALS3 derived from the leukemia cells plays a role as an immune response inhibitor in AML.
  > LGALS9 is emerging as an important immune checkpoint inhibitor molecule as a TIM-3 binding partner [2,57]. LGALS9 also regulates T cell function as a CD44 binding partner [58]. Whereas LGALS3 binding to CD44 promotes metastasis, LGALS9 binding to CD44 suppresses this process [59,60]. Future RPPA studies to determine the role of LGALS9 and galectins other than LGALS3 are warranted.
  > For the first time, an at risk AML population has been found that is associated with active LGALS3 and active CD74 networks (Fig. 9A and B). At present, it is unclear which if any proteins within the LGALS3 or CD74 networks is driving this phenomenon. CD44, SPP1, and CLPP are highly induced in the patient cohort with both networks active compared to patients with normal-like state (Fig. 8).
• Snippet 3 (score: 0.708)
  > LGALS3 is associated with active Fig. 7. Suppression of LGALS3 does not alter gene expression of LGALS3 network protein genes or CD74 in THP-1 cells. RNA from THP-1 transductant cells with either LKO vector control shRNA or LGALS3 shRNA was isolated, cDNA produced, and mRNA levels of ATG7, LGALS3, ITGAL, CCND3, PRKCA, PARP1, CD74, MYC, CD44, SSBP2, PPP2R2A, CLPP, and B2M were determined by qRT-PCR and levels normalized to ABL-1 as described in "Materials and methods".
  > AKT and MAPK signaling. The protein with the strongest positive correlation with LGALS3 is with ATG7, an autophagy protein that has recently been implicated in maintaining hematopoietic stem cells and serving as a survival factor in AML [46,47]. Recent studies implicate LGALS3 in regulation of autophagy via autophagasome formation, though whether the mechanism involves ATG7 is not clear [48]. Interestingly, phosphorylated PKC delta was positively correlated with LGALS3. PKC delta is viewed as a pro-stress kinase but recent studies suggest that the enzyme has pro-survival properties [49][50][51]. Kinehara and colleagues suggest that PKC delta may act in human pluripotent stem cells as part of a mechanism to regulate stem cell renewal [52]. The data also suggest a novel relationship between LGALS3 and PP2A. The negative correlation of LGALS3 expression with PPP2R2A/B/C/D could reflect LGALS3 suppression of PP2A. The PP2A isoform containing PPP2R2A dephosphorylates both AKT and PKC alpha [53]. Thus, potential suppression of the PP2A subunit by LGALS3 could account for elevated AKT and PKC alpha phosphorylation in samples where LGALS3 expression is elevated.

[12] Phenotypic Switching of Vascular Smooth Muscle Cells in Atherosclerosis

• Authors: Runji Chen, D. McVey, D. Shen, Xiaoxin Huang, Shu Ye
• Year: 2023
• Venue: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
• URL: https://www.semanticscholar.org/paper/472c313e2214a97757712ab0a8b39b133bd6a6bc
• DOI: 10.1161/JAHA.123.031121
• PMID: 37815057
• PMCID: 10757534
• Citations: 133
• Influential citations: 2
• Summary: This review article discusses the 9 VSMC phenotypes that have been reported in atherosclerotic lesions and classifies them into differentiated VSMCs, intermediately dedifferentiated VSMCs, and dedifferentiated VSMCs.
• Evidence snippets:
• Snippet 1 (score: 0.711)
  > Lgals3 (also referred to as galectin-3) is considered a marker of macrophage-like cells. 13,31 Rong et al detected a population of VSMCs that expressed Lgals3 following cholesterol loading in vitro. 31 Recently, Alencar et al found that Lgals3 activation is not a specific marker of the differentiation of VSMCs to a macrophage-like state but rather it is a marker of VSMCs entering a transitional state, with increased expression of genes associated with stem cells that are capable of extracellular matrix remodeling. 16 Of note, similar to SEM-like cells, Lgals3 + cells also have increased expression of lymphocyte antigen 6 family member A and vascular cell adhesion molecule 1. Further studies to investigate if SEM-like cells are derived from Lgals3 + cells are warranted.
  > Using mouse, rat, and human models of cholesterolloading in VSMCs, Li et al found that SREBP1 (sterol regulatory-element binding protein-1) and Krüppel-like factor-15 induced up-and downregulation of Lgals3, respectively, via binding to the Lgals3 gene promoter (albeit at different sites). 45 Likewise, Lgals3 promoted SREBP1 gene expression, producing a feedforward loop upregulated by cholesterol loading. 45 Moreover, Lgals3 and SREBP1 downregulated myocardin-related transcription factor A expression in VSMCs. 45 In another study, Owsiany et al used a dual lineage tracing model and found that Lgals3 + VSMCs produce monocyte chemoattractant protein 1, a proinflammatory chemokine. 15 Knockout of monocyte chemoattractant protein 1 specifically in Lgals3 + VSMCs resulted in the formation of atherosclerotic lesions with a greater ACTA2 content in the fibrous cap and decreased Lgals3 + cell content, a feature of stable plaque. 15

[13] LGALS3 Is a Poor Prognostic Factor in Diffusely Infiltrating Gliomas and Is Closely Correlated With CD163+ Tumor-Associated Macrophages

• Authors: Wan-Ming Hu, Yuan-Zhong Yang, Tian Zhang, Changling Qin, Xuenong Li
• Year: 2020
• Venue: Frontiers in Medicine
• URL: https://www.semanticscholar.org/paper/53b083f91a08aefebb5f9edaaa95625e2dc98f2b
• DOI: 10.3389/fmed.2020.00182
• PMID: 32528967
• PMCID: 7254797
• Citations: 18
• Influential citations: 1
• Summary: LGALS3 was an independent poor prognostic marker in diffusely infiltrating gliomas and was positively correlated with immune cell infiltration, particularly CD163+ tumor-associated macrophages in the TCGA dataset, Rembrandt dataset, and the SYSUCC cohort.
• Evidence snippets:
• Snippet 1 (score: 0.706)
  > In the LGALS family, LGALS3 has a special domain that recognizes and binds to β-galactosides on cellular glycoproteins and glycolipids (5).
  > LGALS3 may be observed in the cytoplasm and in the nucleus as well as the extracellular matrix (6). It serves different biological functions, such as cell growth, cell adhesion, angiogenesis, and apoptosis (7).
  > LGALS3 can be expressed in different types of tumors, and accumulating evidence has proved that LGALS3 plays a vital role in tumorigenesis and development (6,(8)(9)(10)(11)(12)(13)(14)(15)(16). Recently, a study indicated that LGALS3 can promote the therapeutic resistance of glioblastoma and is related to tumor risk and prognosis (17). However, its prognostic significance needs to be further confirmed in large glioma samples, and, hitherto, no studies have explored the role of LGALS3 in the glioma immune microenvironment and its correlation with key molecular markers, including isocitrate dehydrogenase 1 (IDH1), alpha-thalassemia/mental retardation X-linked (ATRX), O-6methylguanine-DNA methyltransferase (MGMT), telomerase reverse transcriptase (TERT), and 1p19q.

[14] Identification of an Internal Gene to the Human Galectin-3 Gene with Two Different Overlapping Reading Frames That Do Not Encode Galectin-3*

• Authors: M. Guittaut, Stéphane Charpentier, Thierry Normand, Martine Dubois, J. Raimond et al.
• Year: 2001
• Venue: The Journal of Biological Chemistry
• URL: https://www.semanticscholar.org/paper/75ca62f4b6eb66b3bcdac062664da410941fdcaa
• DOI: 10.1074/JBC.M002523200
• PMID: 11160123
• Citations: 37
• Influential citations: 6
• Summary: It is demonstrated that these transcripts arise from an internal gene embedded within LGALS3 and named galig (Galectin-3 internal gene), which appears to be tightly regulated and principally activated in leukocytes from peripheral blood.
• Evidence snippets:
• Snippet 1 (score: 0.706)
  > Human Rapid-Scan Gene Expression Panel was used to detect the alternative transcripts in various human tissues using RT-PCR. The primers used were designed to amplify a 923-or 629-bp fragment.
  > LGALS3 transcripts were detected as a 457-bp DNA and actin transcripts as a 640-bp DNA. PCR was performed using 0.25 ng or 2.5 ng (10ϫ) template cDNA.
  > average of other human proteins is 10 times lower. This rich content in tryptophans confers hydrophobic properties that may account for the membrane localization of the ORF2⅐EGFP protein (Fig. 6). Consistent with the mitochondrial localization of the ORF2⅐EGFP fusion protein, this sequence exhibits the common properties of mitochondrial-imported proteins such as the enrichment of arginine, leucine, and serine residues (36).
  > Tissue Specificity of galig Expression-Detection of galig transcripts in HOS cells and colon tumor cells revealed a low expression level. Based on this observation, the rationale that the appearance of galig transcripts may have resulted from a leaky transcription of a cryptic promoter rather than from an independently functioning promoter could not be excluded. Screening of several human tissues indicated clearly that galig is a tightly regulated gene whose expression is most efficient in leukocytes from peripheral blood. The low level of transcription in bone marrow indicates that galig is specifically expressed in mature forms of leukocytes. Whereas the precise quantification of galig mRNA has not been addressed in these experiments, it is clear that these transcripts are much less abundant than LGALS3 transcripts. This may not be surprising considering that LGALS3 is known to be highly expressed when activated (37,38). Indeed, the amount of LGALS3 transcripts appeared as abundant as those from actin genes. This shows a different type of regulation by the galig and LGALS3 promoters. In particular, muscle, stomach, and uterus, although expressing low levels of galig transcripts, revealed no LGALS3 transcripts, thus indicating an independent functioning of the two promoters.

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Asta Literature Retrieval: Literature evidence for LGALS3 (Homo sapiens): LGALS3 has neutrophil chemotaxis (GO:0030593). Gene/protein: LGALS3. O...

This report is retrieval-only and is generated directly from Asta results.

• Papers retrieved: 11
• Snippets retrieved: 20

Relevant Papers

[1] High LGALS3 expression induced by HCP5/hsa-miR-27b-3p correlates with poor prognosis and tumor immune infiltration in hepatocellular carcinoma

• Authors: Yinghui Ren, Yongmei Qian, Qicheng Zhang, Xiaoping Li, Mingjiang Li et al.
• Year: 2024
• Venue: Cancer Cell International
• URL: https://www.semanticscholar.org/paper/552bd37c67dea75d0c33a9a0de2acdafcf0dcf6e
• DOI: 10.1186/s12935-024-03309-1
• PMID: 38643145
• PMCID: 11031979
• Citations: 13
• Summary: It is hypothesized that the HCP5/hsa-miR-27b-3p axis could serve as the most promising LGALS3 regulation mechanism in HCC and the upregulation of LGALS3 via the HCP5/hsa-miR-27b-3p axis is associated with unfavorable prognosis and increased tumor immune infiltration in HCC.
• Evidence snippets:
• Snippet 1 (score: 0.929)
  > To delineate the driving mechanism of LGALS3 for the malignant progression of HCC, the KEGG and GO analysis was conducted.The volcano plot and heatmap showed significantly differentially expressed genes between LGALS3 high-and low-expression groups (Figure S3A-B).The KEGG pathway analysis revealed that these LGALS3-related genes were enriched in the IL-17 signaling pathway, ECM-receptor interaction pathway, central carbon metabolism in cancer pathway, leukocyte transendothelial migration pathway and PI3K-Akt signaling pathway.Meanwhile, the GO analysis revealed that these genes were strongly associated with cell chemotaxis, leukocyte chemotaxis, regulation of leukocyte migration, as well as regulation of chemotaxis (Fig. 5A).Accumulating evidence has proven the immune system has an essential role in malignancy pathogenesis [17], and LGALS3 is closely correlated with CD163 + tumor-associated macrophages (TAM) in glioma [10].Therefore, we studied the association between LGALS3 level and the immune infiltration level in HCC.There was no statistical difference in immune cell infiltration levels over a number of LGALS3 copy numbers (Fig. 5B).Meanwhile, immune infiltration analysis revealed that expression of LGALS3 showed a significant positive association with several immune cell populations, involving CD4 + T cell, CD8 + T cell, B cell, neutrophil, macrophage, dendritic cell, as well as cancer-associated fibroblasts (CAFs) within HCC (Fig. 5C-E).Based on these results, we further evaluated the immune score in HCC patients with high and low LGALS3 expression.The scores of immune cells, including CD4 + T cell, CD8 + T cell, B cell, neutrophil, macrophage, and dendritic cell, were significantly higher in the high LGALS3 expression groups, as shown in Fig. 5F.Chemokines are a group of molecules that are important for the chemotaxis of immune cells [18].
• Snippet 2 (score: 0.910)
  > Chemokines are a group of molecules that are important for the chemotaxis of immune cells [18].According to Table S1, the expression of LGALS3 was statistically positively correlated with several chemokines of immune cells, involving monocytes/macrophages (CCL2, CCL3, CCL5, CCL7, CCL13, CCL17, and CCL22), T lymphocytes (CCL2, CCL1, CCL17, and CCL22), eosinophils (CCL11, CCL26, CCL5, CCL7, CCL13, and CCL3), mast cells (CCR1, CCR2, CCR3, CCR4, CCR5, CXCR2, and CXCR4), and neutrophils (CXCL8).Taken together, these outcomes indicate that LGALS3 is positively associated with immune cell infiltration and cell chemotaxis and could have a crucial function in HCC tumor immune microenvironment.
  > LGALS3 expression correlation and immune cell biomarkers in HCC Next, we wanted to investigate the LGALS3 function in HCC tumor immunity further.Utilizing GEPIA databases, we studied the correlation between LGALS3 expression and immune cell biomarkers within HCC.
• Snippet 3 (score: 0.809)
  > Hepatocellular carcinoma (HCC) is widely recognized for its unfavorable prognosis. Increasing evidence has revealed that LGALS3 has an essential function in initiating and developing several malignancies in humans. Nevertheless, thorough analysis of the expression profile, clinical prognosis, pathway prediction, and immune infiltration of LGALS3 has not been fully explored in HCC. In this study, an initial pan-cancer analysis was conducted to investigate the expression and prognosis of LGALS3. Following a comprehensive analysis, which included expression analysis and correlation analysis, noncoding RNAs that contribute to the overexpression of LGALS3 were subsequently identified. This identification was further validated using HCC clinical tissue samples. TIMER2 and GEPIA2 were employed to examine the correlation between LGALS3 and HCP5 with immunological checkpoints, cell chemotaxis, and immune infiltration in HCC. The R program was applied to analyze the expression distribution of immune score in in HCC patients with high and low LGALS3 expression. The expression profiles of immune checkpoints were also analyzed. Use R to perform GSVA analysis in order to explore potential signaling pathways. First, we conducted pan-cancer analysis for LGALS3 expression level through an in-depth analysis of public databases and found that HCC has a high LGALS3 gene and protein expression level, which were then verified in clinical HCC specimens. Meanwhile, high LGALS3 gene expression is related to malignant progression and poor prognosis of HCC. Univariate and multivariate analyses confirmed that LGALS3 could serve as an independent prognostic marker for HCC. Next, by combining comprehensive analysis and validation on HCC clinical tissue samples, we hypothesize that the HCP5/hsa-miR-27b-3p axis could serve as the most promising LGALS3 regulation mechanism in HCC. KEGG and GO analyses highlighted that the LGALS3-related genes were involved in tumor immunity. Furthermore, we detected a significant positive association between LGALS3 and HCP5 with immunological checkpoints, cell chemotaxis, and immune infiltration. In addition, high LGALS3 expression groups had significantly
• Snippet 4 (score: 0.787)
  > analyses highlighted that the LGALS3-related genes were involved in tumor immunity. Furthermore, we detected a significant positive association between LGALS3 and HCP5 with immunological checkpoints, cell chemotaxis, and immune infiltration. In addition, high LGALS3 expression groups had significantly higher immune cell scores and immune checkpoint expression levels. Finally, GSVA analysis was performed to predict potential signaling pathways linked to LGALS3 and HCP5 in immune evasion and metabolic reprogramming of HCC. Our findings indicated that the upregulation of LGALS3 via the HCP5/hsa-miR-27b-3p axis is associated with unfavorable prognosis and increased tumor immune infiltration in HCC.
• Snippet 5 (score: 0.777)
  > Zhang et al. [14] suggested overexpression of LGALS3 promoted HCC bone metastasis and induced associated skeletal complications.Nevertheless, the expression, prognosis, epigenetic, and molecular regulatory mechanisms of LGALS3 in HCC have been incompletely studied.In addition, LGALS3 relation with immune infiltration in HCC TME has yet to be inadequately investigated.
  > This work began with a pan-cancer study of LGALS3 expression and its predictive value in a variety of human malignancies.We further explored the LGALS3 potential upstream regulatory noncoding RNAs (ncRNAs) involving microRNAs (miRNAs) as well as long noncoding RNAs (lncRNAs) throughout HCC.Subsequently, in HCC, a correlation analysis was investigated between LGALS3 and tumor immunity-related indicators involving cell chemotaxis, immune checkpoints, immune cell biomarkers, and infiltration.Eventually, the association between the expression of LGALS3 and signaling pathways was examined in HCC.Findings demonstrated that LGALS3 might have a role in the malignancy of HCC and immune cell infiltration via the HCP5/hsa-miR-27b-3p/ LGALS3 axis, suggesting that a novel HCP5/hsa-miR-27b-3p/LGALS3 axis could be a biomarker for prognosis and treatment target for HCC patients.
• Snippet 6 (score: 0.750)
  > LGALS3 has a crucial function in mediating cell adhesion as well as cell-cell interaction by recognizing complex carbohydrates on the surface of cells [22,23], as well as regulates cell apoptosis, autophagy, and inflammation [24,25].Interestingly, recent studies suggested that LGALS3 involves in essential cancer-related mechanisms, including cellular metabolism, carcinogenesis, metastasis, neoplasia, angiogenesis, as well as immune escape [26][27][28].In addition, LGALS3 is highly expressed and implicated in different cancer types progression such as HCC, gastric, colorectal, pancreatic carcinomas, melanomas or glioblastomas and breast cancer [29,30].Indeed, LGALS3 has been considered a potential marker for these malignancies.Interestingly, LGALS3, which is differentially expressed in different cancers, has been shown to exhibit tumor suppressor activity in certain cancer types.The different roles of LGALS3 may be attributed to different potential mechanisms that appear cancer-type dependent.The different locations and mutations of LGALS3 also contribute to its various functions.However, LGALS3 remains inadequately understood in HCC and requires further investigation.First, we conducted an extensive investigation of the expression profile, clinical prognosis, and pathologic stage of LGALS3 in HCC through an in-depth analysis of the public database.On the basis of TCGA and CPTAC datasets, we found that LGALS3 gene and protein expression was elevated in HCC tissues.Moreover, the OS and DSS were lesser in patients with HCC having higher expression levels of LGALS3 contrasted to those with low expression levels of LGALS3 based on GEPIA2 and Kaplan-Meier plotter datasets.Meanwhile, the expression of LGALS3 within HCC was significantly associated with the advanced tumor stage and grade, indicating that elevated LGALS3 expression could increase tumor progression.Song et al. [31] indicated that galectin-3 promoted HCC tumorigenesis and metastasis via β-catenin signalling in vitro and in vivo.
• Snippet 7 (score: 0.707)
  > Next, the prognostic value of LGALS3 expression in the 23 kinds of cancer patients was then determined.Correlations between LGALS3 expression with OS (overall survival) were evaluated using the GEPIA2 database.In the OS study, only elevated LGALS3 expression indicated poorer survival for HCC patients (Fig. 2A).LGALS3 was not statistically significant for OS of 22 other cancer types patients.Furthermore, DSS (disease-specific survival) LGALS3 in predicting 1-, 3-, and 5-year OS. (H) ROC curve for LGALS3 in predicting 1-, 3-, and 5-year DSS.The higher values of AUC corresponding to higher predictive power.p value < 0.05; **p value < 0.001 was lesser in patients suffering from HCC having higher levels of LGALS3 expression (Fig. 2B).Next, we validated the expression levels of LGALS3 protein in HCC tissues using IF staining.As expected, HCC tumor demonstrated strong LGALS3 expression (Fig. 2C).These findings were further validated by qRT-PCR assay of tumor and adjacent normal tissues from 5 HCC patients.Here, LGALS3 expression was also significantly increased in the HCC tissues (Fig. 2D).In addition, LGALS3 expression was shown to be linked with the pathological stage of HCC, as illustrated in Fig. 2E.High expression of LGALS3 gene is associated with high tumor grade in HCC (Fig. 2F).Moreover, LGALS3 expression was significantly associated with OS and DSS in both univariate and multivariate analyses (Figure S2A-H).Time-dependent ROC analysis showed that the area under the ROC curve was 0.672 at 5 years of OS, and 0.691 at 5 years of DSS (Fig. 2G-H).Taken together, LGALS3 might function as a prospective biomarker for the prognosis of patients suffering from HCC.

[2] Combined High—Throughput Proteomics and Random Forest Machine-Learning Approach Differentiates and Classifies Metabolic, Immune, Signaling and ECM Intra-Tumor Heterogeneity of Colorectal Cancer

• Authors: C. Contini, B. Manconi, A. Olianas, Giulia Guadalupi, Alessandra Schirru et al.
• Year: 2024
• Venue: Cells
• URL: https://www.semanticscholar.org/paper/b7d8516d42c8108cbdf59e6865a8fb424c450946
• DOI: 10.3390/cells13161311
• PMID: 39195201
• PMCID: 11352245
• Citations: 6
• Summary: Different metabolic strategies appeared to be adopted by the two CRC regions to uncouple the Krebs cycle and cytosolic glucose metabolism, promote lipogenesis, promote amino acid synthesis, down-regulate bioenergetics in mitochondria, and up-regulate oxidative stress.
• Evidence snippets:
• Snippet 1 (score: 0.832)
  > The regulatory activity on the cytoskeleton carried out by N-WASP is fundamental for the motility of leukocytes. CgA and Gal-3 are associated with GO annotations concerning the chemotaxis of immune cells, including GO:0002551 "mast cell chemotaxis", GO:0002548 "monocyte chemotaxis", and GO:0030593 "neutrophil chemotaxis".

[3] Pregnancy Galectinology: Insights Into a Complex Network of Glycan Binding Proteins

• Authors: S. Blois, G. Dveksler, G. Vasta, N. Freitag, V. Blanchard et al.
• Year: 2019
• Venue: Frontiers in Immunology
• URL: https://www.semanticscholar.org/paper/68fad2b87411701fa708a1f49f8b918370486857
• DOI: 10.3389/fimmu.2019.01166
• PMID: 31231368
• PMCID: 6558399
• Citations: 56
• Influential citations: 7
• Summary: The relevance of galectin-glycan interactions as potential therapeutic targets in pregnancy disorders is discussed and the importance of angiogenesis during decidualization and in placenta formation is discussed.
• Evidence snippets:
• Snippet 1 (score: 0.770)
  > Lgals3 has been implicated in the regulation of innate and adaptive immune responses, where it participates in the activation or differentiation of immune cells and contributes to phagocytic clearance of microorganisms and apoptotic cells by macrophages (117,118). Lgals3 has been reported to promote but also to inhibit T-cell apoptosis depending on whether it binds to glycoproteins on the cell surface (CD45 and CD71) or to intracellular ligands (Bcl-2) (119, 120). In the placenta, Lgals3 was detected in all trophoblastic lineages including villous cytotrophoblasts (CTB) and EVT with a reduction of Lgals3 expression observed from the VT to the trophoblastic cell columns (121). This pattern of Lgals3 expression correlates with the switch from a proliferative to a migratory trophoblast phenotype and while placental Lgals3 dysregulation has been associated with some obstetric complications including spontaneous or recurrent miscarriages, further studies are needed to understand its contribution to trophoblast biology (81,122). In addition to trophoblasts, Lgals3 is expressed by maternal decidual cells (73). While showing a different expression pattern, both Lgals1 and Lgals3 have been proposed to play a role in cell-cell and cell-matrix interactions of trophoblast during placentation (121). Studies of the importance of Lgals3 in murine pregnancy by Yang et al. indicate that Lgals3 is expressed in the luminal and glandular epithelium and that an increase in Lgals3 is required for proper embryo implantation (123). In addition, Lgals3 affects chemotaxis and morphology of endothelial cells and stimulates capillary tube formation and angiogenesis in vivo (124). Therefore, besides its proposed roles in embryo implantation, immune regulation and trophoblast-matrix interactions, Lgals3 has a potential role in placental angiogenesis.

[4] Macrophages secrete murinoglobulin-1 and galectin-3 to regulate neutrophil degranulation after myocardial infarction

• Authors: Upendra Chalise, M. Daseke, William J. Kalusche, Shelby R. Konfrst, Jocelyn R. Rodriguez-Paar et al.
• Year: 2022
• Venue: Molecular Omics
• URL: https://www.semanticscholar.org/paper/446873a6222f1a5c4299cb80c95f7f9ff792e9f8
• DOI: 10.1039/d1mo00519g
• PMID: 35230372
• PMCID: 8963000
• Citations: 18
• Summary: In conclusion, macrophages at MI day 1 secrete MUG1 to limit and Lgals3 to accentuate neutrophil degranulation to regulate infarct wall thinning.
• Evidence snippets:
• Snippet 1 (score: 0.761)
  > while Lgals3 increased at MI day 7. The ratio of MUG1 to Lgals3 positively correlated with infarct wall thickness, revealing that MUG1 attenuated infarct wall thinning. In conclusion, macrophages at MI day 1 secrete MUG1 to limit and Lgals3 to accentuate neutrophil degranulation to regulate infarct wall thinning.
• Snippet 2 (score: 0.750)
  > Inflammation presides early after myocardial infarction (MI) as a key event in cardiac wound healing. Ischemic cardiomyocytes secrete inflammatory cues to stimulate infiltration of leukocytes, predominantly macrophages and neutrophils. Infiltrating neutrophils degranulate to release a series of proteases including matrix metalloproteinase (MMP)-9 to break down extracellular matrix and remove necrotic myocytes to create space for the infarct scar to form. While neutrophil to macrophage communication has been explored, the reverse has been understudied. We used a proteomics approach to catalogue the macrophage secretome at MI day 1. Murinoglobulin-1 (MUG1) was the highest-ranked secreted protein (4.1-fold upregulated at MI day 1 vs. day 0 pre-MI cardiac macrophages, p = 0.004). By transcriptomics evaluation, galectin-3 (Lgals3) was 2.2-fold upregulated (p = 0.008) in MI day 1 macrophages. We explored the direct roles of MUG1 and Lgals3 on neutrophil degranulation. MUG1 blunted while Lgals3 amplified neutrophil degranulation in response to phorbol 12-myristate 13-acetate or interleukin-1β, as measured by MMP-9 secretion. Lgals3 itself also stimulated MMP-9 secretion. To determine if MUG1 regulated Lgals3, we co-stimulated neutrophils with MUG1 and Lgals3. MUG1 limited degranulation stimulated by Lgals3 by 64% (p < 0.001). In vivo, MUG1 was elevated in the infarct region at MI days 1 and 3, while Lgals3 increased at MI day 7. The ratio of MUG1 to Lgals3 positively correlated with infarct wall thickness, revealing that MUG1 attenuated infarct wall thinning. In conclusion, macrophages at MI day 1 secrete MUG1 to limit and Lgals

[5] Mutation of the galectin‐3 glycan‐binding domain ( Lgals3‐R200S) enhances cortical bone expansion in male mice and trabecular bone mass in female mice

• Authors: Kevin A. Maupin, Daniel T. Dick, Vari Vivarium, Transgenics Core, B. Williams
• Year: 2020
• Venue: FEBS Open Bio
• URL: https://www.semanticscholar.org/paper/6ab62ea9acc6fef617d0b1f237c1a477f45b05c7
• DOI: 10.1002/2211-5463.13483
• PMID: 36062328
• PMCID: 9527582
• Citations: 2
• Summary: The results suggest that the trabecular bone phenotype of Lgals3-KO mice was driven primarily by loss of extracellular galectin-3, while the cortical bone phenotypeof Lgal3- KO mice may have also been influenced by Loss of intracellular galECTin- 3.
• Evidence snippets:
• Snippet 1 (score: 0.728)
  > The study of galectin-3 is complicated by its ability to function both intracellularly and extracellularly. While the mechanism of galectin-3 secretion is unclear, studies have shown that the mutation of a highly conserved arginine to a serine in human galectin-3 (LGALS3-R186S) blocks glycan binding and secretion. To gain insight into the roles of extracellular and intracellular functions of galectin-3, we generated mice with the equivalent mutation (Lgals3-R200S) using CRISPR/Cas9-directed homologous recombination. Consistent with a reduction in galectin-3 secretion, we observed significantly reduced galectin-3 protein levels in the plasma of heterozygous and homozygous mutant mice. We observed a similar increased bone mass phenotype in Lgals3-R200S mutant mice at 36 weeks as we previously observed in Lgals3-KO mice with slight variation. Like Lgals3-KO mice, Lgals3-R200S females, but not males, had significantly increased trabecular bone mass. However, only male Lgals3-R200S mice showed increased cortical bone expansion, which we had previously observed in both male and female Lgals3-KO mice and only in female mice using a separate Lgals3 null allele (Lgals3). These results suggest that the trabecular bone phenotype of Lgals3-KO mice was driven primarily by loss of extracellular galectin-3. However, the cortical bone phenotype of Lgals3-KO mice may have also been influenced by loss of intracellular galectin-3. Future analyses of these mice will aid in identifying the cellular and molecular mechanisms that contribute to the Lgals3-deficient bone phenotype as well as aid in distinguishing the extracellular vs. intracellular roles of galectin-3 in various signaling pathways.

[6] An Inflammation-Immunity Classifier of 11 Chemokines for Prediction of Overall Survival in Head and Neck Squamous Cell Carcinoma

• Authors: Yushan Liang, Guofei Feng, S. Zhong, Xiaoyu Gao, Yan Tong et al.
• Year: 2019
• Venue: Medical Science Monitor : International Medical Journal of Experimental and Clinical Research
• URL: https://www.semanticscholar.org/paper/ca1a2988b75211cc5296d7fc979460ada97a48d4
• DOI: 10.12659/MSM.915248
• PMID: 31203306
• PMCID: 6592142
• Citations: 5
• Summary: This 11-chemokine signature could serve as a reliable prognostic tool for HNSC patients and might be useful to guide individualized treatment or even gene target therapy for high-risk patients.
• Evidence snippets:
• Snippet 1 (score: 0.728)
  > Gene functional analysis indicated 29 GO terms and 4 KEGG pathways which these 11 chemokines were enriched in (Figure 4A, 4B). The main 9 participating GO terms contained chemokine-mediated (GO: 0070098), inflammatory response (GO: 0006954), cellular response to interleukin-1 (GO: 00071347), neutrophil chemotaxis (GO: 0030593), cellular response to tumor necrosis factor (GO: 0071356), lymphocyte chemotaxis (GO: 0048247), monocyte chemotaxis (GO: 0002548), chemokine activity (GO: 0008009), and CCR chemokine receptor (GO: 0048020). The key involved KEGG pathways were chemokine signaling pathway (Kegg: 04062), cytokinecytokine receptor (Kegg: 04060), NOD-like receptor signaling pathway (Kegg: 04621), and Malaria (Kegg: 05144).

[7] LGALS3 is connected to CD74 in a previously unknown protein network that is associated with poor survival in patients with AML

• Authors: P. Ruvolo, Chenyue W. Hu, Y. Qiu, V. Ruvolo, Robin L. Go et al.
• Year: 2019
• Venue: EBioMedicine
• URL: https://www.semanticscholar.org/paper/46bbdbcb4660389e13acba24499cc415d75f18e0
• DOI: 10.1016/j.ebiom.2019.05.025
• PMID: 31105032
• PMCID: 6604360
• Citations: 25
• Influential citations: 2
• Summary: The data suggest that the LGALS3 network and the CD74 network each support AML cell survival and the two networks may cooperate in a novel high risk AML population.
• Evidence snippets:
• Snippet 1 (score: 0.727)
  > LGALS3 is associated with active Fig. 7. Suppression of LGALS3 does not alter gene expression of LGALS3 network protein genes or CD74 in THP-1 cells. RNA from THP-1 transductant cells with either LKO vector control shRNA or LGALS3 shRNA was isolated, cDNA produced, and mRNA levels of ATG7, LGALS3, ITGAL, CCND3, PRKCA, PARP1, CD74, MYC, CD44, SSBP2, PPP2R2A, CLPP, and B2M were determined by qRT-PCR and levels normalized to ABL-1 as described in "Materials and methods".
  > AKT and MAPK signaling. The protein with the strongest positive correlation with LGALS3 is with ATG7, an autophagy protein that has recently been implicated in maintaining hematopoietic stem cells and serving as a survival factor in AML [46,47]. Recent studies implicate LGALS3 in regulation of autophagy via autophagasome formation, though whether the mechanism involves ATG7 is not clear [48]. Interestingly, phosphorylated PKC delta was positively correlated with LGALS3. PKC delta is viewed as a pro-stress kinase but recent studies suggest that the enzyme has pro-survival properties [49][50][51]. Kinehara and colleagues suggest that PKC delta may act in human pluripotent stem cells as part of a mechanism to regulate stem cell renewal [52]. The data also suggest a novel relationship between LGALS3 and PP2A. The negative correlation of LGALS3 expression with PPP2R2A/B/C/D could reflect LGALS3 suppression of PP2A. The PP2A isoform containing PPP2R2A dephosphorylates both AKT and PKC alpha [53]. Thus, potential suppression of the PP2A subunit by LGALS3 could account for elevated AKT and PKC alpha phosphorylation in samples where LGALS3 expression is elevated.
• Snippet 2 (score: 0.725)
  > Thus, potential suppression of the PP2A subunit by LGALS3 could account for elevated AKT and PKC alpha phosphorylation in samples where LGALS3 expression is elevated. Induction of PPP2R2A protein (Fig. 5) but not gene expression (Fig. 7) in THP-1 cells expressing LGALS3 shRNA suggests that LGALS3 acts directly on the PP2A subunits via a post-transcriptional mechanism in these cells. The TCGA data (Table 3) however suggests that there is a positive correlation between gene expression of LGALS3 and PPP2R2A suggesting that a common pathway may regulate the two genes. Fig. 8. Progeny clustering identified an optimal number of 4 distinct protein clusters for this ProFnGrp. Protein networks were generated and showed interactions between "core-proteins" (large nodes) and other probed proteins (small nodes) from the data set. Clustering method has been described in our previous publication (ref. [37]) and further information on these protein networks can be found on our website "Leukemia Profile Atlases", available at https://www.leukemiaatlas.org/. Progeny clustering identified one protein cluster with expression similar to that of the normal CD34+ samples which was designated as "normal-state" while three "leukemia-specific" protein patterns characterized by high expression individually of CD74, LGAL3, and a fourth state with both on. PPP2RA/B/C/D was the only LGALS3 network protein demonstrated to be directly regulated by LGALS3 in the THP-1 cells (Fig. 5). In our previous study we saw potent suppression of AKT signaling by LGALS3 inhibition, so perhaps the mechanism involves LGALS3 suppression of the AKT phosphatase [15]. However, we did not see suppression of LGALS3 affect other network proteins in the THP-1 cells (data not shown). The role of other galectins such as LGALS1 in AML biology is not clear.

[8] Morphological and transcriptional insights into the role of histone phosphorylation-related genes in early development of the chicken duodenum

• Authors: Xiaofeng Li, Bing Yang
• Year: 2025
• Venue: Animal Bioscience
• URL: https://www.semanticscholar.org/paper/b3da4d3a37ec0fae40140d0cf95db98d90b41079
• DOI: 10.5713/ab.25.0108
• PMID: 40506039
• PMCID: 12580959
• Citations: 1
• Summary: A novel paradigm wherein histone phosphorylation coordinates intestinal morphogenesis is established, providing mechanistic insights for optimizing poultry intestinal health and nutritional strategies.
• Evidence snippets:
• Snippet 1 (score: 0.725)
  > Notably, as broilers age (from D0 to D7), the intestinal VH increases accordingly, indicating a positive balance between intestinal cell proliferation and apoptosis (i.e., cell proliferation predominates over apoptosis). Through transcriptional network analysis, we identified eight histone phosphorylation-associated hub genes (LGALS3, ITGB2, IRF7, SOCS3, CSF1R, KIF23, SMC2, and DLGAP5) that mechanistically link epigenetic regulation to developmental programming.
  > LGALS3 (galectin-3) plays critical roles in macrophage chemotaxis, mucosal barrier maintenance, intestinal epithelial cell (IEC) apoptosis regulation, and inflammatory responses [21][22][23]. Our study revealed a 6.59-fold increase in LGALS3 gene expression in the duodenum at D7 compared to D0 (Supplement 6), with functional analysis confirming its involvement in macrophage chemotaxis (Supplement 7). These findings align with Sun et al [21], who reported that LGALS3 silencing in necrotizing enterocolitis models inhibited the TLR4/NF-κB pathway, subsequently reducing IEC apoptosis and inflammation [21]. Emerging evidence further suggests LGALS3' s protective functions through ER stress modulation, autophagy regulation, and inflammasome control in intestinal Behçet' s disease [22], along with its capacity to upregulate key mucosal barrier components (MUC2, Occludin, and ZO-1) [23]. Collectively, these observations suggest LGALS3 promotes duodenal development through: 1) mucosal barrier reinforcement via tight junction protein upregulation, 2) inflammatory control through TLR4/NF-κB-mediated macrophage regulation, and 3) cellular homeostasis maintenance via ER stress/autophagy pathways.

[9] Periplocin suppresses the growth of colorectal cancer cells by triggering LGALS3 (galectin 3)-mediated lysophagy

• Authors: Kui Wang, Shuyue Fu, Lixia Dong, Dingyue Zhang, Mao Wang et al.
• Year: 2023
• Venue: Autophagy
• URL: https://www.semanticscholar.org/paper/3dadfc351823c4e325e65c171ab3765871189c80
• DOI: 10.1080/15548627.2023.2239042
• PMID: 37471054
• Citations: 35
• Influential citations: 2
• Summary: It is shown that periplocin exhibits promising anticancer activity against CRC both in vitro and in vivo, and is indicated as a potential therapeutic option for the treatment of CRC.
• Evidence snippets:
• Snippet 1 (score: 0.714)
  > Scale bar: 10 μm. (I) Immunofluorescent analysis of the colocalization of LGALS3 with ubiquitin in CRC cells treated with or without 0.50 μM periplocin for 24 h. Scale bar: 10 μm. (J) Representative fluorescent images of CRC cells transiently expressing Mrfp-GFP-tandem fluorescent-tagged LGALS3 (tfGal3) followed by 0.50 μM periplocin treatment for 24 h. Scale bar: 10 μm. (K) Quantitative analysis of the GFP + RFP + or GFP − RFP + LGALS3 puncta in (J). (L) the relative decreased ratio of Magic Red intensity, relative increased ratio of LysoSensor Blue intensity, relative increased ratio of the interaction between LGALS3 and TRIM16, and relative increased ratio of LC3B-II protein level in DLD-1 cells following 0.50 μM periplocin treatment at different time periods. Results are representative of three independent experiments. Data are presented as mean ± SD. P < 0.05, P < 0.01, **P < 0.001. for LGALS3 degradation, we generated lysine to arginine mutants of LGALS3 at K196 or Lys210 (LGALS3 K196R or LGALS3 K210R ). As shown in Figure 6I, the ubiquitinconjugated level of LGALS3 K196R mutant was comparable to the wild type (WT), whereas K210 mutation significantly decreased LGALS3 ubiquitination. These results suggest that periplocin elevates LGALS3 level by preventing K210 ubiquitination and proteasomal degradation. In addition, periplocin was found to stabilize the protein level of LGALS3 against thermal changes using a cellular thermal shift assay (CETSA) (Figure 6J,K), implying the binding of periplocin with LGALS3.
• Snippet 2 (score: 0.710)
  > We next investigated the mechanism underlying periplocinmediated lysophagy. The expression of LGALS3, a key lysophagy marker [46], was found to be upregulated following periplocin treatment as evidenced by immunofluorescent staining (Figure 2M). To this end, we presumed that periplocin-induced lysophagy might be attributable to the upregulation of LGALS3. Indeed, periplocin treatment prominently elevated the protein level of LGALS3 as evidence by immunoblotting analysis (Figure 6A). The increased protein level of LGALS3 was further confirmed in tumor xenografts from periplocin-treated mice (Figure 6B,C). However, no obvious change was observed on the mRNA level of LGALS3 in periplocin-treated cells compared with controls (Figure S6A), suggesting that transcriptional regulation was not involved in increased LGALS3 expression following periplocin treatment. Therefore, we postulated that periplocin might elevate LGALS3 by regulating protein stability. Of note, cycloheximide (CHX, a translational inhibitor) treatment led to an obvious decrease in LGALS3 protein level in control cells, but had no obvious effect on the upregulated protein level of LGALS3 in periplocin-treated cells, suggesting periplocin maintains LGALS3 stability (Figure 6D,E). In support of this, treatment with MG132 (a proteasome inhibitor) failed to further enhance the protein level of LGALS3 in response to periplocin treatment (Figure 6F,G). These data suggest that periplocin may prevent proteasomal degradation of LGALS3.
  > We therefore measured the effect of periplocin on LGALS3 ubiquitination. As shown in Figure 6H, periplocin markedly decreased the ubiquitin-conjugated level of LGALS3.

[10] Thyroid malignant neoplasm-associated biomarkers as targets for oncolytic virotherapy

• Authors: Mi Guan, Yanping Ma, S. Shah, G. Romano
• Year: 2016
• Venue: Oncolytic Virotherapy
• URL: https://www.semanticscholar.org/paper/9f79d851e32ad25e83c0a2d64e12919bf81a89f8
• DOI: 10.2147/OV.S99856
• PMID: 27579295
• PMCID: 4996252
• Citations: 4
• Summary: This review focuses on the strategy of biomarkers for the production of novel TMN oncolytic therapeutics, which may improve the specificity of targeting of tumor cells and limit adverse effects in patients.
• Evidence snippets:
• Snippet 1 (score: 0.713)
  > The Galectin-3 (LGALS3) is a protein that is encoded by a single gene, LGALS3, located on chromosome 14, locus q21-q22. 63 The molecular weight of this protein is ∼30 kDa, and it contains a carbohydrate-recognition-binding domain of ∼130 amino acids that enable the specific binding of β-galactosides. This protein localizes to the extracellular matrix, the cytoplasm, and the nucleus. It plays a role in numerous cellular functions including cell adhesion, cell activation and chemoattraction, cell growth, differentiation, cell cycle, apoptosis, innate immunity, cell adhesion, and T-cell regulation. 63,64 It has been known that LGALS3 is distributed widely around the tissues but in a low level.
  > To date, LGALS3 has been extensively studied as an IHC marker of thyroid malignancy, and a high diagnostic accuracy has been reported even for difficult pathological diagnoses. 64 Feilchenfeldt et al reported that the mRNA levels of LGALS3 and thyroglobulin in 28 benign and 31 malignant thyroid samples were quantified by real-time PCR. The LGALS3 expression at the mRNA was 60% (12/20) and the protein level was 100% (8/8), respectively. 65 The positive rate was 84% (41/49) when combined with the LGALS3 and HBME-1 in PTC specimens. 66 Two groups of researchers have detected the LGALS3 by IHC in PTC specimens. Saleh et al have shown that the sensitivity and the specificity for LGALS3 were 92.3% and 77.3%, respectively. 67 Song et al reported that positive expression of LGALS3 was 97% (427/441) in PTC group and 51% (77/151) in the benign thyroid lesions group. 68 These results may further support the notion that the high level of LGALS3 antigen expression occurs in patients with PTC. There are a number of different types of oncolytic viruses that have been altered from natural viruses in the laboratory such as adenovirus, reovirus, measles virus, herpes simplex

[11] In-depth quantitative proteomics analysis revealed C1GALT1 depletion in ECC-1 cells mimics an aggressive endometrial cancer phenotype observed in cancer patients with low C1GALT1 expression

• Authors: A. Montero‐Calle, Á. López-Janeiro, Marta L. Mendes, Daniel Perez-Hernandez, Irene Echevarría et al.
• Year: 2023
• Venue: Cellular Oncology
• URL: https://www.semanticscholar.org/paper/92b64e01bcb30f7457ddb8cc4be26de8b0c7cf69
• DOI: 10.1007/s13402-023-00778-w
• PMID: 36745330
• PMCID: 10205863
• Citations: 19
• Summary: C1GALT1 stably depleted ECC-1 cells mimic an EC aggressive phenotype observed in patients and might be useful for the identification and validation of EC markers of progression.
• Evidence snippets:
• Snippet 1 (score: 0.711)
  > Finally, since LGALS3 (Galectin-3) has been shown to interact with O-glycans in the mucosal epithelium [30], and considering its overexpression observed by proteomics and further confirmed by PCR and WB analyses upon depletion of C1GALT1, we focused on the role of LGALS3 in EC by IHC.
  > A total of 151 out of 178 cores from 79 EC patients were considered adequate for LGALS3 expression assessment by IHC. Morphologic assessment of LGALS3 IHC staining characteristics revealed different staining patterns (Fig. 5 A). Out of the 151 evaluable cores, 45 (29.8%) showed absent LGALS3 expression. LGALS3 positive samples showed variable and low intensity protein expression (mean positive tumor cells per sample = 35.4%). A small subset of cores (13/151, 8.6%) demonstrated diffuse (> 90% positive tumor cells per sample) staining. LGALS3 score varied across histologic types, with serous and undifferentiated tumors displaying the highest protein expression (median IHC LGALS3 score = 10, 20, 50 and 55 for endometrioid, clear cell, serous and undifferentiated tumor types, respectively) (Fig. 5B). Interestingly, the aggressive histologic variants (clear cell, serous and undifferentiated) showed higher LGALS3 IHC scores than endometrioid variants (p value < 0.001). In addition, LGALS3 expression positively correlated with tumor grade. High grade tumors (G3) displayed higher protein expression (median LGALS3 IHC score = 30) compared to low grade tumors (median LGALS3 IHC score for G1/G2 tumors = 10). This finding was independent of histologic type, as similar results were observed when analyzing endometrioid tumors.
  > Finally, we interrogated the correlation between the expression levels of LGALS3 and C1GALT1.

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Asta Literature Retrieval: Literature evidence for LGALS3 (Homo sapiens): LGALS3 has extracellular matrix (GO:0031012). Gene/protein: LGALS3. Or...

This report is retrieval-only and is generated directly from Asta results.

• Papers retrieved: 16
• Snippets retrieved: 20

Relevant Papers

[1] Mutation of the galectin‐3 glycan‐binding domain ( Lgals3‐R200S) enhances cortical bone expansion in male mice and trabecular bone mass in female mice

• Authors: Kevin A. Maupin, Daniel T. Dick, Vari Vivarium, Transgenics Core, B. Williams
• Year: 2020
• Venue: FEBS Open Bio
• URL: https://www.semanticscholar.org/paper/6ab62ea9acc6fef617d0b1f237c1a477f45b05c7
• DOI: 10.1002/2211-5463.13483
• PMID: 36062328
• PMCID: 9527582
• Citations: 2
• Summary: The results suggest that the trabecular bone phenotype of Lgals3-KO mice was driven primarily by loss of extracellular galectin-3, while the cortical bone phenotypeof Lgal3- KO mice may have also been influenced by Loss of intracellular galECTin- 3.
• Evidence snippets:
• Snippet 1 (score: 0.870)
  > The study of galectin-3 is complicated by its ability to function both intracellularly and extracellularly. While the mechanism of galectin-3 secretion is unclear, studies have shown that the mutation of a highly conserved arginine to a serine in human galectin-3 (LGALS3-R186S) blocks glycan binding and secretion. To gain insight into the roles of extracellular and intracellular functions of galectin-3, we generated mice with the equivalent mutation (Lgals3-R200S) using CRISPR/Cas9-directed homologous recombination. Consistent with a reduction in galectin-3 secretion, we observed significantly reduced galectin-3 protein levels in the plasma of heterozygous and homozygous mutant mice. We observed a similar increased bone mass phenotype in Lgals3-R200S mutant mice at 36 weeks as we previously observed in Lgals3-KO mice with slight variation. Like Lgals3-KO mice, Lgals3-R200S females, but not males, had significantly increased trabecular bone mass. However, only male Lgals3-R200S mice showed increased cortical bone expansion, which we had previously observed in both male and female Lgals3-KO mice and only in female mice using a separate Lgals3 null allele (Lgals3). These results suggest that the trabecular bone phenotype of Lgals3-KO mice was driven primarily by loss of extracellular galectin-3. However, the cortical bone phenotype of Lgals3-KO mice may have also been influenced by loss of intracellular galectin-3. Future analyses of these mice will aid in identifying the cellular and molecular mechanisms that contribute to the Lgals3-deficient bone phenotype as well as aid in distinguishing the extracellular vs. intracellular roles of galectin-3 in various signaling pathways.
• Snippet 2 (score: 0.808)
  > We previously observed that genomic loss of galectin-3 (Gal-3; encoded by Lgals3) in mice has a significant protective effect on age-related bone loss. Gal-3 has both intracellular and extracellular functionality, and we wanted to assess whether the affect we observed in the Lgals3 knockout (KO) mice could be attributed to the ability of Gal-3 to bind glycoproteins. Mutation of a highly conserved arginine to a serine in human Gal-3 (LGALS3-R186S) blocks glycan binding and secretion. We generated mice with the equivalent mutation (Lgals3-R200S) and observed a subsequent reduction in Gal-3 secretion from mouse embryonic fibroblasts and in circulating blood. When examining bone structure in aged mice, we noticed some similarities to the Lgals3-KO mice and some differences. First, we observed greater bone mass in Lgals3-R200S mutant mice, as was previously observed in Lgals3-KO mice. Like Lgals3-KO mice, significantly increased trabecular bone mass was only observed in female Lgals3-R200S mice. These results suggest that the greater bone mass observed is driven by the loss of extracellular Gal-3 functionality. However, the results from our cortical bone expansion data showed a sex-dependent difference, with only male Lgals3-KO mice having an increased response, contrasting with our earlier study. These notable sex differences suggest a potential role for sex hormones, most likely androgen signaling, being involved. In summary, our results suggest that targeting extracellular Gal-3 function may be a suitable treatment for age-related loss of bone mass.
  > Galectin-3 (Gal-3; encoded by Lgals3) is a protein that functions outside the cell to regulate glycoprotein secretion and turnover [1,2] and intracellularly in protein chaperoning and mRNA splicing [3,4]. We previously found that genomic deletion of Gal-3 in mice (Lgals3-KO) protects the mice against age-related [5] or sex-hormone deprivation bone loss [6]. A better understanding of the
• Snippet 3 (score: 0.804)
  > expansion in males) likely reflect the role of extracellular Gal-3 loss in increasing bone mass. Conversely, the differences between the two models (tissue stiffness and lack of female cortical bone expansion) could reflect the role of intracellular Gal-3.
  > The female dominance of the cortical bone expansion in Lgals3-KO mice was further supported using a separate Lgals3 null allele (Lgals3-Δ), where females once again had significantly increased trabecular and cortical bone mass at 36 weeks, but male Lgals3-Δ had slight reductions in both cortical and trabecular bone mass. The apparent sex-dependency of the bone phenotype was most likely due to diminished bone mass accrual in Lgals3-KO males before 12 week of age [5,41], which led us to speculate that Lgals3-KO mice might have reduced androgen-induced cortical bone expansion during puberty [42].
  > However, in Lgals3-R200S mice, we observed a male dominant phenotype in cortical bone expansion. Our gonadectomy study suggested that global loss of Gal-3 may lead to reduced bioavailability of androgens [6]. This would reduce the ability of androgen to support bone mass accrual during puberty [42]. Altered sexhormone regulation in the Lgals3-KO mother during fetal development might also explain why a different skeletal phenotype (increased age-related bone loss) has been reported when comparing Lgals3-KO mice to litters of background matched wildtype-mice [43]. Studies looking at systemic changes in hormones and growth factors in Lgals3-KO and Lgals3-R200S mice would help answer this question. In addition, conditional knockout of Lgals3 at later developmental stages, such as pre-and postpuberty or in aged mice, and studies of pre-and postpubescent Lgals3-R200S mouse cortical bone growth, will further clarify the timing of when extracellular Gal-3 affects bone mass expansion. Values are expressed as mean AE SEM (n = 7-14); Holm-Sidak post-

[2] Mice lacking galectin-3 (Lgals3) function have decreased home cage movement

• Authors: Tammy R. Chaudoin, S. Bonasera
• Year: 2018
• Venue: BMC Neuroscience
• URL: https://www.semanticscholar.org/paper/613a09b176431cdca195e6b3c439b4edbe4f92af
• DOI: 10.1186/s12868-018-0428-x
• Summary: P perturbation of behavioral circadian rhythms in Lgals3−/− mice is noted, with mice at both ages demonstrating greater variability in day-to-day performance of feeding, drinking, and movement compared to wildtype.
• Evidence snippets:
• Snippet 1 (score: 0.823)
  > Galectins are an evolutionarily ancient family of proteins sharing a high binding affinity for carbohydrates with β-galactoside linkages. In the extracellular space, galectins interact (through a conserved carbohydrate recognition domain, aka CRD) with glycosylated proteins to mediate both cell-to-cell interactions and cell-to-matrix adhesion. Galectins are thus pattern recognition molecules specialized to distinguish carbohydrate moieties.
  > Within the galectin family, galectin-3 (also known as Lgals3) has unique properties. Its preferred ligand is N-acetyllactosamine [1]. It is also the only galectin containing a conserved N-domain as well as a single CRD domain. This N-domain allows Lgals3 not bound to a carbohydrate target to form multimeric complexes [2].
  > In this manner, low extracellular Lgals3 concentrations tend to inhibit extracellular interactions and adhesion [3], while high Lgals3 extracellular concentrations facilitate cellular adhesion [4,5]. Lgals3 affinity for ECM substrates is also modulated by phosphorylation at its Ser6 residue [6].
  > Lgals3 is an NFκB target gene [7]; Lgals3 protein is widely distributed throughout most tissue sites (as demonstrated by the TiGER Tissue specific gene expression and regulation database; [8]). Furthermore, within specific tissues, Lgals3 protein expression is widespread, with extracellular [9], membrane bound, cytoplasmic, and nuclear localizations (for review, see [10]).

[3] Mice lacking galectin-3 (Lgals3) function have decreased home cage movement

• Authors: Tammy R. Chaudoin, S. Bonasera
• Year: 2018
• Venue: BMC Neuroscience
• URL: https://www.semanticscholar.org/paper/26255eafb963932be62ecb55d4943930217cb63f
• DOI: 10.1186/s12868-018-0428-x
• PMID: 29716523
• PMCID: 5930520
• Citations: 7
• Influential citations: 1
• Summary: P perturbation of behavioral circadian rhythms in Lgals3−/− mice is noted, with mice at both ages demonstrating greater variability in day-to-day performance of feeding, drinking, and movement compared to wildtype.
• Evidence snippets:
• Snippet 1 (score: 0.819)
  > Galectins are an evolutionarily ancient family of proteins sharing a high binding affinity for carbohydrates with β-galactoside linkages. In the extracellular space, galectins interact (through a conserved carbohydrate recognition domain, aka CRD) with glycosylated proteins to mediate both cell-to-cell interactions and cell-to-matrix adhesion. Galectins are thus pattern recognition molecules specialized to distinguish carbohydrate moieties.
  > Within the galectin family, galectin-3 (also known as Lgals3) has unique properties. Its preferred ligand is N-acetyllactosamine [1]. It is also the only galectin containing a conserved N-domain as well as a single CRD domain. This N-domain allows Lgals3 not bound to a carbohydrate target to form multimeric complexes [2].
  > In this manner, low extracellular Lgals3 concentrations tend to inhibit extracellular interactions and adhesion [3], while high Lgals3 extracellular concentrations facilitate cellular adhesion [4,5]. Lgals3 affinity for ECM substrates is also modulated by phosphorylation at its Ser6 residue [6].
  > Lgals3 is an NFκB target gene [7]; Lgals3 protein is widely distributed throughout most tissue sites (as demonstrated by the TiGER Tissue specific gene expression and regulation database; [8]). Furthermore, within specific tissues, Lgals3 protein expression is widespread, with extracellular [9], membrane bound, cytoplasmic, and nuclear localizations (for review, see [10]).

[4] Phenotypic Switching of Vascular Smooth Muscle Cells in Atherosclerosis

• Authors: Runji Chen, D. McVey, D. Shen, Xiaoxin Huang, Shu Ye
• Year: 2023
• Venue: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
• URL: https://www.semanticscholar.org/paper/472c313e2214a97757712ab0a8b39b133bd6a6bc
• DOI: 10.1161/JAHA.123.031121
• PMID: 37815057
• PMCID: 10757534
• Citations: 133
• Influential citations: 2
• Summary: This review article discusses the 9 VSMC phenotypes that have been reported in atherosclerotic lesions and classifies them into differentiated VSMCs, intermediately dedifferentiated VSMCs, and dedifferentiated VSMCs.
• Evidence snippets:
• Snippet 1 (score: 0.813)
  > Lgals3 (also referred to as galectin-3) is considered a marker of macrophage-like cells. 13,31 Rong et al detected a population of VSMCs that expressed Lgals3 following cholesterol loading in vitro. 31 Recently, Alencar et al found that Lgals3 activation is not a specific marker of the differentiation of VSMCs to a macrophage-like state but rather it is a marker of VSMCs entering a transitional state, with increased expression of genes associated with stem cells that are capable of extracellular matrix remodeling. 16 Of note, similar to SEM-like cells, Lgals3 + cells also have increased expression of lymphocyte antigen 6 family member A and vascular cell adhesion molecule 1. Further studies to investigate if SEM-like cells are derived from Lgals3 + cells are warranted.
  > Using mouse, rat, and human models of cholesterolloading in VSMCs, Li et al found that SREBP1 (sterol regulatory-element binding protein-1) and Krüppel-like factor-15 induced up-and downregulation of Lgals3, respectively, via binding to the Lgals3 gene promoter (albeit at different sites). 45 Likewise, Lgals3 promoted SREBP1 gene expression, producing a feedforward loop upregulated by cholesterol loading. 45 Moreover, Lgals3 and SREBP1 downregulated myocardin-related transcription factor A expression in VSMCs. 45 In another study, Owsiany et al used a dual lineage tracing model and found that Lgals3 + VSMCs produce monocyte chemoattractant protein 1, a proinflammatory chemokine. 15 Knockout of monocyte chemoattractant protein 1 specifically in Lgals3 + VSMCs resulted in the formation of atherosclerotic lesions with a greater ACTA2 content in the fibrous cap and decreased Lgals3 + cell content, a feature of stable plaque. 15

[5] Thyroid malignant neoplasm-associated biomarkers as targets for oncolytic virotherapy

• Authors: Mi Guan, Yanping Ma, S. Shah, G. Romano
• Year: 2016
• Venue: Oncolytic Virotherapy
• URL: https://www.semanticscholar.org/paper/9f79d851e32ad25e83c0a2d64e12919bf81a89f8
• DOI: 10.2147/OV.S99856
• PMID: 27579295
• PMCID: 4996252
• Citations: 4
• Summary: This review focuses on the strategy of biomarkers for the production of novel TMN oncolytic therapeutics, which may improve the specificity of targeting of tumor cells and limit adverse effects in patients.
• Evidence snippets:
• Snippet 1 (score: 0.805)
  > The Galectin-3 (LGALS3) is a protein that is encoded by a single gene, LGALS3, located on chromosome 14, locus q21-q22. 63 The molecular weight of this protein is ∼30 kDa, and it contains a carbohydrate-recognition-binding domain of ∼130 amino acids that enable the specific binding of β-galactosides. This protein localizes to the extracellular matrix, the cytoplasm, and the nucleus. It plays a role in numerous cellular functions including cell adhesion, cell activation and chemoattraction, cell growth, differentiation, cell cycle, apoptosis, innate immunity, cell adhesion, and T-cell regulation. 63,64 It has been known that LGALS3 is distributed widely around the tissues but in a low level.
  > To date, LGALS3 has been extensively studied as an IHC marker of thyroid malignancy, and a high diagnostic accuracy has been reported even for difficult pathological diagnoses. 64 Feilchenfeldt et al reported that the mRNA levels of LGALS3 and thyroglobulin in 28 benign and 31 malignant thyroid samples were quantified by real-time PCR. The LGALS3 expression at the mRNA was 60% (12/20) and the protein level was 100% (8/8), respectively. 65 The positive rate was 84% (41/49) when combined with the LGALS3 and HBME-1 in PTC specimens. 66 Two groups of researchers have detected the LGALS3 by IHC in PTC specimens. Saleh et al have shown that the sensitivity and the specificity for LGALS3 were 92.3% and 77.3%, respectively. 67 Song et al reported that positive expression of LGALS3 was 97% (427/441) in PTC group and 51% (77/151) in the benign thyroid lesions group. 68 These results may further support the notion that the high level of LGALS3 antigen expression occurs in patients with PTC. There are a number of different types of oncolytic viruses that have been altered from natural viruses in the laboratory such as adenovirus, reovirus, measles virus, herpes simplex

[6] Beyond Colonoscopy: Exploring New Cell Surface Biomarkers for Detection of Early, Heterogenous Colorectal Lesions

• Authors: Saleh M. Ramezani, Arianna Parkhideh, P. Bhattacharya, M. Farach-Carson, D. Harrington
• Year: 2021
• Venue: Frontiers in Oncology
• URL: https://www.semanticscholar.org/paper/4b48091d0ad86a2121491218707db23e88605000
• DOI: 10.3389/fonc.2021.657701
• PMID: 34290978
• PMCID: 8287259
• Citations: 13
• Summary: This review contextualizes existing and emergent CRC surface biomarkers and assess each’s potential as a candidate marker for early marker-based detection of CRC lesions and presents an overview of recent advances in imaging techniques useful for visual detection of surface biomarker detection.
• Evidence snippets:
• Snippet 1 (score: 0.799)
  > Galectin 3, or LGALS3, is a member of the galectin family, a group of carbohydrate-binding lectins characterized by their binding affinity for beta-galactosides (85).
  > LGALS3 is expressed at the cell surface, where it interacts with the extracellular matrix, especially with glycoproteins, and has the ability to affect intracellular signaling pathways (42). LGALS3-expressing cells also possess higher ALDH1 activity, which often correlates with a dedifferentiated cancer stem cell phenotype, than do their LGALS3-negative counterparts (86).
  > The correlation of LGALS3 expression in CRC with clinical pathological characteristics has been explored in several immunohistochemical and RT-PCR studies. In one study, the IHC staining of CRC tissue (n=61) and normal adjacent tissue (n=23) samples showed significantly higher LGALS3 expression in cancer tissue (62.5%) versus normal cancer-adjacent tissue (13.0%) (41). In another study, 75% of CRC tissue samples stain high for LGALS3, and ten CRC cell lines were shown to have increased LGALS3 protein levels compared to HeLa cells (42).
  > LGALS3 expression varies according to cancer staging and the degree of differentiation of the adenocarcinoma. LGALS3 mRNA levels were higher in early stage colorectal cancers (58% in stage I) compared to advanced cancers (50% in stage IV) (43). Protein analysis found higher LGALS3 levels in primary adenocarcinomas than in metastatic adenocarcinomas, and stronger LGALS3 staining in well-differentiated tumor areas compared to poorly differentiated tumor areas (43). Conversely, colorectal adenocarcinomas may display higher levels of LGALS3 than do colorectal adenomas; one study sets the rate of colorectal adenocarcinoma expression of LGALS3 at 95% while only 73% of adenomas were positive for LGALS3 (43).

[7] Prognostic risk analysis related to radioresistance genes in colorectal cancer

• Authors: Haoren Qin, Heng Zhang, Haipeng Li, Qiong Xu, Wan-jun Sun et al.
• Year: 2023
• Venue: Frontiers in Oncology
• URL: https://www.semanticscholar.org/paper/49a148168d686123fb072be1d332606425d67aa7
• DOI: 10.3389/fonc.2022.1100481
• PMID: 36741692
• PMCID: 9890073
• Citations: 11
• Summary: The risk score model built with five radioresistance genes in this study, including TNFRSF13C, CD36, ANGPTL4, LAMB3, and SERPINA1, showed favorable performance in prognosis prediction after radiotherapy for CRC.
• Evidence snippets:
• Snippet 1 (score: 0.799)
  > Therefore, the cell adhesion and ECM-related DEGs were screened as candidate genes for subsequent analyses.
  > We cross-referenced the cell adhesion and extracellular matrixrelated genes with the above-mentioned DEGs by releasing all genes containing the following annotations or their subdivisions: GO:0031012 extracellular matrix; GO:0030198 GO:0031012 extracellular matrix; GO:0030198 extracellular matrix organization; GO:1903053 regulation of extracellular matrix organization; GO:0035426 extracellular matrix-cell signaling; GO:0007155 cell adhesion; GO:0030155 regulation of cell adhesion; GO:0007160 cell-matrix adhesion; and GO:0050840 extracellular matrix binding. A total of 94 overlapping genes from DEGs and ECM-related genes were retained as candidate genes for subsequent analysis (Figure 1G). For these 94 genes, the interaction network of the encoded proteins was mapped using the STRING database (Figure 1H).

[8] High LGALS3 expression induced by HCP5/hsa-miR-27b-3p correlates with poor prognosis and tumor immune infiltration in hepatocellular carcinoma

• Authors: Yinghui Ren, Yongmei Qian, Qicheng Zhang, Xiaoping Li, Mingjiang Li et al.
• Year: 2024
• Venue: Cancer Cell International
• URL: https://www.semanticscholar.org/paper/552bd37c67dea75d0c33a9a0de2acdafcf0dcf6e
• DOI: 10.1186/s12935-024-03309-1
• PMID: 38643145
• PMCID: 11031979
• Citations: 13
• Summary: It is hypothesized that the HCP5/hsa-miR-27b-3p axis could serve as the most promising LGALS3 regulation mechanism in HCC and the upregulation of LGALS3 via the HCP5/hsa-miR-27b-3p axis is associated with unfavorable prognosis and increased tumor immune infiltration in HCC.
• Evidence snippets:
• Snippet 1 (score: 0.794)
  > LGALS3 has a crucial function in mediating cell adhesion as well as cell-cell interaction by recognizing complex carbohydrates on the surface of cells [22,23], as well as regulates cell apoptosis, autophagy, and inflammation [24,25].Interestingly, recent studies suggested that LGALS3 involves in essential cancer-related mechanisms, including cellular metabolism, carcinogenesis, metastasis, neoplasia, angiogenesis, as well as immune escape [26][27][28].In addition, LGALS3 is highly expressed and implicated in different cancer types progression such as HCC, gastric, colorectal, pancreatic carcinomas, melanomas or glioblastomas and breast cancer [29,30].Indeed, LGALS3 has been considered a potential marker for these malignancies.Interestingly, LGALS3, which is differentially expressed in different cancers, has been shown to exhibit tumor suppressor activity in certain cancer types.The different roles of LGALS3 may be attributed to different potential mechanisms that appear cancer-type dependent.The different locations and mutations of LGALS3 also contribute to its various functions.However, LGALS3 remains inadequately understood in HCC and requires further investigation.First, we conducted an extensive investigation of the expression profile, clinical prognosis, and pathologic stage of LGALS3 in HCC through an in-depth analysis of the public database.On the basis of TCGA and CPTAC datasets, we found that LGALS3 gene and protein expression was elevated in HCC tissues.Moreover, the OS and DSS were lesser in patients with HCC having higher expression levels of LGALS3 contrasted to those with low expression levels of LGALS3 based on GEPIA2 and Kaplan-Meier plotter datasets.Meanwhile, the expression of LGALS3 within HCC was significantly associated with the advanced tumor stage and grade, indicating that elevated LGALS3 expression could increase tumor progression.Song et al. [31] indicated that galectin-3 promoted HCC tumorigenesis and metastasis via β-catenin signalling in vitro and in vivo.
• Snippet 2 (score: 0.764)
  > Next, the prognostic value of LGALS3 expression in the 23 kinds of cancer patients was then determined.Correlations between LGALS3 expression with OS (overall survival) were evaluated using the GEPIA2 database.In the OS study, only elevated LGALS3 expression indicated poorer survival for HCC patients (Fig. 2A).LGALS3 was not statistically significant for OS of 22 other cancer types patients.Furthermore, DSS (disease-specific survival) LGALS3 in predicting 1-, 3-, and 5-year OS. (H) ROC curve for LGALS3 in predicting 1-, 3-, and 5-year DSS.The higher values of AUC corresponding to higher predictive power.p value < 0.05; **p value < 0.001 was lesser in patients suffering from HCC having higher levels of LGALS3 expression (Fig. 2B).Next, we validated the expression levels of LGALS3 protein in HCC tissues using IF staining.As expected, HCC tumor demonstrated strong LGALS3 expression (Fig. 2C).These findings were further validated by qRT-PCR assay of tumor and adjacent normal tissues from 5 HCC patients.Here, LGALS3 expression was also significantly increased in the HCC tissues (Fig. 2D).In addition, LGALS3 expression was shown to be linked with the pathological stage of HCC, as illustrated in Fig. 2E.High expression of LGALS3 gene is associated with high tumor grade in HCC (Fig. 2F).Moreover, LGALS3 expression was significantly associated with OS and DSS in both univariate and multivariate analyses (Figure S2A-H).Time-dependent ROC analysis showed that the area under the ROC curve was 0.672 at 5 years of OS, and 0.691 at 5 years of DSS (Fig. 2G-H).Taken together, LGALS3 might function as a prospective biomarker for the prognosis of patients suffering from HCC.

[9] LGALS3 Is a Poor Prognostic Factor in Diffusely Infiltrating Gliomas and Is Closely Correlated With CD163+ Tumor-Associated Macrophages

• Authors: Wan-Ming Hu, Yuan-Zhong Yang, Tian Zhang, Changling Qin, Xuenong Li
• Year: 2020
• Venue: Frontiers in Medicine
• URL: https://www.semanticscholar.org/paper/53b083f91a08aefebb5f9edaaa95625e2dc98f2b
• DOI: 10.3389/fmed.2020.00182
• PMID: 32528967
• PMCID: 7254797
• Citations: 18
• Influential citations: 1
• Summary: LGALS3 was an independent poor prognostic marker in diffusely infiltrating gliomas and was positively correlated with immune cell infiltration, particularly CD163+ tumor-associated macrophages in the TCGA dataset, Rembrandt dataset, and the SYSUCC cohort.
• Evidence snippets:
• Snippet 1 (score: 0.793)
  > In the LGALS family, LGALS3 has a special domain that recognizes and binds to β-galactosides on cellular glycoproteins and glycolipids (5).
  > LGALS3 may be observed in the cytoplasm and in the nucleus as well as the extracellular matrix (6). It serves different biological functions, such as cell growth, cell adhesion, angiogenesis, and apoptosis (7).
  > LGALS3 can be expressed in different types of tumors, and accumulating evidence has proved that LGALS3 plays a vital role in tumorigenesis and development (6,(8)(9)(10)(11)(12)(13)(14)(15)(16). Recently, a study indicated that LGALS3 can promote the therapeutic resistance of glioblastoma and is related to tumor risk and prognosis (17). However, its prognostic significance needs to be further confirmed in large glioma samples, and, hitherto, no studies have explored the role of LGALS3 in the glioma immune microenvironment and its correlation with key molecular markers, including isocitrate dehydrogenase 1 (IDH1), alpha-thalassemia/mental retardation X-linked (ATRX), O-6methylguanine-DNA methyltransferase (MGMT), telomerase reverse transcriptase (TERT), and 1p19q.

[10] Identification of an Internal Gene to the Human Galectin-3 Gene with Two Different Overlapping Reading Frames That Do Not Encode Galectin-3*

• Authors: M. Guittaut, Stéphane Charpentier, Thierry Normand, Martine Dubois, J. Raimond et al.
• Year: 2001
• Venue: The Journal of Biological Chemistry
• URL: https://www.semanticscholar.org/paper/75ca62f4b6eb66b3bcdac062664da410941fdcaa
• DOI: 10.1074/JBC.M002523200
• PMID: 11160123
• Citations: 37
• Influential citations: 6
• Summary: It is demonstrated that these transcripts arise from an internal gene embedded within LGALS3 and named galig (Galectin-3 internal gene), which appears to be tightly regulated and principally activated in leukocytes from peripheral blood.
• Evidence snippets:
• Snippet 1 (score: 0.774)
  > Human Rapid-Scan Gene Expression Panel was used to detect the alternative transcripts in various human tissues using RT-PCR. The primers used were designed to amplify a 923-or 629-bp fragment.
  > LGALS3 transcripts were detected as a 457-bp DNA and actin transcripts as a 640-bp DNA. PCR was performed using 0.25 ng or 2.5 ng (10ϫ) template cDNA.
  > average of other human proteins is 10 times lower. This rich content in tryptophans confers hydrophobic properties that may account for the membrane localization of the ORF2⅐EGFP protein (Fig. 6). Consistent with the mitochondrial localization of the ORF2⅐EGFP fusion protein, this sequence exhibits the common properties of mitochondrial-imported proteins such as the enrichment of arginine, leucine, and serine residues (36).
  > Tissue Specificity of galig Expression-Detection of galig transcripts in HOS cells and colon tumor cells revealed a low expression level. Based on this observation, the rationale that the appearance of galig transcripts may have resulted from a leaky transcription of a cryptic promoter rather than from an independently functioning promoter could not be excluded. Screening of several human tissues indicated clearly that galig is a tightly regulated gene whose expression is most efficient in leukocytes from peripheral blood. The low level of transcription in bone marrow indicates that galig is specifically expressed in mature forms of leukocytes. Whereas the precise quantification of galig mRNA has not been addressed in these experiments, it is clear that these transcripts are much less abundant than LGALS3 transcripts. This may not be surprising considering that LGALS3 is known to be highly expressed when activated (37,38). Indeed, the amount of LGALS3 transcripts appeared as abundant as those from actin genes. This shows a different type of regulation by the galig and LGALS3 promoters. In particular, muscle, stomach, and uterus, although expressing low levels of galig transcripts, revealed no LGALS3 transcripts, thus indicating an independent functioning of the two promoters.

[11] Periplocin suppresses the growth of colorectal cancer cells by triggering LGALS3 (galectin 3)-mediated lysophagy

• Authors: Kui Wang, Shuyue Fu, Lixia Dong, Dingyue Zhang, Mao Wang et al.
• Year: 2023
• Venue: Autophagy
• URL: https://www.semanticscholar.org/paper/3dadfc351823c4e325e65c171ab3765871189c80
• DOI: 10.1080/15548627.2023.2239042
• PMID: 37471054
• Citations: 35
• Influential citations: 2
• Summary: It is shown that periplocin exhibits promising anticancer activity against CRC both in vitro and in vivo, and is indicated as a potential therapeutic option for the treatment of CRC.
• Evidence snippets:
• Snippet 1 (score: 0.771)
  > We next investigated the mechanism underlying periplocinmediated lysophagy. The expression of LGALS3, a key lysophagy marker [46], was found to be upregulated following periplocin treatment as evidenced by immunofluorescent staining (Figure 2M). To this end, we presumed that periplocin-induced lysophagy might be attributable to the upregulation of LGALS3. Indeed, periplocin treatment prominently elevated the protein level of LGALS3 as evidence by immunoblotting analysis (Figure 6A). The increased protein level of LGALS3 was further confirmed in tumor xenografts from periplocin-treated mice (Figure 6B,C). However, no obvious change was observed on the mRNA level of LGALS3 in periplocin-treated cells compared with controls (Figure S6A), suggesting that transcriptional regulation was not involved in increased LGALS3 expression following periplocin treatment. Therefore, we postulated that periplocin might elevate LGALS3 by regulating protein stability. Of note, cycloheximide (CHX, a translational inhibitor) treatment led to an obvious decrease in LGALS3 protein level in control cells, but had no obvious effect on the upregulated protein level of LGALS3 in periplocin-treated cells, suggesting periplocin maintains LGALS3 stability (Figure 6D,E). In support of this, treatment with MG132 (a proteasome inhibitor) failed to further enhance the protein level of LGALS3 in response to periplocin treatment (Figure 6F,G). These data suggest that periplocin may prevent proteasomal degradation of LGALS3.
  > We therefore measured the effect of periplocin on LGALS3 ubiquitination. As shown in Figure 6H, periplocin markedly decreased the ubiquitin-conjugated level of LGALS3.

[12] In-depth quantitative proteomics analysis revealed C1GALT1 depletion in ECC-1 cells mimics an aggressive endometrial cancer phenotype observed in cancer patients with low C1GALT1 expression

• Authors: A. Montero‐Calle, Á. López-Janeiro, Marta L. Mendes, Daniel Perez-Hernandez, Irene Echevarría et al.
• Year: 2023
• Venue: Cellular Oncology
• URL: https://www.semanticscholar.org/paper/92b64e01bcb30f7457ddb8cc4be26de8b0c7cf69
• DOI: 10.1007/s13402-023-00778-w
• PMID: 36745330
• PMCID: 10205863
• Citations: 19
• Summary: C1GALT1 stably depleted ECC-1 cells mimic an EC aggressive phenotype observed in patients and might be useful for the identification and validation of EC markers of progression.
• Evidence snippets:
• Snippet 1 (score: 0.768)
  > However, opposite DNA methylation patterns (associated with a higher mutation rate in aggressive ECs) were found between type I and type II ECs, thus confirming the more aggressive phenotype of ECC-1 cells induced upon C1GALT1 depletion [82]. These data suggest that NCOA1 and DNMT3A levels might be used as biomarkers of EC malignancy. In contrast, dysregulation of ERCC3 (Excision repair cross-complementation group 3) levels has not been previously associated to EC, although different studies highlight the suppressor role of ERCC3 silencing in different cancers, as pancreatic or liver carcinomas [83,84].
  > Finally, LGALS3 (Galectin-3) is a protein that interacts with glycoproteins from the extracellular matrix in a galactose-dependent manner, favoring cell interactions, or with cytosolic or nuclear targets in a glycosylation independent manner [46]. Importantly, LGALS3 has been reported as EC marker [85][86][87], and as unfavorable marker for overall survival [73]. Here, we have found that the LGALS3 upregulation occurred in parallel to the downregulation of C1GALT1 both in vitro and in vivo in tumor tissue, with a significant negative correlation between them. Therefore, it can be suggested that LGALS3 upregulation in aggressive EC was a consequence of the downregulation of O-glycosylation in proteins from the extracellular matrix, which avoids LGALS3 interaction in the extracellular matrix of EC tumors, and as a compensatory effect an increase and release of LGALS3 should be produced.
  > In conclusion, quantitative proteomics of a well-characterized cellular model, where upon C1GALT1 depletion a more aggressive phenotype was induced, allow for the identification of proteins dysregulated in aggressive ECs and related pathways that might be of interest for a better understanding of the mechanisms undergoing EC pathogenesis related to O-glycosylation.

[13] Pregnancy Galectinology: Insights Into a Complex Network of Glycan Binding Proteins

• Authors: S. Blois, G. Dveksler, G. Vasta, N. Freitag, V. Blanchard et al.
• Year: 2019
• Venue: Frontiers in Immunology
• URL: https://www.semanticscholar.org/paper/68fad2b87411701fa708a1f49f8b918370486857
• DOI: 10.3389/fimmu.2019.01166
• PMID: 31231368
• PMCID: 6558399
• Citations: 56
• Influential citations: 7
• Summary: The relevance of galectin-glycan interactions as potential therapeutic targets in pregnancy disorders is discussed and the importance of angiogenesis during decidualization and in placenta formation is discussed.
• Evidence snippets:
• Snippet 1 (score: 0.768)
  > Lgals3 has been implicated in the regulation of innate and adaptive immune responses, where it participates in the activation or differentiation of immune cells and contributes to phagocytic clearance of microorganisms and apoptotic cells by macrophages (117,118). Lgals3 has been reported to promote but also to inhibit T-cell apoptosis depending on whether it binds to glycoproteins on the cell surface (CD45 and CD71) or to intracellular ligands (Bcl-2) (119, 120). In the placenta, Lgals3 was detected in all trophoblastic lineages including villous cytotrophoblasts (CTB) and EVT with a reduction of Lgals3 expression observed from the VT to the trophoblastic cell columns (121). This pattern of Lgals3 expression correlates with the switch from a proliferative to a migratory trophoblast phenotype and while placental Lgals3 dysregulation has been associated with some obstetric complications including spontaneous or recurrent miscarriages, further studies are needed to understand its contribution to trophoblast biology (81,122). In addition to trophoblasts, Lgals3 is expressed by maternal decidual cells (73). While showing a different expression pattern, both Lgals1 and Lgals3 have been proposed to play a role in cell-cell and cell-matrix interactions of trophoblast during placentation (121). Studies of the importance of Lgals3 in murine pregnancy by Yang et al. indicate that Lgals3 is expressed in the luminal and glandular epithelium and that an increase in Lgals3 is required for proper embryo implantation (123). In addition, Lgals3 affects chemotaxis and morphology of endothelial cells and stimulates capillary tube formation and angiogenesis in vivo (124). Therefore, besides its proposed roles in embryo implantation, immune regulation and trophoblast-matrix interactions, Lgals3 has a potential role in placental angiogenesis.

[14] LGALS3 is connected to CD74 in a previously unknown protein network that is associated with poor survival in patients with AML

• Authors: P. Ruvolo, Chenyue W. Hu, Y. Qiu, V. Ruvolo, Robin L. Go et al.
• Year: 2019
• Venue: EBioMedicine
• URL: https://www.semanticscholar.org/paper/46bbdbcb4660389e13acba24499cc415d75f18e0
• DOI: 10.1016/j.ebiom.2019.05.025
• PMID: 31105032
• PMCID: 6604360
• Citations: 25
• Influential citations: 2
• Summary: The data suggest that the LGALS3 network and the CD74 network each support AML cell survival and the two networks may cooperate in a novel high risk AML population.
• Evidence snippets:
• Snippet 1 (score: 0.768)
  > Thus, potential suppression of the PP2A subunit by LGALS3 could account for elevated AKT and PKC alpha phosphorylation in samples where LGALS3 expression is elevated. Induction of PPP2R2A protein (Fig. 5) but not gene expression (Fig. 7) in THP-1 cells expressing LGALS3 shRNA suggests that LGALS3 acts directly on the PP2A subunits via a post-transcriptional mechanism in these cells. The TCGA data (Table 3) however suggests that there is a positive correlation between gene expression of LGALS3 and PPP2R2A suggesting that a common pathway may regulate the two genes. Fig. 8. Progeny clustering identified an optimal number of 4 distinct protein clusters for this ProFnGrp. Protein networks were generated and showed interactions between "core-proteins" (large nodes) and other probed proteins (small nodes) from the data set. Clustering method has been described in our previous publication (ref. [37]) and further information on these protein networks can be found on our website "Leukemia Profile Atlases", available at https://www.leukemiaatlas.org/. Progeny clustering identified one protein cluster with expression similar to that of the normal CD34+ samples which was designated as "normal-state" while three "leukemia-specific" protein patterns characterized by high expression individually of CD74, LGAL3, and a fourth state with both on. PPP2RA/B/C/D was the only LGALS3 network protein demonstrated to be directly regulated by LGALS3 in the THP-1 cells (Fig. 5). In our previous study we saw potent suppression of AKT signaling by LGALS3 inhibition, so perhaps the mechanism involves LGALS3 suppression of the AKT phosphatase [15]. However, we did not see suppression of LGALS3 affect other network proteins in the THP-1 cells (data not shown). The role of other galectins such as LGALS1 in AML biology is not clear.
• Snippet 2 (score: 0.766)
  > LGALS3 is associated with active Fig. 7. Suppression of LGALS3 does not alter gene expression of LGALS3 network protein genes or CD74 in THP-1 cells. RNA from THP-1 transductant cells with either LKO vector control shRNA or LGALS3 shRNA was isolated, cDNA produced, and mRNA levels of ATG7, LGALS3, ITGAL, CCND3, PRKCA, PARP1, CD74, MYC, CD44, SSBP2, PPP2R2A, CLPP, and B2M were determined by qRT-PCR and levels normalized to ABL-1 as described in "Materials and methods".
  > AKT and MAPK signaling. The protein with the strongest positive correlation with LGALS3 is with ATG7, an autophagy protein that has recently been implicated in maintaining hematopoietic stem cells and serving as a survival factor in AML [46,47]. Recent studies implicate LGALS3 in regulation of autophagy via autophagasome formation, though whether the mechanism involves ATG7 is not clear [48]. Interestingly, phosphorylated PKC delta was positively correlated with LGALS3. PKC delta is viewed as a pro-stress kinase but recent studies suggest that the enzyme has pro-survival properties [49][50][51]. Kinehara and colleagues suggest that PKC delta may act in human pluripotent stem cells as part of a mechanism to regulate stem cell renewal [52]. The data also suggest a novel relationship between LGALS3 and PP2A. The negative correlation of LGALS3 expression with PPP2R2A/B/C/D could reflect LGALS3 suppression of PP2A. The PP2A isoform containing PPP2R2A dephosphorylates both AKT and PKC alpha [53]. Thus, potential suppression of the PP2A subunit by LGALS3 could account for elevated AKT and PKC alpha phosphorylation in samples where LGALS3 expression is elevated.

[15] Lgals3 Promotes Calcium Oxalate Crystal Formation and Kidney Injury Through Histone Lactylation‐Mediated FGFR4 Activation

• Authors: Zehua Ye, Yushi Sun, Songyuan Yang, Lei Li, Bojun Li et al.
• Year: 2025
• Venue: Advanced Science
• URL: https://www.semanticscholar.org/paper/adbfa30b5832407d200a5eade9196d41be08050e
• DOI: 10.1002/advs.202413937
• PMID: 39903812
• PMCID: 11947994
• Citations: 18
• Summary: Findings suggest that Lgals3 may play a key role in CaOx stone formation and kidney injury by interacting with PKM2 and promoting both H3K18la‐mediated gene transcription and activation.
• Evidence snippets:
• Snippet 1 (score: 0.766)
  > To investigate whether Lgals3 promoted kidney injury and renal fibrosis caused by CaOx crystal, a kidney-specific overexpression system that overexpressed Lgals3 was utilized in mice (Figure S5A, Supporting Information). After four weeks of injection, the effectiveness of Lgals3 overexpression was confirmed by qPCR and Western blot (Figure S5B,C, Supporting Information). Subsequently, a CaOx kidney stone model was established (Figure 3A). The serum BUN and Creatinine results showed that Lgals3 overexpression migrates the kidney injury (Figure 3B,C). HE and Von Kossa staining found that Lgals3 overexpression aggravated kidney injury and CaOx crystal deposition (Figure 3D). In addition, pathology staining and Western blot analysis found that overexpression of Lgals3 significantly increased renal fibrosis and inflammation response caused by CaOx crystal deposition (Figure 3E,F; Figure S5D, Supporting Information).
  > An adenoviral vector encoding the Lgals3 gene was utilized in vitro to investigate the effects of Lgals3 overexpression. The overexpression efficiency was confirmed by Western blot (Figure S4B, Supporting Information). Western blot analysis and immunofluorescence staining of ROS found that overexpression of Lgals3 significantly increased the expression of fibrosis-related protein and ROS expression (Figure S4F,G, Supporting Information). Taken together, these results indicate that Lgals3 overexpression can promote CaOx crystal deposition and renal fibrosis.

[16] Krüppel-like Factor 3 (KLF3/BKLF) Is Required for Widespread Repression of the Inflammatory Modulator Galectin-3 (Lgals3)*

• Authors: Alexander J. Knights, Jinfen. J. Yik, Hanapi Mat Jusoh, Laura J. Norton, Alister P. W. Funnell et al.
• Year: 2016
• Venue: The Journal of Biological Chemistry
• URL: https://www.semanticscholar.org/paper/dce84b7faec66ad9234b04f596d036ed32078971
• DOI: 10.1074/jbc.M116.715748
• PMID: 27226561
• Citations: 27
• Influential citations: 1
• Summary: It is shown that the zinc finger transcription factor Krüppel-like factor 3 (KLF3) directly represses galectin-3 transcription, and mechanistic insights into the regulation of Lgals3 are provided, demonstrating that C-terminal binding protein (CtBP) is required to drive optimal KLF3-mediated silencing.
• Evidence snippets:
• Snippet 1 (score: 0.760)
  > Lgals3 Is Up-regulated in the Absence of KLF3-In studies of the role of KLF3 in hematopoiesis and red blood cell development, microarrays performed on Ter119 ϩ fetal liver cells lacking KLF3 revealed that the Lgals3 gene was consistently up-regulated in knockout animals (15). Because of the importance of galectin-3 in a number of biological settings, we undertook a fuller analysis of whether the expression of Lgals3 was altered in a range of mouse tissues in the absence of KLF3. Lgals3 mRNA levels were assessed in cultured murine embryonic fibroblasts (MEFs) as well as a series of primary tissues from wild-type and Klf3 Ϫ/Ϫ mice by quantitative real-time PCR. In primary and immortalized Klf3 Ϫ/Ϫ MEFs, Lgals3 mRNA was up-regulated 4.7-and 4.3-fold, respectively, compared with wild-type expression (Fig. 1A). Importantly, Lgals3 levels were also found to be elevated in a number of primary tissues dissected from KLF3-deficient mice (Fig. 1B). Derepression was most evident in Klf3 Ϫ/Ϫ subcutaneous (6.7-fold) and epididymal (3.3-fold) white adipose depots and in the heart (6.6-fold) and pancreas (4.2-fold).
  > Following the demonstration that Lgals3 is derepressed in Klf3 Ϫ/Ϫ tissues at the mRNA level, we next sought to determine whether this up-regulation was reflected at the protein level. Whole cell protein extracts were prepared from wild-type and Klf3 Ϫ/Ϫ fat depots and spleens, and the expression of galectin-3 protein was assessed by Western blotting (Fig. 1, C-F).

Notes

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Asta Literature Retrieval: Literature evidence for LGALS3 (Homo sapiens): LGALS3 has laminin binding (GO:0043236). Gene/protein: LGALS3. Organis...

This report is retrieval-only and is generated directly from Asta results.

• Papers retrieved: 13
• Snippets retrieved: 20

Relevant Papers

[1] Periplocin suppresses the growth of colorectal cancer cells by triggering LGALS3 (galectin 3)-mediated lysophagy

• Authors: Kui Wang, Shuyue Fu, Lixia Dong, Dingyue Zhang, Mao Wang et al.
• Year: 2023
• Venue: Autophagy
• URL: https://www.semanticscholar.org/paper/3dadfc351823c4e325e65c171ab3765871189c80
• DOI: 10.1080/15548627.2023.2239042
• PMID: 37471054
• Citations: 35
• Influential citations: 2
• Summary: It is shown that periplocin exhibits promising anticancer activity against CRC both in vitro and in vivo, and is indicated as a potential therapeutic option for the treatment of CRC.
• Evidence snippets:
• Snippet 1 (score: 0.841)
  > Scale bar: 10 μm. (I) Immunofluorescent analysis of the colocalization of LGALS3 with ubiquitin in CRC cells treated with or without 0.50 μM periplocin for 24 h. Scale bar: 10 μm. (J) Representative fluorescent images of CRC cells transiently expressing Mrfp-GFP-tandem fluorescent-tagged LGALS3 (tfGal3) followed by 0.50 μM periplocin treatment for 24 h. Scale bar: 10 μm. (K) Quantitative analysis of the GFP + RFP + or GFP − RFP + LGALS3 puncta in (J). (L) the relative decreased ratio of Magic Red intensity, relative increased ratio of LysoSensor Blue intensity, relative increased ratio of the interaction between LGALS3 and TRIM16, and relative increased ratio of LC3B-II protein level in DLD-1 cells following 0.50 μM periplocin treatment at different time periods. Results are representative of three independent experiments. Data are presented as mean ± SD. P < 0.05, P < 0.01, **P < 0.001. for LGALS3 degradation, we generated lysine to arginine mutants of LGALS3 at K196 or Lys210 (LGALS3 K196R or LGALS3 K210R ). As shown in Figure 6I, the ubiquitinconjugated level of LGALS3 K196R mutant was comparable to the wild type (WT), whereas K210 mutation significantly decreased LGALS3 ubiquitination. These results suggest that periplocin elevates LGALS3 level by preventing K210 ubiquitination and proteasomal degradation. In addition, periplocin was found to stabilize the protein level of LGALS3 against thermal changes using a cellular thermal shift assay (CETSA) (Figure 6J,K), implying the binding of periplocin with LGALS3.
• Snippet 2 (score: 0.834)
  > In addition, periplocin was found to stabilize the protein level of LGALS3 against thermal changes using a cellular thermal shift assay (CETSA) (Figure 6J,K), implying the binding of periplocin with LGALS3. The interaction between periplocin and LGALS3 was further confirmed by drug affinity responsive target stability (DARTS) analysis, as evidenced by a more stable property of LGALS3 protein against pronase digestion in response to periplocin treatment (Figure 6L,M). Moreover, using semiflexible docking analysis, we found that LGALS3 showed a good binding activity for periplocin, with a binding energy of −6.689 kcal/mol. Glu165, Arg162, Gly152, Gln150, Arg144, and Asn143 of LGALS3 were identified as possible sites for periplocin binding (Figure 6N,O), which required further experimental investigation. Together, these data suggest that periplocin binds and prevents ubiquitin-mediated degradation of LGALS3 in CRC cells.

[2] Identification of an Internal Gene to the Human Galectin-3 Gene with Two Different Overlapping Reading Frames That Do Not Encode Galectin-3*

• Authors: M. Guittaut, Stéphane Charpentier, Thierry Normand, Martine Dubois, J. Raimond et al.
• Year: 2001
• Venue: The Journal of Biological Chemistry
• URL: https://www.semanticscholar.org/paper/75ca62f4b6eb66b3bcdac062664da410941fdcaa
• DOI: 10.1074/JBC.M002523200
• PMID: 11160123
• Citations: 37
• Influential citations: 6
• Summary: It is demonstrated that these transcripts arise from an internal gene embedded within LGALS3 and named galig (Galectin-3 internal gene), which appears to be tightly regulated and principally activated in leukocytes from peripheral blood.
• Evidence snippets:
• Snippet 1 (score: 0.798)
  > Human Rapid-Scan Gene Expression Panel was used to detect the alternative transcripts in various human tissues using RT-PCR. The primers used were designed to amplify a 923-or 629-bp fragment.
  > LGALS3 transcripts were detected as a 457-bp DNA and actin transcripts as a 640-bp DNA. PCR was performed using 0.25 ng or 2.5 ng (10ϫ) template cDNA.
  > average of other human proteins is 10 times lower. This rich content in tryptophans confers hydrophobic properties that may account for the membrane localization of the ORF2⅐EGFP protein (Fig. 6). Consistent with the mitochondrial localization of the ORF2⅐EGFP fusion protein, this sequence exhibits the common properties of mitochondrial-imported proteins such as the enrichment of arginine, leucine, and serine residues (36).
  > Tissue Specificity of galig Expression-Detection of galig transcripts in HOS cells and colon tumor cells revealed a low expression level. Based on this observation, the rationale that the appearance of galig transcripts may have resulted from a leaky transcription of a cryptic promoter rather than from an independently functioning promoter could not be excluded. Screening of several human tissues indicated clearly that galig is a tightly regulated gene whose expression is most efficient in leukocytes from peripheral blood. The low level of transcription in bone marrow indicates that galig is specifically expressed in mature forms of leukocytes. Whereas the precise quantification of galig mRNA has not been addressed in these experiments, it is clear that these transcripts are much less abundant than LGALS3 transcripts. This may not be surprising considering that LGALS3 is known to be highly expressed when activated (37,38). Indeed, the amount of LGALS3 transcripts appeared as abundant as those from actin genes. This shows a different type of regulation by the galig and LGALS3 promoters. In particular, muscle, stomach, and uterus, although expressing low levels of galig transcripts, revealed no LGALS3 transcripts, thus indicating an independent functioning of the two promoters.

[3] Mutation of the galectin‐3 glycan‐binding domain ( Lgals3‐R200S) enhances cortical bone expansion in male mice and trabecular bone mass in female mice

• Authors: Kevin A. Maupin, Daniel T. Dick, Vari Vivarium, Transgenics Core, B. Williams
• Year: 2020
• Venue: FEBS Open Bio
• URL: https://www.semanticscholar.org/paper/6ab62ea9acc6fef617d0b1f237c1a477f45b05c7
• DOI: 10.1002/2211-5463.13483
• PMID: 36062328
• PMCID: 9527582
• Citations: 2
• Summary: The results suggest that the trabecular bone phenotype of Lgals3-KO mice was driven primarily by loss of extracellular galectin-3, while the cortical bone phenotypeof Lgal3- KO mice may have also been influenced by Loss of intracellular galECTin- 3.
• Evidence snippets:
• Snippet 1 (score: 0.792)
  > The study of galectin-3 is complicated by its ability to function both intracellularly and extracellularly. While the mechanism of galectin-3 secretion is unclear, studies have shown that the mutation of a highly conserved arginine to a serine in human galectin-3 (LGALS3-R186S) blocks glycan binding and secretion. To gain insight into the roles of extracellular and intracellular functions of galectin-3, we generated mice with the equivalent mutation (Lgals3-R200S) using CRISPR/Cas9-directed homologous recombination. Consistent with a reduction in galectin-3 secretion, we observed significantly reduced galectin-3 protein levels in the plasma of heterozygous and homozygous mutant mice. We observed a similar increased bone mass phenotype in Lgals3-R200S mutant mice at 36 weeks as we previously observed in Lgals3-KO mice with slight variation. Like Lgals3-KO mice, Lgals3-R200S females, but not males, had significantly increased trabecular bone mass. However, only male Lgals3-R200S mice showed increased cortical bone expansion, which we had previously observed in both male and female Lgals3-KO mice and only in female mice using a separate Lgals3 null allele (Lgals3). These results suggest that the trabecular bone phenotype of Lgals3-KO mice was driven primarily by loss of extracellular galectin-3. However, the cortical bone phenotype of Lgals3-KO mice may have also been influenced by loss of intracellular galectin-3. Future analyses of these mice will aid in identifying the cellular and molecular mechanisms that contribute to the Lgals3-deficient bone phenotype as well as aid in distinguishing the extracellular vs. intracellular roles of galectin-3 in various signaling pathways.
• Snippet 2 (score: 0.770)
  > We previously observed that genomic loss of galectin-3 (Gal-3; encoded by Lgals3) in mice has a significant protective effect on age-related bone loss. Gal-3 has both intracellular and extracellular functionality, and we wanted to assess whether the affect we observed in the Lgals3 knockout (KO) mice could be attributed to the ability of Gal-3 to bind glycoproteins. Mutation of a highly conserved arginine to a serine in human Gal-3 (LGALS3-R186S) blocks glycan binding and secretion. We generated mice with the equivalent mutation (Lgals3-R200S) and observed a subsequent reduction in Gal-3 secretion from mouse embryonic fibroblasts and in circulating blood. When examining bone structure in aged mice, we noticed some similarities to the Lgals3-KO mice and some differences. First, we observed greater bone mass in Lgals3-R200S mutant mice, as was previously observed in Lgals3-KO mice. Like Lgals3-KO mice, significantly increased trabecular bone mass was only observed in female Lgals3-R200S mice. These results suggest that the greater bone mass observed is driven by the loss of extracellular Gal-3 functionality. However, the results from our cortical bone expansion data showed a sex-dependent difference, with only male Lgals3-KO mice having an increased response, contrasting with our earlier study. These notable sex differences suggest a potential role for sex hormones, most likely androgen signaling, being involved. In summary, our results suggest that targeting extracellular Gal-3 function may be a suitable treatment for age-related loss of bone mass.
  > Galectin-3 (Gal-3; encoded by Lgals3) is a protein that functions outside the cell to regulate glycoprotein secretion and turnover [1,2] and intracellularly in protein chaperoning and mRNA splicing [3,4]. We previously found that genomic deletion of Gal-3 in mice (Lgals3-KO) protects the mice against age-related [5] or sex-hormone deprivation bone loss [6]. A better understanding of the
• Snippet 3 (score: 0.755)
  > s3 +/+ ), heterozygous (Lgals3-R200S KI/+ ), and homozygous (Lgals3-R200S KI/KI ) mutant mice (Fig. 1C). Consistent with a reduction in Gal-3 secretion, we observed significantly reduced Gal-3 protein levels in the plasma of adult heterozygous and homozygous mutant mice (Fig. 1D).
  > We generated mouse embryonic fibroblasts (MEFs) to look at cell-surface proteins, to confirm reduction of extracellular Gal-3 protein in Lgals3-R200S cells. Cell surface proteins were biotinylated and captured with NeutrAvidin Agarose. Western blot analysis showed cell surface Gal-3 levels were decreased in Lgals3-R200S KI/+ and Lgals3-R200S KI/KI cells compared to wild-type (Fig. 1E). The absence of the cytoplasmic protein, vinculin, from the pull-down lanes confirmed that the experiments worked to preferentially pull-down biotinylated cell surface proteins. Immunocytochemistry of MEFs from Lgals3-R200S KI/KI mice confirmed that Gal-3 is present in the cytosol and nucleus (Fig. 1F). Quantification of the mean and median amount of fluorescence per unit area indicated that Galectin-3 both on the cell surface and inside the cell was reduced, by approximately 30% and 26% respectively, in Lgals3-R200S KI/KI MEFs (P = 0.024). From these studies, we conclude that the R200S mutation in mice reduced cell surface Gal-3 and may have contributed to lower intracellular Gal-3 levels. Further studies will be necessary to determine if the 25-30% reduction in intracellular Gal-3 is biologically significant.

[4] Regulation and use of the extracellular matrix by Trypanosoma cruzi during early infection

• Authors: P. Nde, M. Lima, Candice A. Johnson, S. Pratap, F. Villalta
• Year: 2012
• Venue: Frontiers in Immunology
• URL: https://www.semanticscholar.org/paper/0f8537bce448a98bc55bef38dcc8d4b462ab72b5
• DOI: 10.3389/fimmu.2012.00337
• PMID: 23133440
• PMCID: 3490126
• Citations: 43
• Influential citations: 2
• Summary: The first elucidation of the human ECM interactome network regulated by T. cruzi is presented, a ligand that mediates the attachment of trypanosomes to cells to initiate infection, up-regulates LAMC1 expression to enhance cellular infection.
• Evidence snippets:
• Snippet 1 (score: 0.790)
  > The fact that LAMC1 is connected to LGALS3 through MYOC in the ECM interactome suggests the importance of LGALS3 in the manipulation of host ECM by T. cruzi.
  > Increased LGALS3 expression in the ECM promotes the adhesion of T. cruzi to host cells and subsequent infection (Kleshchenko et al., 2004). In addition, LGALS3 has numerous ECM interacting partners (Dumic et al., 2006), including collagen IV, hensin, laminins, fibronectin, vitronectin, tenascin, and elastin. LGALS3 regulates adhesion of these ECM proteins to a variety of host cells. Matrix metalloproteases, which are more active in T. cruzi infected mice, regulate LGAL3 function (Gutierrez et al., 2008). When metalloproteases are activated in the ECM, they can cleave LGALS3 and negatively regulate its function. Consequently, increased activation of MMP1 and MMP9 is associated with ECM destruction and myocarditis in T. cruzi infection.
  > Multiple types of collagen interact with the three central seed nodes, THBS1, LGALS3, and LAMC1. A glimpse of the importance of collagen in early T. cruzi infection was reported (Velge et al., 1988).

[5] Beyond Colonoscopy: Exploring New Cell Surface Biomarkers for Detection of Early, Heterogenous Colorectal Lesions

• Authors: Saleh M. Ramezani, Arianna Parkhideh, P. Bhattacharya, M. Farach-Carson, D. Harrington
• Year: 2021
• Venue: Frontiers in Oncology
• URL: https://www.semanticscholar.org/paper/4b48091d0ad86a2121491218707db23e88605000
• DOI: 10.3389/fonc.2021.657701
• PMID: 34290978
• PMCID: 8287259
• Citations: 13
• Summary: This review contextualizes existing and emergent CRC surface biomarkers and assess each’s potential as a candidate marker for early marker-based detection of CRC lesions and presents an overview of recent advances in imaging techniques useful for visual detection of surface biomarker detection.
• Evidence snippets:
• Snippet 1 (score: 0.787)
  > Galectin 3, or LGALS3, is a member of the galectin family, a group of carbohydrate-binding lectins characterized by their binding affinity for beta-galactosides (85).
  > LGALS3 is expressed at the cell surface, where it interacts with the extracellular matrix, especially with glycoproteins, and has the ability to affect intracellular signaling pathways (42). LGALS3-expressing cells also possess higher ALDH1 activity, which often correlates with a dedifferentiated cancer stem cell phenotype, than do their LGALS3-negative counterparts (86).
  > The correlation of LGALS3 expression in CRC with clinical pathological characteristics has been explored in several immunohistochemical and RT-PCR studies. In one study, the IHC staining of CRC tissue (n=61) and normal adjacent tissue (n=23) samples showed significantly higher LGALS3 expression in cancer tissue (62.5%) versus normal cancer-adjacent tissue (13.0%) (41). In another study, 75% of CRC tissue samples stain high for LGALS3, and ten CRC cell lines were shown to have increased LGALS3 protein levels compared to HeLa cells (42).
  > LGALS3 expression varies according to cancer staging and the degree of differentiation of the adenocarcinoma. LGALS3 mRNA levels were higher in early stage colorectal cancers (58% in stage I) compared to advanced cancers (50% in stage IV) (43). Protein analysis found higher LGALS3 levels in primary adenocarcinomas than in metastatic adenocarcinomas, and stronger LGALS3 staining in well-differentiated tumor areas compared to poorly differentiated tumor areas (43). Conversely, colorectal adenocarcinomas may display higher levels of LGALS3 than do colorectal adenomas; one study sets the rate of colorectal adenocarcinoma expression of LGALS3 at 95% while only 73% of adenomas were positive for LGALS3 (43).

[6] LGALS3 is connected to CD74 in a previously unknown protein network that is associated with poor survival in patients with AML

• Authors: P. Ruvolo, Chenyue W. Hu, Y. Qiu, V. Ruvolo, Robin L. Go et al.
• Year: 2019
• Venue: EBioMedicine
• URL: https://www.semanticscholar.org/paper/46bbdbcb4660389e13acba24499cc415d75f18e0
• DOI: 10.1016/j.ebiom.2019.05.025
• PMID: 31105032
• PMCID: 6604360
• Citations: 25
• Influential citations: 2
• Summary: The data suggest that the LGALS3 network and the CD74 network each support AML cell survival and the two networks may cooperate in a novel high risk AML population.
• Evidence snippets:
• Snippet 1 (score: 0.780)
  > Thus, potential suppression of the PP2A subunit by LGALS3 could account for elevated AKT and PKC alpha phosphorylation in samples where LGALS3 expression is elevated. Induction of PPP2R2A protein (Fig. 5) but not gene expression (Fig. 7) in THP-1 cells expressing LGALS3 shRNA suggests that LGALS3 acts directly on the PP2A subunits via a post-transcriptional mechanism in these cells. The TCGA data (Table 3) however suggests that there is a positive correlation between gene expression of LGALS3 and PPP2R2A suggesting that a common pathway may regulate the two genes. Fig. 8. Progeny clustering identified an optimal number of 4 distinct protein clusters for this ProFnGrp. Protein networks were generated and showed interactions between "core-proteins" (large nodes) and other probed proteins (small nodes) from the data set. Clustering method has been described in our previous publication (ref. [37]) and further information on these protein networks can be found on our website "Leukemia Profile Atlases", available at https://www.leukemiaatlas.org/. Progeny clustering identified one protein cluster with expression similar to that of the normal CD34+ samples which was designated as "normal-state" while three "leukemia-specific" protein patterns characterized by high expression individually of CD74, LGAL3, and a fourth state with both on. PPP2RA/B/C/D was the only LGALS3 network protein demonstrated to be directly regulated by LGALS3 in the THP-1 cells (Fig. 5). In our previous study we saw potent suppression of AKT signaling by LGALS3 inhibition, so perhaps the mechanism involves LGALS3 suppression of the AKT phosphatase [15]. However, we did not see suppression of LGALS3 affect other network proteins in the THP-1 cells (data not shown). The role of other galectins such as LGALS1 in AML biology is not clear.
• Snippet 2 (score: 0.777)
  > However, CD44 is present and interestingly is most elevated in patients with active LGALS3 network and CD74 network (Fig. 8). LGALS3 has been shown to be critical for CD44 endocytosis so LGALS3 would be expected to promote CD44 surface expression [54]. In AML cells with LGALS3 supported CD44 surface expression, CD74 would be predicted to augment signaling mediated by CD44.
  > LGALS3 is well known as an immune regulatory molecule that suppresses host anti-tumor immune surveillance by diverse mechanisms [1,2,55].
  > LGALS3 blocks or at least dampens immune cell function by reducing surface expression of glycosylated T cell receptor in T cells and preventing NK cell receptor binding to antigen [1,2]. LGALS3 has emerged as a critical component in MSC in AML patients to impact response to therapy [56]. It is likely that LGALS3 secreted from MSC and other support cells in the AML microenvironment negatively impacts immune surveillance in AML patients. It is yet to be determined if LGALS3 derived from the leukemia cells plays a role as an immune response inhibitor in AML.
  > LGALS9 is emerging as an important immune checkpoint inhibitor molecule as a TIM-3 binding partner [2,57]. LGALS9 also regulates T cell function as a CD44 binding partner [58]. Whereas LGALS3 binding to CD44 promotes metastasis, LGALS9 binding to CD44 suppresses this process [59,60]. Future RPPA studies to determine the role of LGALS9 and galectins other than LGALS3 are warranted.
  > For the first time, an at risk AML population has been found that is associated with active LGALS3 and active CD74 networks (Fig. 9A and B). At present, it is unclear which if any proteins within the LGALS3 or CD74 networks is driving this phenomenon. CD44, SPP1, and CLPP are highly induced in the patient cohort with both networks active compared to patients with normal-like state (Fig. 8).
• Snippet 3 (score: 0.772)
  > LGALS3 is associated with active Fig. 7. Suppression of LGALS3 does not alter gene expression of LGALS3 network protein genes or CD74 in THP-1 cells. RNA from THP-1 transductant cells with either LKO vector control shRNA or LGALS3 shRNA was isolated, cDNA produced, and mRNA levels of ATG7, LGALS3, ITGAL, CCND3, PRKCA, PARP1, CD74, MYC, CD44, SSBP2, PPP2R2A, CLPP, and B2M were determined by qRT-PCR and levels normalized to ABL-1 as described in "Materials and methods".
  > AKT and MAPK signaling. The protein with the strongest positive correlation with LGALS3 is with ATG7, an autophagy protein that has recently been implicated in maintaining hematopoietic stem cells and serving as a survival factor in AML [46,47]. Recent studies implicate LGALS3 in regulation of autophagy via autophagasome formation, though whether the mechanism involves ATG7 is not clear [48]. Interestingly, phosphorylated PKC delta was positively correlated with LGALS3. PKC delta is viewed as a pro-stress kinase but recent studies suggest that the enzyme has pro-survival properties [49][50][51]. Kinehara and colleagues suggest that PKC delta may act in human pluripotent stem cells as part of a mechanism to regulate stem cell renewal [52]. The data also suggest a novel relationship between LGALS3 and PP2A. The negative correlation of LGALS3 expression with PPP2R2A/B/C/D could reflect LGALS3 suppression of PP2A. The PP2A isoform containing PPP2R2A dephosphorylates both AKT and PKC alpha [53]. Thus, potential suppression of the PP2A subunit by LGALS3 could account for elevated AKT and PKC alpha phosphorylation in samples where LGALS3 expression is elevated.
• Snippet 4 (score: 0.751)
  > LGALS3 levels correlate with a variety of signaling molecules in blast cells from AML patients RPPA was used to examine correlations of LGALS3 with 230 other proteins. As shown in Fig. 3A, 68 of 231 proteins showed statistically significant (p b 0.0001, R N 0.25) correlation with LGALS3, with positive correlation for 27 total and 10 phospho-proteins and negative correlation for 24 total and 7 phospho-proteins. The strongest positive correlation was with the autophagy protein ATG7. The phospho-proteins positively correlated with LGALS3 included survival kinases such as p-ERK (pY202/pY204), p-AKT (pT308), three phospho-protein variants of PKC delta (i.e. pT507, pS645, and pS664), and p-PKC alpha (pS657) (Fig. 3). LGALS3 expression also positively correlated with phosphorylation of the tyrosine kinase SRC (i.e. pY416 and pY527). The most negatively correlated protein was Single Stranded DNA Binding Protein 2 (SSBP2) (Fig. 3). Among the other proteins negatively correlated with LGALS3 was the members of the PP2A B55 family (PPP2R2A, PPP2R2B, PPP2R2C, and PPP2R2D).
  > Protein network analysis was performed on the set of proteins associated with LGALS3 using String software (String 10.1; website: http:// string-db.org; ref. 38). The network of LGALS3 proteins identified by RPPA are highly associated with a protein:protein enrichment p value b1.0e−16 (Fig. 4) by String. Numerous biological pathways (N = 588) and KEGG pathways (N = 86) associated with LGALS3 network were identified using the String software. Data are presented in Supplemental Table 1 and Supplemental Table 2, respectively.

[7] Clusterin Seals the Ocular Surface Barrier in Mouse Dry Eye

• Authors: Aditi Bauskar, W. Mack, J. Mauris, P. Argüeso, M. Heur et al.
• Year: 2015
• Venue: PLoS ONE
• URL: https://www.semanticscholar.org/paper/ddc53237e6b4b7c325cb047e4eaf34098273148e
• DOI: 10.1371/journal.pone.0138958
• PMID: 26402857
• PMCID: 4581869
• Citations: 35
• Influential citations: 2
• Summary: It is shown that CLU prevents and ameliorates ocular surface barrier disruption by a remarkable sealing mechanism dependent on attainment of a critical all-or-none concentration, and suggests CLU as a biotherapeutic for dry eye.
• Evidence snippets:
• Snippet 1 (score: 0.779)
  > In other cases, CLU spots were clearly separate.
  > Next we considered what kinds of ocular surface molecules might bind CLU.
  > LGALS3, a key component of the ocular surface barrier, is a member of the galectin class of beta-galactosidebinding proteins. What is known about the glycosyl moiety of CLU is consistent with LGALS3 binding [25,27]. CLU applied to an LGALS3-sepharose affinity column bound to the beads and was not eluted 0.1 M sucrose, a disaccharide that does not compete with LGALS3 sugar binding, but was mostly eluted with a competitive inhibitor of LGALS3 sugar binding, 0.1 M beta-lactose (Fig 5C). This suggests that CLU binding to LGALS3 is specific for the beta-galactoside-binding function.

[8] Thyroid malignant neoplasm-associated biomarkers as targets for oncolytic virotherapy

• Authors: Mi Guan, Yanping Ma, S. Shah, G. Romano
• Year: 2016
• Venue: Oncolytic Virotherapy
• URL: https://www.semanticscholar.org/paper/9f79d851e32ad25e83c0a2d64e12919bf81a89f8
• DOI: 10.2147/OV.S99856
• PMID: 27579295
• PMCID: 4996252
• Citations: 4
• Summary: This review focuses on the strategy of biomarkers for the production of novel TMN oncolytic therapeutics, which may improve the specificity of targeting of tumor cells and limit adverse effects in patients.
• Evidence snippets:
• Snippet 1 (score: 0.771)
  > The Galectin-3 (LGALS3) is a protein that is encoded by a single gene, LGALS3, located on chromosome 14, locus q21-q22. 63 The molecular weight of this protein is ∼30 kDa, and it contains a carbohydrate-recognition-binding domain of ∼130 amino acids that enable the specific binding of β-galactosides. This protein localizes to the extracellular matrix, the cytoplasm, and the nucleus. It plays a role in numerous cellular functions including cell adhesion, cell activation and chemoattraction, cell growth, differentiation, cell cycle, apoptosis, innate immunity, cell adhesion, and T-cell regulation. 63,64 It has been known that LGALS3 is distributed widely around the tissues but in a low level.
  > To date, LGALS3 has been extensively studied as an IHC marker of thyroid malignancy, and a high diagnostic accuracy has been reported even for difficult pathological diagnoses. 64 Feilchenfeldt et al reported that the mRNA levels of LGALS3 and thyroglobulin in 28 benign and 31 malignant thyroid samples were quantified by real-time PCR. The LGALS3 expression at the mRNA was 60% (12/20) and the protein level was 100% (8/8), respectively. 65 The positive rate was 84% (41/49) when combined with the LGALS3 and HBME-1 in PTC specimens. 66 Two groups of researchers have detected the LGALS3 by IHC in PTC specimens. Saleh et al have shown that the sensitivity and the specificity for LGALS3 were 92.3% and 77.3%, respectively. 67 Song et al reported that positive expression of LGALS3 was 97% (427/441) in PTC group and 51% (77/151) in the benign thyroid lesions group. 68 These results may further support the notion that the high level of LGALS3 antigen expression occurs in patients with PTC. There are a number of different types of oncolytic viruses that have been altered from natural viruses in the laboratory such as adenovirus, reovirus, measles virus, herpes simplex

[9] High LGALS3 expression induced by HCP5/hsa-miR-27b-3p correlates with poor prognosis and tumor immune infiltration in hepatocellular carcinoma

• Authors: Yinghui Ren, Yongmei Qian, Qicheng Zhang, Xiaoping Li, Mingjiang Li et al.
• Year: 2024
• Venue: Cancer Cell International
• URL: https://www.semanticscholar.org/paper/552bd37c67dea75d0c33a9a0de2acdafcf0dcf6e
• DOI: 10.1186/s12935-024-03309-1
• PMID: 38643145
• PMCID: 11031979
• Citations: 13
• Summary: It is hypothesized that the HCP5/hsa-miR-27b-3p axis could serve as the most promising LGALS3 regulation mechanism in HCC and the upregulation of LGALS3 via the HCP5/hsa-miR-27b-3p axis is associated with unfavorable prognosis and increased tumor immune infiltration in HCC.
• Evidence snippets:
• Snippet 1 (score: 0.770)
  > LGALS3 has a crucial function in mediating cell adhesion as well as cell-cell interaction by recognizing complex carbohydrates on the surface of cells [22,23], as well as regulates cell apoptosis, autophagy, and inflammation [24,25].Interestingly, recent studies suggested that LGALS3 involves in essential cancer-related mechanisms, including cellular metabolism, carcinogenesis, metastasis, neoplasia, angiogenesis, as well as immune escape [26][27][28].In addition, LGALS3 is highly expressed and implicated in different cancer types progression such as HCC, gastric, colorectal, pancreatic carcinomas, melanomas or glioblastomas and breast cancer [29,30].Indeed, LGALS3 has been considered a potential marker for these malignancies.Interestingly, LGALS3, which is differentially expressed in different cancers, has been shown to exhibit tumor suppressor activity in certain cancer types.The different roles of LGALS3 may be attributed to different potential mechanisms that appear cancer-type dependent.The different locations and mutations of LGALS3 also contribute to its various functions.However, LGALS3 remains inadequately understood in HCC and requires further investigation.First, we conducted an extensive investigation of the expression profile, clinical prognosis, and pathologic stage of LGALS3 in HCC through an in-depth analysis of the public database.On the basis of TCGA and CPTAC datasets, we found that LGALS3 gene and protein expression was elevated in HCC tissues.Moreover, the OS and DSS were lesser in patients with HCC having higher expression levels of LGALS3 contrasted to those with low expression levels of LGALS3 based on GEPIA2 and Kaplan-Meier plotter datasets.Meanwhile, the expression of LGALS3 within HCC was significantly associated with the advanced tumor stage and grade, indicating that elevated LGALS3 expression could increase tumor progression.Song et al. [31] indicated that galectin-3 promoted HCC tumorigenesis and metastasis via β-catenin signalling in vitro and in vivo.

[10] SMURF1 controls the PPP3/calcineurin complex and TFEB at a regulatory node for lysosomal biogenesis

• Authors: Qin Xia, Hanfei Zheng, Yang Li, Wanting Xu, Chengwei Wu et al.
• Year: 2023
• Venue: Autophagy
• URL: https://www.semanticscholar.org/paper/7ab13fe72fa12a55aa9304ce52199d1494c8974a
• DOI: 10.1080/15548627.2023.2267413
• PMID: 37909662
• PMCID: 11062382
• Citations: 20
• Summary: This study showed that SMURF1 affected lysosomal biogenesis in response to lysosomal damage by preventing TFEB nuclear translocation, and determined that LLOMe-mediated TFEB nuclear import is dependent on SMURF1 under the condition of MTORC1 inhibition.
• Evidence snippets:
• Snippet 1 (score: 0.760)
  > Consistently,
  > LGALS3 and PPP3R1 were required for binding of PPP3CB and TFEB evidenced by knocking down LGALS3 or PPP3R1 decreased, while overexpression of LGALS3 or PPP3R1 increased, the interaction of PPP3CB and TFEB (Figure 8K, L).Of note, we found that the enhanced PPP3CB and TFEB interaction mediated by SMURF1 overexpression was abolished by LGALS3 deletion (Figure 8M).Overall, these data strengthened our hypothesis that LGALS3 and SMURF1 contribute to PPP3CB from "close" to "open" form, which facilitates TFEB docking to the AID domain (Figure 8N).
• Snippet 2 (score: 0.758)
  > Immunofluorescence assay showed that PPP3R1 was also recruited to lysosomes upon LLOMe treatment in a LGALS3-dependent manner (Figure S4A).To identify the role of PPP3R1 in the formation of complex, as expected, we first found that PPP3CB directly binds with PPP3R1 in a LLOMe-enhanced manner (Figure 6A, B).Considering that PPP3CB was directly associated with LGALS3, we also checked the interaction between PPP3R1 and LGALS3.The results showed that PPP3R1 indirectly binds with LGALS3 (Figure 6C).Similarly, LLOMe treatment also promoted the binding affinity between PPP3R1 and LGALS3 (Figure 6D).We next mapped the key interaction domain of LGALS3 with PPP3R1, and showed the NT domain of LGALS3 was essential for the association with PPP3R1 (Figure 6E, F).Furthermore, overexpression of PPP3CB increased, suppression of PPP3CB abolished, the interactions of PPP3R1 and LGALS3 (Figure 6G, H), suggesting PPP3CB is also the bridge for the interaction between LGALS3 and PPP3R1.Interestingly, we also detected that SMURF1 indirectly interacted with PPP3R1, but not MCOLN1, in a LLOMe-enhanced manner (Figure S4B-E).Given that both SMURF1 and PPP3R1 were indirectly bound with the NT domain of LGALS3, we asked whether SMURF1 affected the interactions between PPP3R1 and LGALS3.Our data indicated that suppression of SMURF1 decreased, overexpression of SMURF1 increased, the interactions of PPP3R1 and LGALS3 (Figure 6I, J), suggesting SMURF1 promotes the recruitment of PPP3R1 by LGALS3.We next mapped the key HECT domain of SMURF1 which was essential for interaction with PPP3R1 (Figure 6K, L).

[11] Krüppel-like Factor 3 (KLF3/BKLF) Is Required for Widespread Repression of the Inflammatory Modulator Galectin-3 (Lgals3)*

• Authors: Alexander J. Knights, Jinfen. J. Yik, Hanapi Mat Jusoh, Laura J. Norton, Alister P. W. Funnell et al.
• Year: 2016
• Venue: The Journal of Biological Chemistry
• URL: https://www.semanticscholar.org/paper/dce84b7faec66ad9234b04f596d036ed32078971
• DOI: 10.1074/jbc.M116.715748
• PMID: 27226561
• Citations: 27
• Influential citations: 1
• Summary: It is shown that the zinc finger transcription factor Krüppel-like factor 3 (KLF3) directly represses galectin-3 transcription, and mechanistic insights into the regulation of Lgals3 are provided, demonstrating that C-terminal binding protein (CtBP) is required to drive optimal KLF3-mediated silencing.
• Evidence snippets:
• Snippet 1 (score: 0.757)
  > Despite the importance of galectin-3 in a host of biological settings, little is known about how its gene is activated (32)(33)(34), and to our knowledge, there is no published work on the repression of Lgals3. Here we have shown that galectin-3 expression is up-regulated in the absence of KLF3, and we have demonstrated that KLF3 directly binds and represses the Lgals3 promoter in vivo. Furthermore, we have provided mechanistic insights into KLF3 repression of Lgals3. In reporter assays, a KLF3 mutant that is unable to bind the co-repressor CtBP showed a reduced ability to repress Lgals3. Analysis of the expression levels of Lgals3 in Klf3 Ϫ/Ϫ MEFs rescued with KLF3 or a KLF3 mutant unable to bind to CtBP also showed that KLF3 recruitment of CtBP is necessary for optimal Lgals3 repression. These two lines of evidence suggest that recruitment of the co-repressor CtBP is important for KLF3 repression of Lgals3 but that CtBP-independent mechanisms also exist. We also assessed the contribution of the KLF3 functional domain to repression in Klf3 Ϫ/Ϫ MEF rescue experiments. KLF3 DNA-binding domain only showed only a modest ability to rescue Lgals3 repression when introduced into Klf3 Ϫ/Ϫ MEFs, suggesting that the functional domain (where CtBP binds) is important and also that direct competition for DNA binding to the Lgals3 promoter between KLF3 and the activating KLF1 is not likely to be a major feature of the mechanism of repression.
  > Galectin-3 has been identified as an important regulator of inflammation in metabolic tissues (27). Its deficiency in mice is associated with increased adiposity, systemic inflammation, and an accumulation of inflammatory cells in metabolic tissues (26,28). This phenotype poses a striking contrast to that seen in mice lacking KLF3, which display reduced fat mass and are protected from diet-induced obesity and glucose intolerance (23).

[12] In-depth quantitative proteomics analysis revealed C1GALT1 depletion in ECC-1 cells mimics an aggressive endometrial cancer phenotype observed in cancer patients with low C1GALT1 expression

• Authors: A. Montero‐Calle, Á. López-Janeiro, Marta L. Mendes, Daniel Perez-Hernandez, Irene Echevarría et al.
• Year: 2023
• Venue: Cellular Oncology
• URL: https://www.semanticscholar.org/paper/92b64e01bcb30f7457ddb8cc4be26de8b0c7cf69
• DOI: 10.1007/s13402-023-00778-w
• PMID: 36745330
• PMCID: 10205863
• Citations: 19
• Summary: C1GALT1 stably depleted ECC-1 cells mimic an EC aggressive phenotype observed in patients and might be useful for the identification and validation of EC markers of progression.
• Evidence snippets:
• Snippet 1 (score: 0.755)
  > Finally, since LGALS3 (Galectin-3) has been shown to interact with O-glycans in the mucosal epithelium [30], and considering its overexpression observed by proteomics and further confirmed by PCR and WB analyses upon depletion of C1GALT1, we focused on the role of LGALS3 in EC by IHC.
  > A total of 151 out of 178 cores from 79 EC patients were considered adequate for LGALS3 expression assessment by IHC. Morphologic assessment of LGALS3 IHC staining characteristics revealed different staining patterns (Fig. 5 A). Out of the 151 evaluable cores, 45 (29.8%) showed absent LGALS3 expression. LGALS3 positive samples showed variable and low intensity protein expression (mean positive tumor cells per sample = 35.4%). A small subset of cores (13/151, 8.6%) demonstrated diffuse (> 90% positive tumor cells per sample) staining. LGALS3 score varied across histologic types, with serous and undifferentiated tumors displaying the highest protein expression (median IHC LGALS3 score = 10, 20, 50 and 55 for endometrioid, clear cell, serous and undifferentiated tumor types, respectively) (Fig. 5B). Interestingly, the aggressive histologic variants (clear cell, serous and undifferentiated) showed higher LGALS3 IHC scores than endometrioid variants (p value < 0.001). In addition, LGALS3 expression positively correlated with tumor grade. High grade tumors (G3) displayed higher protein expression (median LGALS3 IHC score = 30) compared to low grade tumors (median LGALS3 IHC score for G1/G2 tumors = 10). This finding was independent of histologic type, as similar results were observed when analyzing endometrioid tumors.
  > Finally, we interrogated the correlation between the expression levels of LGALS3 and C1GALT1.

[13] Lysosomal damage is a therapeutic target in Duchenne muscular dystrophy

• Authors: Abbass Jaber, Laura Palmieri, R. Bakour, N. Bourg, A. Hong et al.
• Year: 2025
• Venue: Science Advances
• URL: https://www.semanticscholar.org/paper/3265a29ad8c2d48b294017fd50b6df9188b55ecb
• DOI: 10.1126/sciadv.adv6805
• PMID: 41124255
• PMCID: 12542950
• Citations: 7
• Summary: Lysosomal perturbations in myofibers of patients with DMD and animal models are identified, highlighting lysosomal damage as an important pathomechanism in DMD and suggesting that combining trehalose with gene therapy could enhance therapeutic efficacy.
• Evidence snippets:
• Snippet 1 (score: 0.753)
  > To investigate whether cholesterol accumulation in dystrophic muscle is associated with the impaired lysosomal function, we sought a method to quantify lysosomal damage. Several studies have recently focused on lysosomal dysfunction, in which LMP plays a central role (18). However, very few studies have investigated lysosome damage in muscle. One identified marker of LMP is Gal-3 (or LGALS3), which is part of the galectins, a family of lectins that bind specifically to carbohydrates (19). These lectins are present in the cytosol, nucleus, and extracellular matrix and are translocated to the membrane of damaged lysosomes before their removal by the autophagy machinery (20). To analyze LGALS3 expression in a myogenic environment and its capacity to detect LMP, we differentiated healthy human immortalized myoblasts into elongated myotubes for 7 days and then performed immunostaining for LGALS3 and lysosome-associated membrane protein 2 (LAMP2), which is commonly used as a lysosome marker (21). A diffuse expression of LGALS3 was observed in the cells (fig. S1A). Treatment with l-leucyl-l-leucine methyl ester (LLOMe), a lysomotropic agent that induces lysosome-specific membrane damage (22), for 30 min at 2.5 mM triggered the formation of LGALS3-positive puncta, which colocalized with LAMP2, indicating typical damaged lysosomes. An up-regulation of LGALS3 was also detected by Western blotting after 30 min to 1 hour of LLOMe treatment (fig. S1, B and C). LGALS3 puncta were markedly reduced 3 hours after treatment, and LGALS3 expression was restored to the control level, demonstrating efficient lysosomal repair by the cells. This pattern correlated inversely with the amount of LGALS3 released in the media, detected by an enzyme-linked immunosorbent assay (ELISA) assay (fig.

Notes

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Asta Literature Retrieval: Literature evidence for LGALS3 (Homo sapiens): LGALS3 has negative regulation of endocytosis (GO:0045806). Gene/prote...

This report is retrieval-only and is generated directly from Asta results.

• Papers retrieved: 11
• Snippets retrieved: 20

Relevant Papers

[1] LGALS3 is connected to CD74 in a previously unknown protein network that is associated with poor survival in patients with AML

• Authors: P. Ruvolo, Chenyue W. Hu, Y. Qiu, V. Ruvolo, Robin L. Go et al.
• Year: 2019
• Venue: EBioMedicine
• URL: https://www.semanticscholar.org/paper/46bbdbcb4660389e13acba24499cc415d75f18e0
• DOI: 10.1016/j.ebiom.2019.05.025
• PMID: 31105032
• PMCID: 6604360
• Citations: 25
• Influential citations: 2
• Summary: The data suggest that the LGALS3 network and the CD74 network each support AML cell survival and the two networks may cooperate in a novel high risk AML population.
• Evidence snippets:
• Snippet 1 (score: 0.768)
  > LGALS3 is associated with active Fig. 7. Suppression of LGALS3 does not alter gene expression of LGALS3 network protein genes or CD74 in THP-1 cells. RNA from THP-1 transductant cells with either LKO vector control shRNA or LGALS3 shRNA was isolated, cDNA produced, and mRNA levels of ATG7, LGALS3, ITGAL, CCND3, PRKCA, PARP1, CD74, MYC, CD44, SSBP2, PPP2R2A, CLPP, and B2M were determined by qRT-PCR and levels normalized to ABL-1 as described in "Materials and methods".
  > AKT and MAPK signaling. The protein with the strongest positive correlation with LGALS3 is with ATG7, an autophagy protein that has recently been implicated in maintaining hematopoietic stem cells and serving as a survival factor in AML [46,47]. Recent studies implicate LGALS3 in regulation of autophagy via autophagasome formation, though whether the mechanism involves ATG7 is not clear [48]. Interestingly, phosphorylated PKC delta was positively correlated with LGALS3. PKC delta is viewed as a pro-stress kinase but recent studies suggest that the enzyme has pro-survival properties [49][50][51]. Kinehara and colleagues suggest that PKC delta may act in human pluripotent stem cells as part of a mechanism to regulate stem cell renewal [52]. The data also suggest a novel relationship between LGALS3 and PP2A. The negative correlation of LGALS3 expression with PPP2R2A/B/C/D could reflect LGALS3 suppression of PP2A. The PP2A isoform containing PPP2R2A dephosphorylates both AKT and PKC alpha [53]. Thus, potential suppression of the PP2A subunit by LGALS3 could account for elevated AKT and PKC alpha phosphorylation in samples where LGALS3 expression is elevated.
• Snippet 2 (score: 0.757)
  > To determine if LGALS3 may be involved in regulation of the gene expression of the proteins most positively correlated with LGALS3 expression, we utilized THP-1 cells that expressed control lentiviral plasmid (LKO) and THP-1 cells that expressed LGALS3 shRNA. qRT-PCR analysis of cDNA generated from RNA from these cells revealed that there was 90% reduction of LGALS3 expression by the shRNA (Fig. 7). However, suppression of LGALS3 did not result in a major alteration of expression of ATG7, ITGAL, CCND3, PRKCA, PARP1, LGALS3 expression positively correlates with ATG7 and ITGAL and negatively correlates with SSBP2 and ERG in AML. CBioportal software was used to compare RNASeq measured gene expression of LGALS3 with ATG7, ITGAL, SSBP2, ERG, and other genes (listed in Table 3) in AML samples in the TCGA dataset from ref. [39].
• Snippet 3 (score: 0.749)
  > LGALS3 were similarly correlated with gene expression, we utilized cBioPortal software (http://www.cbioportal.org/) to query the TCGA AML database that derived from the 2013 New England Journal of Medicine publication [39]. Of the top nine unmodified proteins that were positively correlated with LGALS3 protein expression, expression of genes for eight proteins (ATG7, ITGAL, MAP2K1, MAPK1, JMJD6, CCND3, VASP, and PRKCA) were significantly higher (q value b0.05) in AML cells with elevated LGALS3 expression in the TCGA database (Fig. 6; Table 3).Expression of LCK was not correlated with LGALS3 (q value = 0.282; Table 3). Of the top nine unmodified proteins that were negatively correlated with LGALS3 protein expression, expression of genes for seven proteins (SSBP2, ERG, KIT, PPP2R2A, PARP1, MYC, and TRIM24) were significantly lower (q value b0.05) in AML cells with elevated LGALS3 expression (Fig. 6; Table 3). Expression of SMAD1 trended lower in cells with elevated LGALS3 (q value = 0.0726; Table 3). Expression of NR4A1 was actually higher in cells with elevated LGALS3 (q value = 0.0399; Table 3). At present, it is not clear if LGALS3 regulates gene expression of any of these genes, whether any of the network proteins may serve as a regulator of LGALS3 gene expression, or whether there is a yet unidentified common regulator to the genes in the LGALS3 RPPA network. To determine if LGALS3 may be involved in regulation of the gene expression of the proteins most positively correlated with LGALS3 expression, we utilized THP-1 cells that expressed control lentiviral plasmid (LKO) and THP-1 cells that expressed LGALS3 shRNA.
• Snippet 4 (score: 0.747)
  > Thus, potential suppression of the PP2A subunit by LGALS3 could account for elevated AKT and PKC alpha phosphorylation in samples where LGALS3 expression is elevated. Induction of PPP2R2A protein (Fig. 5) but not gene expression (Fig. 7) in THP-1 cells expressing LGALS3 shRNA suggests that LGALS3 acts directly on the PP2A subunits via a post-transcriptional mechanism in these cells. The TCGA data (Table 3) however suggests that there is a positive correlation between gene expression of LGALS3 and PPP2R2A suggesting that a common pathway may regulate the two genes. Fig. 8. Progeny clustering identified an optimal number of 4 distinct protein clusters for this ProFnGrp. Protein networks were generated and showed interactions between "core-proteins" (large nodes) and other probed proteins (small nodes) from the data set. Clustering method has been described in our previous publication (ref. [37]) and further information on these protein networks can be found on our website "Leukemia Profile Atlases", available at https://www.leukemiaatlas.org/. Progeny clustering identified one protein cluster with expression similar to that of the normal CD34+ samples which was designated as "normal-state" while three "leukemia-specific" protein patterns characterized by high expression individually of CD74, LGAL3, and a fourth state with both on. PPP2RA/B/C/D was the only LGALS3 network protein demonstrated to be directly regulated by LGALS3 in the THP-1 cells (Fig. 5). In our previous study we saw potent suppression of AKT signaling by LGALS3 inhibition, so perhaps the mechanism involves LGALS3 suppression of the AKT phosphatase [15]. However, we did not see suppression of LGALS3 affect other network proteins in the THP-1 cells (data not shown). The role of other galectins such as LGALS1 in AML biology is not clear.
• Snippet 5 (score: 0.704)
  > To assess whether LGALS3 acts directly on the various LGALS3 correlated proteins identified by RPPA, we utilized THP-1 transductant cells that express control shRNA (LKO) or LGALS3 shRNA that we have previously described [15]. At least in THP-1 cells, in most cases LGALS3 did not regulate protein expression of many of the LGALS3 associated proteins including ATG7, ITGAL, SSBP2, or ERG (Fig. 5; data not shown). At present, it is not clear whether these proteins act to regulate LGALS3 expression or if LGALS3 shares common regulators with these proteins. However, one exception was the PP2A B subunit family PPP2R2A/B/C/D. Suppression of LGALS3 resulted in near 2× fold increase in expression of the PP2A B subunits (Fig. 5) which is consistent
  > LGALS3 expression is prognostic for poor survival outcome in some AML populations. Kaplan Meir curves for overall survival (A) and remission duration (B) in the total AML patients studied are presented. Kaplan Meir curvrves for overall survival among the AML patient population that achieved complete remission (C) and for survival after relapse (D) are also included. with the negative correlation found between the proteins by RPPA (Fig. 3).
• Snippet 6 (score: 0.696)
  > LGALS3 positively regulates BCL2 and MCL-1 gene and protein expression in AML cells by supporting both ERK and AKT pathways [1,2,[12][13][14][15][16][17]. Suppression of LGALS3 by shRNA or with GCS-100 (an inhibitor of LGALS1 and LGALS3) blocks both AKT and ERK signaling pathways [15,17].
  > LGALS3 regulated pathways are involved in expression of genes and protein associated with cancer stem cells (CSC) and thus the galectin likely supports CSC [9]. Recent data suggests that LGALS3 supports malignant cell survival in AML [6,15,18]. In a cohort of Taiwanese AML patients, Cheng and colleagues reported that elevated LGALS3 mRNA was prognostic for poor survival outcome [18]. However, in that study the impact of LGALS3 protein expression or associations of the galectin with potential LGALS3 target proteins was not examined.
  > CD74 (also known as the invariant chain protein) is best known as a chaperone for major histocompatibility (MHC) Class II molecules involved in antigen presentation [19,20]. In addition to mediating MHC Class II molecule endocytosis, CD74 protects these molecules from proteolysis [19][20][21]. CD74 also has MHC Class II independent functions that involve the pro-inflammatory cytokine macrophage inhibitory factor (MIF) and cell surface signaling molecules CD44 and CXCR4 [19][20][21]. CD74 was found to bind MIF but CD74 alone is unable to initiate MIF signaling which requires either CD44 or CXCR4 [19][20][21][22][23]. CD74 dependent MIF signaling pathways include ERK, JNK, and AKT [24][25][26][27]. CD74 dependent MIF signaling has been shown to suppress p53 function and to activate NF kappa B [26,28].
• Snippet 7 (score: 0.692)
  > The role of other galectins such as LGALS1 in AML biology is not clear.
  > LGALS1 may substitute for some LGALS3 functions particularly those involved in survival pathways as knock down of either LGALS1 or LGALS3 sensitized AML cells to BH3 mimetic drugs [15]. The failure of LGALS3 suppression to affect many of the RPPA identified proteins with the exception of PPP2R2A/B/C/D (Fig. 5) may reflect LGALS1 activity in these cells that may not be present in the primary AML cells. It is possible that many of the LGALS3 network proteins act to regulate LGALS3 rather than being regulated by the galectin. It is also possible that LGALS3 and some of the LGALS3 network proteins are subject to regulation by a yet unidentified common regulator(s). Further examination of the mechanism regulating the LGALS3 network is ongoing.
  > Network analysis from the data identifies a new extremely poor prognosis group based on the interaction between the LGALS3 and CD74 associated protein networks revealing potential biological pathways that may be critical in supporting AML cell survival. AML patients with both networks active are 8.5% of patients in the study (Fig. 9A) and thus this group may represent a sizeable population of AML patients. It is possible the two proteins regulate independent survival pathways that may have a synergistic effect on survival when both are active. The top ten biological processes associated with LGALS3 network include processes associated with cell metabolism (GO:0031325; GO:0032268; and GO:0032270), cell migration (GO:0030355), and response to growth factor stimulus (GO:0071363) and response to chemical stimulus (GO:0070887) (Supplemental Table 1). While it is unclear how LGALS3 might mechanistically influence leukemic cell recovery and growth after therapy, perhaps regulation of these cellular processes are important in addition to the well documented role of LGALS3 in regulation of cell cycle and cell proliferation [1,2,13,14].
• Snippet 8 (score: 0.679)
  > However, CD44 is present and interestingly is most elevated in patients with active LGALS3 network and CD74 network (Fig. 8). LGALS3 has been shown to be critical for CD44 endocytosis so LGALS3 would be expected to promote CD44 surface expression [54]. In AML cells with LGALS3 supported CD44 surface expression, CD74 would be predicted to augment signaling mediated by CD44.
  > LGALS3 is well known as an immune regulatory molecule that suppresses host anti-tumor immune surveillance by diverse mechanisms [1,2,55].
  > LGALS3 blocks or at least dampens immune cell function by reducing surface expression of glycosylated T cell receptor in T cells and preventing NK cell receptor binding to antigen [1,2]. LGALS3 has emerged as a critical component in MSC in AML patients to impact response to therapy [56]. It is likely that LGALS3 secreted from MSC and other support cells in the AML microenvironment negatively impacts immune surveillance in AML patients. It is yet to be determined if LGALS3 derived from the leukemia cells plays a role as an immune response inhibitor in AML.
  > LGALS9 is emerging as an important immune checkpoint inhibitor molecule as a TIM-3 binding partner [2,57]. LGALS9 also regulates T cell function as a CD44 binding partner [58]. Whereas LGALS3 binding to CD44 promotes metastasis, LGALS9 binding to CD44 suppresses this process [59,60]. Future RPPA studies to determine the role of LGALS9 and galectins other than LGALS3 are warranted.
  > For the first time, an at risk AML population has been found that is associated with active LGALS3 and active CD74 networks (Fig. 9A and B). At present, it is unclear which if any proteins within the LGALS3 or CD74 networks is driving this phenomenon. CD44, SPP1, and CLPP are highly induced in the patient cohort with both networks active compared to patients with normal-like state (Fig. 8).
• Snippet 9 (score: 0.662)
  > While it is unclear how LGALS3 might mechanistically influence leukemic cell recovery and growth after therapy, perhaps regulation of these cellular processes are important in addition to the well documented role of LGALS3 in regulation of cell cycle and cell proliferation [1,2,13,14]. Many of the CD74 network associated biological processes involved immune regulation (Supplemental Table 3) though it is unclear if CD74 network regulates potential immune response in AML. Many of the CD74 network associated biological processes did include those involved in regulation of cell death and apoptosis (Supplemental Table 3). Of the 31 proteins correlated with CD74 expression, 19 are associated with the biological pathway regulation of cell death (GO.0010941) and 16 are associated with the biological pathway negative regulation of apoptotic process (GO.0043066). The raises the question of what the cross-talk is between the LGALS3 and CD74 networks? Gene expression analysis of CD74, CD44, and CLPP in the THP-1 LKO cells versus THP-1 cells with LGALS3 shRNA showed no or only slight changes in these genes (Fig. 7). Protein expression of CD74, CD44, and CLPP were similar in THP-1 LKO and THP-1 LGALS3 shRNA cells (data not shown). While LGALS3 supports AKT activation via RAS, CD74 would be expected to support AKT via MIF mediated signaling involving CD44 and/or CXCR4 [19][20][21][22][23][24][25][26][27]. Though the functional roles of LGALS3 and CD74 in this process are very different, each network would contribute to activation and perhaps may explain why patients with both active networks do so poorly (Fig. 9A and B). Unfortunately, CXCR4 is not represented in the RPPA panel due to lack of validated antibody. However, CD44 is present and interestingly is most elevated in patients with active LGALS3 network and CD74 network (Fig. 8).

[2] Comparative Proteomic Profiling of Tumor-Associated Proteins in Human Gastric Cancer Cells Treated with Pectolinarigenin

• Authors: Ho Jeong Lee, Venu Venkatarame Gowda Saralamma, S. Kim, S. Ha, P. Vetrivel et al.
• Year: 2018
• Venue: Nutrients
• URL: https://www.semanticscholar.org/paper/630404664201d86cc15f629d5770143629ee1859
• DOI: 10.3390/nu10111596
• PMID: 30380781
• PMCID: 6265996
• Citations: 18
• Summary: Pectolinarigenin, a natural flavonoid that is present in citrus fruits, has been reported to exhibit antitumor effects in several cancers, and proteomic analysis provides vital information about target proteins that are important for PEC-induced cell death in gastric cancer cells.
• Evidence snippets:
• Snippet 1 (score: 0.717)
  > In order to understand the biological relevance of PEC regulated proteins, as shown in Figure 10A,B and Table 3, the gene ontology (GO) terms for biological processes were investigated for all identified proteins. The GO results demonstrated that the highest associations were with the biological processes regulation of the epidermal growth factor receptor signaling pathway (GO: 0042058), related cell cycle (GO: 0007049), and negative regulation of endocytosis (GO: 0045806) in PEC-treated AGS cells. Apoptotic process (GO: 0006915), M phase of mitotic cell cycle (GO: 0000087), cell death (GO: 0008219), positive regulation of receptor-mediated endocytosis (GO: 0048260), and positive regulation of macrophage fusion (GO: 0034241) in PEC-treated MKN28 cells.
  > Figure 10. Gene ontology analysis of (A) AGS and (B) MKN28 cells. The pie charts representing the distribution of the identified proteins according to their biological process. Gene ontology analyses of the determined proteins were assigned according to their biological function, using the web-based tool at GeneCodis (http://genecodis.cnb.csic.es).

[3] High LGALS3 expression induced by HCP5/hsa-miR-27b-3p correlates with poor prognosis and tumor immune infiltration in hepatocellular carcinoma

• Authors: Yinghui Ren, Yongmei Qian, Qicheng Zhang, Xiaoping Li, Mingjiang Li et al.
• Year: 2024
• Venue: Cancer Cell International
• URL: https://www.semanticscholar.org/paper/552bd37c67dea75d0c33a9a0de2acdafcf0dcf6e
• DOI: 10.1186/s12935-024-03309-1
• PMID: 38643145
• PMCID: 11031979
• Citations: 13
• Summary: It is hypothesized that the HCP5/hsa-miR-27b-3p axis could serve as the most promising LGALS3 regulation mechanism in HCC and the upregulation of LGALS3 via the HCP5/hsa-miR-27b-3p axis is associated with unfavorable prognosis and increased tumor immune infiltration in HCC.
• Evidence snippets:
• Snippet 1 (score: 0.717)
  > LGALS3 has a crucial function in mediating cell adhesion as well as cell-cell interaction by recognizing complex carbohydrates on the surface of cells [22,23], as well as regulates cell apoptosis, autophagy, and inflammation [24,25].Interestingly, recent studies suggested that LGALS3 involves in essential cancer-related mechanisms, including cellular metabolism, carcinogenesis, metastasis, neoplasia, angiogenesis, as well as immune escape [26][27][28].In addition, LGALS3 is highly expressed and implicated in different cancer types progression such as HCC, gastric, colorectal, pancreatic carcinomas, melanomas or glioblastomas and breast cancer [29,30].Indeed, LGALS3 has been considered a potential marker for these malignancies.Interestingly, LGALS3, which is differentially expressed in different cancers, has been shown to exhibit tumor suppressor activity in certain cancer types.The different roles of LGALS3 may be attributed to different potential mechanisms that appear cancer-type dependent.The different locations and mutations of LGALS3 also contribute to its various functions.However, LGALS3 remains inadequately understood in HCC and requires further investigation.First, we conducted an extensive investigation of the expression profile, clinical prognosis, and pathologic stage of LGALS3 in HCC through an in-depth analysis of the public database.On the basis of TCGA and CPTAC datasets, we found that LGALS3 gene and protein expression was elevated in HCC tissues.Moreover, the OS and DSS were lesser in patients with HCC having higher expression levels of LGALS3 contrasted to those with low expression levels of LGALS3 based on GEPIA2 and Kaplan-Meier plotter datasets.Meanwhile, the expression of LGALS3 within HCC was significantly associated with the advanced tumor stage and grade, indicating that elevated LGALS3 expression could increase tumor progression.Song et al. [31] indicated that galectin-3 promoted HCC tumorigenesis and metastasis via β-catenin signalling in vitro and in vivo.
• Snippet 2 (score: 0.676)
  > Hepatocellular carcinoma (HCC) is widely recognized for its unfavorable prognosis. Increasing evidence has revealed that LGALS3 has an essential function in initiating and developing several malignancies in humans. Nevertheless, thorough analysis of the expression profile, clinical prognosis, pathway prediction, and immune infiltration of LGALS3 has not been fully explored in HCC. In this study, an initial pan-cancer analysis was conducted to investigate the expression and prognosis of LGALS3. Following a comprehensive analysis, which included expression analysis and correlation analysis, noncoding RNAs that contribute to the overexpression of LGALS3 were subsequently identified. This identification was further validated using HCC clinical tissue samples. TIMER2 and GEPIA2 were employed to examine the correlation between LGALS3 and HCP5 with immunological checkpoints, cell chemotaxis, and immune infiltration in HCC. The R program was applied to analyze the expression distribution of immune score in in HCC patients with high and low LGALS3 expression. The expression profiles of immune checkpoints were also analyzed. Use R to perform GSVA analysis in order to explore potential signaling pathways. First, we conducted pan-cancer analysis for LGALS3 expression level through an in-depth analysis of public databases and found that HCC has a high LGALS3 gene and protein expression level, which were then verified in clinical HCC specimens. Meanwhile, high LGALS3 gene expression is related to malignant progression and poor prognosis of HCC. Univariate and multivariate analyses confirmed that LGALS3 could serve as an independent prognostic marker for HCC. Next, by combining comprehensive analysis and validation on HCC clinical tissue samples, we hypothesize that the HCP5/hsa-miR-27b-3p axis could serve as the most promising LGALS3 regulation mechanism in HCC. KEGG and GO analyses highlighted that the LGALS3-related genes were involved in tumor immunity. Furthermore, we detected a significant positive association between LGALS3 and HCP5 with immunological checkpoints, cell chemotaxis, and immune infiltration. In addition, high LGALS3 expression groups had significantly

[4] Krüppel-like Factor 3 (KLF3/BKLF) Is Required for Widespread Repression of the Inflammatory Modulator Galectin-3 (Lgals3)*

• Authors: Alexander J. Knights, Jinfen. J. Yik, Hanapi Mat Jusoh, Laura J. Norton, Alister P. W. Funnell et al.
• Year: 2016
• Venue: The Journal of Biological Chemistry
• URL: https://www.semanticscholar.org/paper/dce84b7faec66ad9234b04f596d036ed32078971
• DOI: 10.1074/jbc.M116.715748
• PMID: 27226561
• Citations: 27
• Influential citations: 1
• Summary: It is shown that the zinc finger transcription factor Krüppel-like factor 3 (KLF3) directly represses galectin-3 transcription, and mechanistic insights into the regulation of Lgals3 are provided, demonstrating that C-terminal binding protein (CtBP) is required to drive optimal KLF3-mediated silencing.
• Evidence snippets:
• Snippet 1 (score: 0.717)
  > Lgals3 Is Up-regulated in the Absence of KLF3-In studies of the role of KLF3 in hematopoiesis and red blood cell development, microarrays performed on Ter119 ϩ fetal liver cells lacking KLF3 revealed that the Lgals3 gene was consistently up-regulated in knockout animals (15). Because of the importance of galectin-3 in a number of biological settings, we undertook a fuller analysis of whether the expression of Lgals3 was altered in a range of mouse tissues in the absence of KLF3. Lgals3 mRNA levels were assessed in cultured murine embryonic fibroblasts (MEFs) as well as a series of primary tissues from wild-type and Klf3 Ϫ/Ϫ mice by quantitative real-time PCR. In primary and immortalized Klf3 Ϫ/Ϫ MEFs, Lgals3 mRNA was up-regulated 4.7-and 4.3-fold, respectively, compared with wild-type expression (Fig. 1A). Importantly, Lgals3 levels were also found to be elevated in a number of primary tissues dissected from KLF3-deficient mice (Fig. 1B). Derepression was most evident in Klf3 Ϫ/Ϫ subcutaneous (6.7-fold) and epididymal (3.3-fold) white adipose depots and in the heart (6.6-fold) and pancreas (4.2-fold).
  > Following the demonstration that Lgals3 is derepressed in Klf3 Ϫ/Ϫ tissues at the mRNA level, we next sought to determine whether this up-regulation was reflected at the protein level. Whole cell protein extracts were prepared from wild-type and Klf3 Ϫ/Ϫ fat depots and spleens, and the expression of galectin-3 protein was assessed by Western blotting (Fig. 1, C-F).

[5] Pregnancy Galectinology: Insights Into a Complex Network of Glycan Binding Proteins

• Authors: S. Blois, G. Dveksler, G. Vasta, N. Freitag, V. Blanchard et al.
• Year: 2019
• Venue: Frontiers in Immunology
• URL: https://www.semanticscholar.org/paper/68fad2b87411701fa708a1f49f8b918370486857
• DOI: 10.3389/fimmu.2019.01166
• PMID: 31231368
• PMCID: 6558399
• Citations: 56
• Influential citations: 7
• Summary: The relevance of galectin-glycan interactions as potential therapeutic targets in pregnancy disorders is discussed and the importance of angiogenesis during decidualization and in placenta formation is discussed.
• Evidence snippets:
• Snippet 1 (score: 0.701)
  > Lgals3 has been implicated in the regulation of innate and adaptive immune responses, where it participates in the activation or differentiation of immune cells and contributes to phagocytic clearance of microorganisms and apoptotic cells by macrophages (117,118). Lgals3 has been reported to promote but also to inhibit T-cell apoptosis depending on whether it binds to glycoproteins on the cell surface (CD45 and CD71) or to intracellular ligands (Bcl-2) (119, 120). In the placenta, Lgals3 was detected in all trophoblastic lineages including villous cytotrophoblasts (CTB) and EVT with a reduction of Lgals3 expression observed from the VT to the trophoblastic cell columns (121). This pattern of Lgals3 expression correlates with the switch from a proliferative to a migratory trophoblast phenotype and while placental Lgals3 dysregulation has been associated with some obstetric complications including spontaneous or recurrent miscarriages, further studies are needed to understand its contribution to trophoblast biology (81,122). In addition to trophoblasts, Lgals3 is expressed by maternal decidual cells (73). While showing a different expression pattern, both Lgals1 and Lgals3 have been proposed to play a role in cell-cell and cell-matrix interactions of trophoblast during placentation (121). Studies of the importance of Lgals3 in murine pregnancy by Yang et al. indicate that Lgals3 is expressed in the luminal and glandular epithelium and that an increase in Lgals3 is required for proper embryo implantation (123). In addition, Lgals3 affects chemotaxis and morphology of endothelial cells and stimulates capillary tube formation and angiogenesis in vivo (124). Therefore, besides its proposed roles in embryo implantation, immune regulation and trophoblast-matrix interactions, Lgals3 has a potential role in placental angiogenesis.

[6] Periplocin suppresses the growth of colorectal cancer cells by triggering LGALS3 (galectin 3)-mediated lysophagy

• Authors: Kui Wang, Shuyue Fu, Lixia Dong, Dingyue Zhang, Mao Wang et al.
• Year: 2023
• Venue: Autophagy
• URL: https://www.semanticscholar.org/paper/3dadfc351823c4e325e65c171ab3765871189c80
• DOI: 10.1080/15548627.2023.2239042
• PMID: 37471054
• Citations: 35
• Influential citations: 2
• Summary: It is shown that periplocin exhibits promising anticancer activity against CRC both in vitro and in vivo, and is indicated as a potential therapeutic option for the treatment of CRC.
• Evidence snippets:
• Snippet 1 (score: 0.692)
  > We next investigated the mechanism underlying periplocinmediated lysophagy. The expression of LGALS3, a key lysophagy marker [46], was found to be upregulated following periplocin treatment as evidenced by immunofluorescent staining (Figure 2M). To this end, we presumed that periplocin-induced lysophagy might be attributable to the upregulation of LGALS3. Indeed, periplocin treatment prominently elevated the protein level of LGALS3 as evidence by immunoblotting analysis (Figure 6A). The increased protein level of LGALS3 was further confirmed in tumor xenografts from periplocin-treated mice (Figure 6B,C). However, no obvious change was observed on the mRNA level of LGALS3 in periplocin-treated cells compared with controls (Figure S6A), suggesting that transcriptional regulation was not involved in increased LGALS3 expression following periplocin treatment. Therefore, we postulated that periplocin might elevate LGALS3 by regulating protein stability. Of note, cycloheximide (CHX, a translational inhibitor) treatment led to an obvious decrease in LGALS3 protein level in control cells, but had no obvious effect on the upregulated protein level of LGALS3 in periplocin-treated cells, suggesting periplocin maintains LGALS3 stability (Figure 6D,E). In support of this, treatment with MG132 (a proteasome inhibitor) failed to further enhance the protein level of LGALS3 in response to periplocin treatment (Figure 6F,G). These data suggest that periplocin may prevent proteasomal degradation of LGALS3.
  > We therefore measured the effect of periplocin on LGALS3 ubiquitination. As shown in Figure 6H, periplocin markedly decreased the ubiquitin-conjugated level of LGALS3.

[7] Identification of an Internal Gene to the Human Galectin-3 Gene with Two Different Overlapping Reading Frames That Do Not Encode Galectin-3*

• Authors: M. Guittaut, Stéphane Charpentier, Thierry Normand, Martine Dubois, J. Raimond et al.
• Year: 2001
• Venue: The Journal of Biological Chemistry
• URL: https://www.semanticscholar.org/paper/75ca62f4b6eb66b3bcdac062664da410941fdcaa
• DOI: 10.1074/JBC.M002523200
• PMID: 11160123
• Citations: 37
• Influential citations: 6
• Summary: It is demonstrated that these transcripts arise from an internal gene embedded within LGALS3 and named galig (Galectin-3 internal gene), which appears to be tightly regulated and principally activated in leukocytes from peripheral blood.
• Evidence snippets:
• Snippet 1 (score: 0.690)
  > Human Rapid-Scan Gene Expression Panel was used to detect the alternative transcripts in various human tissues using RT-PCR. The primers used were designed to amplify a 923-or 629-bp fragment.
  > LGALS3 transcripts were detected as a 457-bp DNA and actin transcripts as a 640-bp DNA. PCR was performed using 0.25 ng or 2.5 ng (10ϫ) template cDNA.
  > average of other human proteins is 10 times lower. This rich content in tryptophans confers hydrophobic properties that may account for the membrane localization of the ORF2⅐EGFP protein (Fig. 6). Consistent with the mitochondrial localization of the ORF2⅐EGFP fusion protein, this sequence exhibits the common properties of mitochondrial-imported proteins such as the enrichment of arginine, leucine, and serine residues (36).
  > Tissue Specificity of galig Expression-Detection of galig transcripts in HOS cells and colon tumor cells revealed a low expression level. Based on this observation, the rationale that the appearance of galig transcripts may have resulted from a leaky transcription of a cryptic promoter rather than from an independently functioning promoter could not be excluded. Screening of several human tissues indicated clearly that galig is a tightly regulated gene whose expression is most efficient in leukocytes from peripheral blood. The low level of transcription in bone marrow indicates that galig is specifically expressed in mature forms of leukocytes. Whereas the precise quantification of galig mRNA has not been addressed in these experiments, it is clear that these transcripts are much less abundant than LGALS3 transcripts. This may not be surprising considering that LGALS3 is known to be highly expressed when activated (37,38). Indeed, the amount of LGALS3 transcripts appeared as abundant as those from actin genes. This shows a different type of regulation by the galig and LGALS3 promoters. In particular, muscle, stomach, and uterus, although expressing low levels of galig transcripts, revealed no LGALS3 transcripts, thus indicating an independent functioning of the two promoters.

[8] LGALS3 (galectin 3) mediates an unconventional secretion of SNCA/α-synuclein in response to lysosomal membrane damage by the autophagic-lysosomal pathway in human midbrain dopamine neurons

• Authors: Kevin J. Burbidge, D. J. Rademacher, Jessica E Mattick, Stephanie R. Zack, A. Grillini et al.
• Year: 2021
• Venue: Autophagy
• URL: https://www.semanticscholar.org/paper/cc5e102f7ebd04ebabcf3db8dfc995e5999c4629
• DOI: 10.1080/15548627.2021.1967615
• PMID: 34612142
• PMCID: 9196737
• Citations: 49
• Summary: A human midbrain dopamine (mDA) neuronal culture model is used to provide evidence in support of a cellular mechanism that explains the cell-to-cell transfer of pathological forms of SNCA that are observed in PD and it is demonstrated that LGALS3 (galectin 3) mediates the release of S NCA following vesicular damage.
• Evidence snippets:
• Snippet 1 (score: 0.682)
  > Galectin recruitment to damaged vesicles leads to their recognition by autophagic adapter proteins and, subsequently, to their degradation via autophagy [25][26][27]. We and others have demonstrated that fibrillar forms of SNCA, MAPT/tau and other amyloids can induce vesicle damage following endocytosis, leading to the recruitment of LGALS3, LGALS8, autophagic adaptors, and effector proteins [6,[28][29][30]. When postmortem brain tissue from five PD patients was stained for LGALS3 and SNCA phosphorylated at serine 129 (p-S129) to identify LBs, a majority of the examined LBs displayed LGALS3 coronas [28]. The presence of LGALS3 in LBs suggests a history of membrane damage.
  > Accumulating evidence reveals that the biological functions of galectin proteins are central to the ALP impairment that occurs in PD and other neurodegenerative diseases [31][32][33][34][35]. The Deretic group demonstrated that the re-localization of LGALS3, LGALS8, and LGALS9 to damaged lysosomal compartments coordinates the cellular autophagic response [36][37][38][39][40]. Specifically, in combination with ULK1, TRIM16 (tripartite motif containing 16), and ATG16L1, LGALS3 facilitates the recruitment of autophagic adaptors, receptors, and effectors to damaged lysosomal membranes [38,40]. A recent genome-wide association study reported that single nucleotide polymorphisms in LGALS3 (gene transcript) are associated with an increased risk of PD [35]. Additionally, increased LGALS3 in the cerebrospinal fluid of PD patients has been reported [31,34,41].
  > Recent studies have also demonstrated that galectins and proteins normally associated with ALP degradation also act to promote an unconventional secretory mechanism referred to as secretory autophagy [39,42,43].

[9] Beyond Colonoscopy: Exploring New Cell Surface Biomarkers for Detection of Early, Heterogenous Colorectal Lesions

• Authors: Saleh M. Ramezani, Arianna Parkhideh, P. Bhattacharya, M. Farach-Carson, D. Harrington
• Year: 2021
• Venue: Frontiers in Oncology
• URL: https://www.semanticscholar.org/paper/4b48091d0ad86a2121491218707db23e88605000
• DOI: 10.3389/fonc.2021.657701
• PMID: 34290978
• PMCID: 8287259
• Citations: 13
• Summary: This review contextualizes existing and emergent CRC surface biomarkers and assess each’s potential as a candidate marker for early marker-based detection of CRC lesions and presents an overview of recent advances in imaging techniques useful for visual detection of surface biomarker detection.
• Evidence snippets:
• Snippet 1 (score: 0.673)
  > Galectin 3, or LGALS3, is a member of the galectin family, a group of carbohydrate-binding lectins characterized by their binding affinity for beta-galactosides (85).
  > LGALS3 is expressed at the cell surface, where it interacts with the extracellular matrix, especially with glycoproteins, and has the ability to affect intracellular signaling pathways (42). LGALS3-expressing cells also possess higher ALDH1 activity, which often correlates with a dedifferentiated cancer stem cell phenotype, than do their LGALS3-negative counterparts (86).
  > The correlation of LGALS3 expression in CRC with clinical pathological characteristics has been explored in several immunohistochemical and RT-PCR studies. In one study, the IHC staining of CRC tissue (n=61) and normal adjacent tissue (n=23) samples showed significantly higher LGALS3 expression in cancer tissue (62.5%) versus normal cancer-adjacent tissue (13.0%) (41). In another study, 75% of CRC tissue samples stain high for LGALS3, and ten CRC cell lines were shown to have increased LGALS3 protein levels compared to HeLa cells (42).
  > LGALS3 expression varies according to cancer staging and the degree of differentiation of the adenocarcinoma. LGALS3 mRNA levels were higher in early stage colorectal cancers (58% in stage I) compared to advanced cancers (50% in stage IV) (43). Protein analysis found higher LGALS3 levels in primary adenocarcinomas than in metastatic adenocarcinomas, and stronger LGALS3 staining in well-differentiated tumor areas compared to poorly differentiated tumor areas (43). Conversely, colorectal adenocarcinomas may display higher levels of LGALS3 than do colorectal adenomas; one study sets the rate of colorectal adenocarcinoma expression of LGALS3 at 95% while only 73% of adenomas were positive for LGALS3 (43).

[10] Thyroid malignant neoplasm-associated biomarkers as targets for oncolytic virotherapy

• Authors: Mi Guan, Yanping Ma, S. Shah, G. Romano
• Year: 2016
• Venue: Oncolytic Virotherapy
• URL: https://www.semanticscholar.org/paper/9f79d851e32ad25e83c0a2d64e12919bf81a89f8
• DOI: 10.2147/OV.S99856
• PMID: 27579295
• PMCID: 4996252
• Citations: 4
• Summary: This review focuses on the strategy of biomarkers for the production of novel TMN oncolytic therapeutics, which may improve the specificity of targeting of tumor cells and limit adverse effects in patients.
• Evidence snippets:
• Snippet 1 (score: 0.671)
  > The Galectin-3 (LGALS3) is a protein that is encoded by a single gene, LGALS3, located on chromosome 14, locus q21-q22. 63 The molecular weight of this protein is ∼30 kDa, and it contains a carbohydrate-recognition-binding domain of ∼130 amino acids that enable the specific binding of β-galactosides. This protein localizes to the extracellular matrix, the cytoplasm, and the nucleus. It plays a role in numerous cellular functions including cell adhesion, cell activation and chemoattraction, cell growth, differentiation, cell cycle, apoptosis, innate immunity, cell adhesion, and T-cell regulation. 63,64 It has been known that LGALS3 is distributed widely around the tissues but in a low level.
  > To date, LGALS3 has been extensively studied as an IHC marker of thyroid malignancy, and a high diagnostic accuracy has been reported even for difficult pathological diagnoses. 64 Feilchenfeldt et al reported that the mRNA levels of LGALS3 and thyroglobulin in 28 benign and 31 malignant thyroid samples were quantified by real-time PCR. The LGALS3 expression at the mRNA was 60% (12/20) and the protein level was 100% (8/8), respectively. 65 The positive rate was 84% (41/49) when combined with the LGALS3 and HBME-1 in PTC specimens. 66 Two groups of researchers have detected the LGALS3 by IHC in PTC specimens. Saleh et al have shown that the sensitivity and the specificity for LGALS3 were 92.3% and 77.3%, respectively. 67 Song et al reported that positive expression of LGALS3 was 97% (427/441) in PTC group and 51% (77/151) in the benign thyroid lesions group. 68 These results may further support the notion that the high level of LGALS3 antigen expression occurs in patients with PTC. There are a number of different types of oncolytic viruses that have been altered from natural viruses in the laboratory such as adenovirus, reovirus, measles virus, herpes simplex

[11] Gene Prioritization for Imaging Genetics Studies Using Gene Ontology and a Stratified False Discovery Rate Approach

• Authors: R. Baldock, A. Ferguson, W. M. Brown, Sejal Patel, M Mallar Chakravarty et al.
• Year: 2016
• Venue: Frontiers in Neuroinformatics
• URL: https://www.semanticscholar.org/paper/9a53e7ac6c4f67e80679c6eb8016c4ccced3d7c9
• DOI: 10.3389/fninf.2016.00014
• PMID: 27092072
• PMCID: 4823264
• Citations: 8
• Influential citations: 1
• Summary: A novel method that utilizes Gene Ontology, an online database, to select and prioritize certain genes, employing a stratified false discovery rate (sFDR) approach to investigate their associations with imaging phenotypes is developed.
• Evidence snippets:
• Snippet 1 (score: 0.665)
  > Therefore the parent term that is regulated was selected, in this case the term "receptormediated endocytosis, " and the parent term that regulates a biological process but does not specify positive or negative regulation ("regulation of receptor-mediated endocytosis") is removed-shown in a yellow box -because the child term is more specific in terms of explaining how it is regulating the parent term (e.g., negative regulation of receptor-mediated endocytosis), Figure 3C.
  > Step 4: Quick GO was used to extract all the genes that are associated to the OGO terms (as displayed in Figure 4 in green boxes) in the pruned "transport system" network. SNPs from these genes were extracted from the ENIGMA2 and ADNI1 (Supplementary Section 2) dataset using a reference file containing the start and end positions of the transcribed gene portion according to the Homo sapiens build 37 protein and coding genes from National Center for Biotechnology Information (NCBI). This list of SNPs formed the priority list for sFDR.

Notes

• This provider combines search_papers_by_relevance with snippet_search.
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Asta Literature Retrieval: Literature evidence for LGALS3 (Homo sapiens): LGALS3 has disaccharide binding (GO:0048030). Gene/protein: LGALS3. Or...

This report is retrieval-only and is generated directly from Asta results.

• Papers retrieved: 15
• Snippets retrieved: 20

Relevant Papers

[1] Clusterin Seals the Ocular Surface Barrier in Mouse Dry Eye

• Authors: Aditi Bauskar, W. Mack, J. Mauris, P. Argüeso, M. Heur et al.
• Year: 2015
• Venue: PLoS ONE
• URL: https://www.semanticscholar.org/paper/ddc53237e6b4b7c325cb047e4eaf34098273148e
• DOI: 10.1371/journal.pone.0138958
• PMID: 26402857
• PMCID: 4581869
• Citations: 35
• Influential citations: 2
• Summary: It is shown that CLU prevents and ameliorates ocular surface barrier disruption by a remarkable sealing mechanism dependent on attainment of a critical all-or-none concentration, and suggests CLU as a biotherapeutic for dry eye.
• Evidence snippets:
• Snippet 1 (score: 0.933)
  > In other cases, CLU spots were clearly separate.
  > Next we considered what kinds of ocular surface molecules might bind CLU.
  > LGALS3, a key component of the ocular surface barrier, is a member of the galectin class of beta-galactosidebinding proteins. What is known about the glycosyl moiety of CLU is consistent with LGALS3 binding [25,27]. CLU applied to an LGALS3-sepharose affinity column bound to the beads and was not eluted 0.1 M sucrose, a disaccharide that does not compete with LGALS3 sugar binding, but was mostly eluted with a competitive inhibitor of LGALS3 sugar binding, 0.1 M beta-lactose (Fig 5C). This suggests that CLU binding to LGALS3 is specific for the beta-galactoside-binding function.

[2] Beyond Colonoscopy: Exploring New Cell Surface Biomarkers for Detection of Early, Heterogenous Colorectal Lesions

• Authors: Saleh M. Ramezani, Arianna Parkhideh, P. Bhattacharya, M. Farach-Carson, D. Harrington
• Year: 2021
• Venue: Frontiers in Oncology
• URL: https://www.semanticscholar.org/paper/4b48091d0ad86a2121491218707db23e88605000
• DOI: 10.3389/fonc.2021.657701
• PMID: 34290978
• PMCID: 8287259
• Citations: 13
• Summary: This review contextualizes existing and emergent CRC surface biomarkers and assess each’s potential as a candidate marker for early marker-based detection of CRC lesions and presents an overview of recent advances in imaging techniques useful for visual detection of surface biomarker detection.
• Evidence snippets:
• Snippet 1 (score: 0.812)
  > Galectin 3, or LGALS3, is a member of the galectin family, a group of carbohydrate-binding lectins characterized by their binding affinity for beta-galactosides (85).
  > LGALS3 is expressed at the cell surface, where it interacts with the extracellular matrix, especially with glycoproteins, and has the ability to affect intracellular signaling pathways (42). LGALS3-expressing cells also possess higher ALDH1 activity, which often correlates with a dedifferentiated cancer stem cell phenotype, than do their LGALS3-negative counterparts (86).
  > The correlation of LGALS3 expression in CRC with clinical pathological characteristics has been explored in several immunohistochemical and RT-PCR studies. In one study, the IHC staining of CRC tissue (n=61) and normal adjacent tissue (n=23) samples showed significantly higher LGALS3 expression in cancer tissue (62.5%) versus normal cancer-adjacent tissue (13.0%) (41). In another study, 75% of CRC tissue samples stain high for LGALS3, and ten CRC cell lines were shown to have increased LGALS3 protein levels compared to HeLa cells (42).
  > LGALS3 expression varies according to cancer staging and the degree of differentiation of the adenocarcinoma. LGALS3 mRNA levels were higher in early stage colorectal cancers (58% in stage I) compared to advanced cancers (50% in stage IV) (43). Protein analysis found higher LGALS3 levels in primary adenocarcinomas than in metastatic adenocarcinomas, and stronger LGALS3 staining in well-differentiated tumor areas compared to poorly differentiated tumor areas (43). Conversely, colorectal adenocarcinomas may display higher levels of LGALS3 than do colorectal adenomas; one study sets the rate of colorectal adenocarcinoma expression of LGALS3 at 95% while only 73% of adenomas were positive for LGALS3 (43).

[3] Periplocin suppresses the growth of colorectal cancer cells by triggering LGALS3 (galectin 3)-mediated lysophagy

• Authors: Kui Wang, Shuyue Fu, Lixia Dong, Dingyue Zhang, Mao Wang et al.
• Year: 2023
• Venue: Autophagy
• URL: https://www.semanticscholar.org/paper/3dadfc351823c4e325e65c171ab3765871189c80
• DOI: 10.1080/15548627.2023.2239042
• PMID: 37471054
• Citations: 35
• Influential citations: 2
• Summary: It is shown that periplocin exhibits promising anticancer activity against CRC both in vitro and in vivo, and is indicated as a potential therapeutic option for the treatment of CRC.
• Evidence snippets:
• Snippet 1 (score: 0.809)
  > In addition, periplocin was found to stabilize the protein level of LGALS3 against thermal changes using a cellular thermal shift assay (CETSA) (Figure 6J,K), implying the binding of periplocin with LGALS3. The interaction between periplocin and LGALS3 was further confirmed by drug affinity responsive target stability (DARTS) analysis, as evidenced by a more stable property of LGALS3 protein against pronase digestion in response to periplocin treatment (Figure 6L,M). Moreover, using semiflexible docking analysis, we found that LGALS3 showed a good binding activity for periplocin, with a binding energy of −6.689 kcal/mol. Glu165, Arg162, Gly152, Gln150, Arg144, and Asn143 of LGALS3 were identified as possible sites for periplocin binding (Figure 6N,O), which required further experimental investigation. Together, these data suggest that periplocin binds and prevents ubiquitin-mediated degradation of LGALS3 in CRC cells.
• Snippet 2 (score: 0.753)
  > Scale bar: 10 μm. (I) Immunofluorescent analysis of the colocalization of LGALS3 with ubiquitin in CRC cells treated with or without 0.50 μM periplocin for 24 h. Scale bar: 10 μm. (J) Representative fluorescent images of CRC cells transiently expressing Mrfp-GFP-tandem fluorescent-tagged LGALS3 (tfGal3) followed by 0.50 μM periplocin treatment for 24 h. Scale bar: 10 μm. (K) Quantitative analysis of the GFP + RFP + or GFP − RFP + LGALS3 puncta in (J). (L) the relative decreased ratio of Magic Red intensity, relative increased ratio of LysoSensor Blue intensity, relative increased ratio of the interaction between LGALS3 and TRIM16, and relative increased ratio of LC3B-II protein level in DLD-1 cells following 0.50 μM periplocin treatment at different time periods. Results are representative of three independent experiments. Data are presented as mean ± SD. P < 0.05, P < 0.01, **P < 0.001. for LGALS3 degradation, we generated lysine to arginine mutants of LGALS3 at K196 or Lys210 (LGALS3 K196R or LGALS3 K210R ). As shown in Figure 6I, the ubiquitinconjugated level of LGALS3 K196R mutant was comparable to the wild type (WT), whereas K210 mutation significantly decreased LGALS3 ubiquitination. These results suggest that periplocin elevates LGALS3 level by preventing K210 ubiquitination and proteasomal degradation. In addition, periplocin was found to stabilize the protein level of LGALS3 against thermal changes using a cellular thermal shift assay (CETSA) (Figure 6J,K), implying the binding of periplocin with LGALS3.

[4] Impairment of lysosomal quality control in Huntington disease

• Authors: P. Rusmini, F. Mina, M. Valenza, Martina Vitali, V. Ferrari et al.
• Year: 2025
• Venue: Cell Death & Disease
• URL: https://www.semanticscholar.org/paper/c874bbb3c9e6aa0a3f74519c022f3fa822daf4a8
• DOI: 10.1038/s41419-025-08103-z
• PMID: 41145409
• PMCID: 12559425
• Citations: 4
• Influential citations: 1
• Summary: TFEB and TFE3 are sequestered in muHTT aggregates, and muHTT proteins associates with LMP triggering the translocation of LGALS3 to the lumen of lysosomes, with a close relation between polyQ size and severity of these events.
• Evidence snippets:
• Snippet 1 (score: 0.791)
  > In HD, high levels of LGALS3 have been found in plasma and brain of patients and mice. LGALS3 upregulation was observed in HD mice before the motor symptoms, in the microglia LGALS3 was found associated to damaged lysosomes and its suppression in microglia ameliorated the HD mice phenotype [36].
  > LGALS3 is emerging as a key factor for NDs for its intracellular role in lysosomal damage, but also for its functions linked to its secretion in the extracellular space. Many pieces of evidence suggest its detrimental role in neurodegeneration, even if a protective role of LGALS3 has been reported (reviewed in ref. [75]). LGALS3 mechanisms of action need further investigation but its pharmacological modulation might represent a valuable target for intervention for NDs. LGALS3 inhibitors have already been tested in metabolic and fibrotic diseases, and these approaches might be applied to NDs. 3′-bis-(4aryltriazol-1-yl) thiodigalactoside (GB039, formerly named TD139), a synthetic small molecule that antagonizes LGALS3 activity by binding to the carbohydrate recognition domain, was effective in idiopathic pulmonary fibrosis and retinal degeneration [76,77]. Pectins, plant cell wall polysaccharides, mostly obtained from citrus and apples, represent natural LGALS3 inhibitors [78,79].
  > In summary, our experiments suggest that LQC impairment might contribute to HD. Indeed, the LGALS3 accumulation observed in HD cellular models due to TFEB and TFE3 sequestration by muHTT inclusions causes LMP and lysophagy impairment, in turn, influences LQC.
  > Fig. 8 TFEB and TFE3 sequestration affects the LQC. A, B NSC-34 cells were transfected with wt or muHTT.

[5] Mutation of the galectin‐3 glycan‐binding domain ( Lgals3‐R200S) enhances cortical bone expansion in male mice and trabecular bone mass in female mice

• Authors: Kevin A. Maupin, Daniel T. Dick, Vari Vivarium, Transgenics Core, B. Williams
• Year: 2020
• Venue: FEBS Open Bio
• URL: https://www.semanticscholar.org/paper/6ab62ea9acc6fef617d0b1f237c1a477f45b05c7
• DOI: 10.1002/2211-5463.13483
• PMID: 36062328
• PMCID: 9527582
• Citations: 2
• Summary: The results suggest that the trabecular bone phenotype of Lgals3-KO mice was driven primarily by loss of extracellular galectin-3, while the cortical bone phenotypeof Lgal3- KO mice may have also been influenced by Loss of intracellular galECTin- 3.
• Evidence snippets:
• Snippet 1 (score: 0.791)
  > We previously observed that genomic loss of galectin-3 (Gal-3; encoded by Lgals3) in mice has a significant protective effect on age-related bone loss. Gal-3 has both intracellular and extracellular functionality, and we wanted to assess whether the affect we observed in the Lgals3 knockout (KO) mice could be attributed to the ability of Gal-3 to bind glycoproteins. Mutation of a highly conserved arginine to a serine in human Gal-3 (LGALS3-R186S) blocks glycan binding and secretion. We generated mice with the equivalent mutation (Lgals3-R200S) and observed a subsequent reduction in Gal-3 secretion from mouse embryonic fibroblasts and in circulating blood. When examining bone structure in aged mice, we noticed some similarities to the Lgals3-KO mice and some differences. First, we observed greater bone mass in Lgals3-R200S mutant mice, as was previously observed in Lgals3-KO mice. Like Lgals3-KO mice, significantly increased trabecular bone mass was only observed in female Lgals3-R200S mice. These results suggest that the greater bone mass observed is driven by the loss of extracellular Gal-3 functionality. However, the results from our cortical bone expansion data showed a sex-dependent difference, with only male Lgals3-KO mice having an increased response, contrasting with our earlier study. These notable sex differences suggest a potential role for sex hormones, most likely androgen signaling, being involved. In summary, our results suggest that targeting extracellular Gal-3 function may be a suitable treatment for age-related loss of bone mass.
  > Galectin-3 (Gal-3; encoded by Lgals3) is a protein that functions outside the cell to regulate glycoprotein secretion and turnover [1,2] and intracellularly in protein chaperoning and mRNA splicing [3,4]. We previously found that genomic deletion of Gal-3 in mice (Lgals3-KO) protects the mice against age-related [5] or sex-hormone deprivation bone loss [6]. A better understanding of the
• Snippet 2 (score: 0.785)
  > The study of galectin-3 is complicated by its ability to function both intracellularly and extracellularly. While the mechanism of galectin-3 secretion is unclear, studies have shown that the mutation of a highly conserved arginine to a serine in human galectin-3 (LGALS3-R186S) blocks glycan binding and secretion. To gain insight into the roles of extracellular and intracellular functions of galectin-3, we generated mice with the equivalent mutation (Lgals3-R200S) using CRISPR/Cas9-directed homologous recombination. Consistent with a reduction in galectin-3 secretion, we observed significantly reduced galectin-3 protein levels in the plasma of heterozygous and homozygous mutant mice. We observed a similar increased bone mass phenotype in Lgals3-R200S mutant mice at 36 weeks as we previously observed in Lgals3-KO mice with slight variation. Like Lgals3-KO mice, Lgals3-R200S females, but not males, had significantly increased trabecular bone mass. However, only male Lgals3-R200S mice showed increased cortical bone expansion, which we had previously observed in both male and female Lgals3-KO mice and only in female mice using a separate Lgals3 null allele (Lgals3). These results suggest that the trabecular bone phenotype of Lgals3-KO mice was driven primarily by loss of extracellular galectin-3. However, the cortical bone phenotype of Lgals3-KO mice may have also been influenced by loss of intracellular galectin-3. Future analyses of these mice will aid in identifying the cellular and molecular mechanisms that contribute to the Lgals3-deficient bone phenotype as well as aid in distinguishing the extracellular vs. intracellular roles of galectin-3 in various signaling pathways.
• Snippet 3 (score: 0.750)
  > In this study, we generated the Lgals3-R200S allele using CRISPR/Cas9 and a single-stranded DNA oligonucleotide as a template for homologous recombination. Mutation of the cognate arginine to serine in human Gal-3 (R186S) prevents Gal-3 secretion and glycan-binding [30,31,40]. Because mutation of the functionally equivalent arginine in galectin-7 also prevents glycan-binding [32,33], the R200S mutation in Gal-3 should be functionally equivalent. As confirmation, our surface biotinylation experiment demonstrated a dose-dependent reduction in surface Gal-3 in heterozygous and homozygous Lgals3-R200S mice. In our aged mouse bone studies, we observed a sexdependent increase in trabecular bone mass in female Lgals3-R200S mice. Yet only male Lgals3-R200S had significant increase in cortical bone expansion. The increased cortical bone expansion was coupled with reduced tissue quality (reduced max stress), and no change in tissue or whole bone stiffness values.
  > Similar to the findings presented here, we previously observed that female mice with genomic loss of Gal-3 (Lgals3-KO mice) had significant protection against age-related trabecular bone loss between 24 and 36 weeks of age [5]. But Lgals3-KO mice also had increased cortical bone expansion, whereas only male Lgals3-R200S did in this study. The effect size of the increases in cortical bone size was greater in Lgals3-KO females than males [5]. The similarities between Lgals3-R200S and Lgals3-KO mice (i.e., increased trabecular bone mass in female mice and increased cortical bone expansion in males) likely reflect the role of extracellular Gal-3 loss in increasing bone mass. Conversely, the differences between the two models (tissue stiffness and lack of female cortical bone expansion) could reflect the role of intracellular Gal-3.
  > The female dominance of the cortical bone expansion in

[6] Thyroid malignant neoplasm-associated biomarkers as targets for oncolytic virotherapy

• Authors: Mi Guan, Yanping Ma, S. Shah, G. Romano
• Year: 2016
• Venue: Oncolytic Virotherapy
• URL: https://www.semanticscholar.org/paper/9f79d851e32ad25e83c0a2d64e12919bf81a89f8
• DOI: 10.2147/OV.S99856
• PMID: 27579295
• PMCID: 4996252
• Citations: 4
• Summary: This review focuses on the strategy of biomarkers for the production of novel TMN oncolytic therapeutics, which may improve the specificity of targeting of tumor cells and limit adverse effects in patients.
• Evidence snippets:
• Snippet 1 (score: 0.780)
  > The Galectin-3 (LGALS3) is a protein that is encoded by a single gene, LGALS3, located on chromosome 14, locus q21-q22. 63 The molecular weight of this protein is ∼30 kDa, and it contains a carbohydrate-recognition-binding domain of ∼130 amino acids that enable the specific binding of β-galactosides. This protein localizes to the extracellular matrix, the cytoplasm, and the nucleus. It plays a role in numerous cellular functions including cell adhesion, cell activation and chemoattraction, cell growth, differentiation, cell cycle, apoptosis, innate immunity, cell adhesion, and T-cell regulation. 63,64 It has been known that LGALS3 is distributed widely around the tissues but in a low level.
  > To date, LGALS3 has been extensively studied as an IHC marker of thyroid malignancy, and a high diagnostic accuracy has been reported even for difficult pathological diagnoses. 64 Feilchenfeldt et al reported that the mRNA levels of LGALS3 and thyroglobulin in 28 benign and 31 malignant thyroid samples were quantified by real-time PCR. The LGALS3 expression at the mRNA was 60% (12/20) and the protein level was 100% (8/8), respectively. 65 The positive rate was 84% (41/49) when combined with the LGALS3 and HBME-1 in PTC specimens. 66 Two groups of researchers have detected the LGALS3 by IHC in PTC specimens. Saleh et al have shown that the sensitivity and the specificity for LGALS3 were 92.3% and 77.3%, respectively. 67 Song et al reported that positive expression of LGALS3 was 97% (427/441) in PTC group and 51% (77/151) in the benign thyroid lesions group. 68 These results may further support the notion that the high level of LGALS3 antigen expression occurs in patients with PTC. There are a number of different types of oncolytic viruses that have been altered from natural viruses in the laboratory such as adenovirus, reovirus, measles virus, herpes simplex

[7] SMURF1 controls the PPP3/calcineurin complex and TFEB at a regulatory node for lysosomal biogenesis

• Authors: Qin Xia, Hanfei Zheng, Yang Li, Wanting Xu, Chengwei Wu et al.
• Year: 2023
• Venue: Autophagy
• URL: https://www.semanticscholar.org/paper/7ab13fe72fa12a55aa9304ce52199d1494c8974a
• DOI: 10.1080/15548627.2023.2267413
• PMID: 37909662
• PMCID: 11062382
• Citations: 20
• Summary: This study showed that SMURF1 affected lysosomal biogenesis in response to lysosomal damage by preventing TFEB nuclear translocation, and determined that LLOMe-mediated TFEB nuclear import is dependent on SMURF1 under the condition of MTORC1 inhibition.
• Evidence snippets:
• Snippet 1 (score: 0.758)
  > Immunofluorescence assay showed that PPP3R1 was also recruited to lysosomes upon LLOMe treatment in a LGALS3-dependent manner (Figure S4A).To identify the role of PPP3R1 in the formation of complex, as expected, we first found that PPP3CB directly binds with PPP3R1 in a LLOMe-enhanced manner (Figure 6A, B).Considering that PPP3CB was directly associated with LGALS3, we also checked the interaction between PPP3R1 and LGALS3.The results showed that PPP3R1 indirectly binds with LGALS3 (Figure 6C).Similarly, LLOMe treatment also promoted the binding affinity between PPP3R1 and LGALS3 (Figure 6D).We next mapped the key interaction domain of LGALS3 with PPP3R1, and showed the NT domain of LGALS3 was essential for the association with PPP3R1 (Figure 6E, F).Furthermore, overexpression of PPP3CB increased, suppression of PPP3CB abolished, the interactions of PPP3R1 and LGALS3 (Figure 6G, H), suggesting PPP3CB is also the bridge for the interaction between LGALS3 and PPP3R1.Interestingly, we also detected that SMURF1 indirectly interacted with PPP3R1, but not MCOLN1, in a LLOMe-enhanced manner (Figure S4B-E).Given that both SMURF1 and PPP3R1 were indirectly bound with the NT domain of LGALS3, we asked whether SMURF1 affected the interactions between PPP3R1 and LGALS3.Our data indicated that suppression of SMURF1 decreased, overexpression of SMURF1 increased, the interactions of PPP3R1 and LGALS3 (Figure 6I, J), suggesting SMURF1 promotes the recruitment of PPP3R1 by LGALS3.We next mapped the key HECT domain of SMURF1 which was essential for interaction with PPP3R1 (Figure 6K, L).
• Snippet 2 (score: 0.748)
  > Consistently,
  > LGALS3 and PPP3R1 were required for binding of PPP3CB and TFEB evidenced by knocking down LGALS3 or PPP3R1 decreased, while overexpression of LGALS3 or PPP3R1 increased, the interaction of PPP3CB and TFEB (Figure 8K, L).Of note, we found that the enhanced PPP3CB and TFEB interaction mediated by SMURF1 overexpression was abolished by LGALS3 deletion (Figure 8M).Overall, these data strengthened our hypothesis that LGALS3 and SMURF1 contribute to PPP3CB from "close" to "open" form, which facilitates TFEB docking to the AID domain (Figure 8N).

[8] High LGALS3 expression induced by HCP5/hsa-miR-27b-3p correlates with poor prognosis and tumor immune infiltration in hepatocellular carcinoma

• Authors: Yinghui Ren, Yongmei Qian, Qicheng Zhang, Xiaoping Li, Mingjiang Li et al.
• Year: 2024
• Venue: Cancer Cell International
• URL: https://www.semanticscholar.org/paper/552bd37c67dea75d0c33a9a0de2acdafcf0dcf6e
• DOI: 10.1186/s12935-024-03309-1
• PMID: 38643145
• PMCID: 11031979
• Citations: 13
• Summary: It is hypothesized that the HCP5/hsa-miR-27b-3p axis could serve as the most promising LGALS3 regulation mechanism in HCC and the upregulation of LGALS3 via the HCP5/hsa-miR-27b-3p axis is associated with unfavorable prognosis and increased tumor immune infiltration in HCC.
• Evidence snippets:
• Snippet 1 (score: 0.750)
  > LGALS3 has a crucial function in mediating cell adhesion as well as cell-cell interaction by recognizing complex carbohydrates on the surface of cells [22,23], as well as regulates cell apoptosis, autophagy, and inflammation [24,25].Interestingly, recent studies suggested that LGALS3 involves in essential cancer-related mechanisms, including cellular metabolism, carcinogenesis, metastasis, neoplasia, angiogenesis, as well as immune escape [26][27][28].In addition, LGALS3 is highly expressed and implicated in different cancer types progression such as HCC, gastric, colorectal, pancreatic carcinomas, melanomas or glioblastomas and breast cancer [29,30].Indeed, LGALS3 has been considered a potential marker for these malignancies.Interestingly, LGALS3, which is differentially expressed in different cancers, has been shown to exhibit tumor suppressor activity in certain cancer types.The different roles of LGALS3 may be attributed to different potential mechanisms that appear cancer-type dependent.The different locations and mutations of LGALS3 also contribute to its various functions.However, LGALS3 remains inadequately understood in HCC and requires further investigation.First, we conducted an extensive investigation of the expression profile, clinical prognosis, and pathologic stage of LGALS3 in HCC through an in-depth analysis of the public database.On the basis of TCGA and CPTAC datasets, we found that LGALS3 gene and protein expression was elevated in HCC tissues.Moreover, the OS and DSS were lesser in patients with HCC having higher expression levels of LGALS3 contrasted to those with low expression levels of LGALS3 based on GEPIA2 and Kaplan-Meier plotter datasets.Meanwhile, the expression of LGALS3 within HCC was significantly associated with the advanced tumor stage and grade, indicating that elevated LGALS3 expression could increase tumor progression.Song et al. [31] indicated that galectin-3 promoted HCC tumorigenesis and metastasis via β-catenin signalling in vitro and in vivo.

[9] LGALS3 is connected to CD74 in a previously unknown protein network that is associated with poor survival in patients with AML

• Authors: P. Ruvolo, Chenyue W. Hu, Y. Qiu, V. Ruvolo, Robin L. Go et al.
• Year: 2019
• Venue: EBioMedicine
• URL: https://www.semanticscholar.org/paper/46bbdbcb4660389e13acba24499cc415d75f18e0
• DOI: 10.1016/j.ebiom.2019.05.025
• PMID: 31105032
• PMCID: 6604360
• Citations: 25
• Influential citations: 2
• Summary: The data suggest that the LGALS3 network and the CD74 network each support AML cell survival and the two networks may cooperate in a novel high risk AML population.
• Evidence snippets:
• Snippet 1 (score: 0.747)
  > LGALS3 is associated with active Fig. 7. Suppression of LGALS3 does not alter gene expression of LGALS3 network protein genes or CD74 in THP-1 cells. RNA from THP-1 transductant cells with either LKO vector control shRNA or LGALS3 shRNA was isolated, cDNA produced, and mRNA levels of ATG7, LGALS3, ITGAL, CCND3, PRKCA, PARP1, CD74, MYC, CD44, SSBP2, PPP2R2A, CLPP, and B2M were determined by qRT-PCR and levels normalized to ABL-1 as described in "Materials and methods".
  > AKT and MAPK signaling. The protein with the strongest positive correlation with LGALS3 is with ATG7, an autophagy protein that has recently been implicated in maintaining hematopoietic stem cells and serving as a survival factor in AML [46,47]. Recent studies implicate LGALS3 in regulation of autophagy via autophagasome formation, though whether the mechanism involves ATG7 is not clear [48]. Interestingly, phosphorylated PKC delta was positively correlated with LGALS3. PKC delta is viewed as a pro-stress kinase but recent studies suggest that the enzyme has pro-survival properties [49][50][51]. Kinehara and colleagues suggest that PKC delta may act in human pluripotent stem cells as part of a mechanism to regulate stem cell renewal [52]. The data also suggest a novel relationship between LGALS3 and PP2A. The negative correlation of LGALS3 expression with PPP2R2A/B/C/D could reflect LGALS3 suppression of PP2A. The PP2A isoform containing PPP2R2A dephosphorylates both AKT and PKC alpha [53]. Thus, potential suppression of the PP2A subunit by LGALS3 could account for elevated AKT and PKC alpha phosphorylation in samples where LGALS3 expression is elevated.
• Snippet 2 (score: 0.747)
  > However, CD44 is present and interestingly is most elevated in patients with active LGALS3 network and CD74 network (Fig. 8). LGALS3 has been shown to be critical for CD44 endocytosis so LGALS3 would be expected to promote CD44 surface expression [54]. In AML cells with LGALS3 supported CD44 surface expression, CD74 would be predicted to augment signaling mediated by CD44.
  > LGALS3 is well known as an immune regulatory molecule that suppresses host anti-tumor immune surveillance by diverse mechanisms [1,2,55].
  > LGALS3 blocks or at least dampens immune cell function by reducing surface expression of glycosylated T cell receptor in T cells and preventing NK cell receptor binding to antigen [1,2]. LGALS3 has emerged as a critical component in MSC in AML patients to impact response to therapy [56]. It is likely that LGALS3 secreted from MSC and other support cells in the AML microenvironment negatively impacts immune surveillance in AML patients. It is yet to be determined if LGALS3 derived from the leukemia cells plays a role as an immune response inhibitor in AML.
  > LGALS9 is emerging as an important immune checkpoint inhibitor molecule as a TIM-3 binding partner [2,57]. LGALS9 also regulates T cell function as a CD44 binding partner [58]. Whereas LGALS3 binding to CD44 promotes metastasis, LGALS9 binding to CD44 suppresses this process [59,60]. Future RPPA studies to determine the role of LGALS9 and galectins other than LGALS3 are warranted.
  > For the first time, an at risk AML population has been found that is associated with active LGALS3 and active CD74 networks (Fig. 9A and B). At present, it is unclear which if any proteins within the LGALS3 or CD74 networks is driving this phenomenon. CD44, SPP1, and CLPP are highly induced in the patient cohort with both networks active compared to patients with normal-like state (Fig. 8).

[10] In-depth quantitative proteomics analysis revealed C1GALT1 depletion in ECC-1 cells mimics an aggressive endometrial cancer phenotype observed in cancer patients with low C1GALT1 expression

• Authors: A. Montero‐Calle, Á. López-Janeiro, Marta L. Mendes, Daniel Perez-Hernandez, Irene Echevarría et al.
• Year: 2023
• Venue: Cellular Oncology
• URL: https://www.semanticscholar.org/paper/92b64e01bcb30f7457ddb8cc4be26de8b0c7cf69
• DOI: 10.1007/s13402-023-00778-w
• PMID: 36745330
• PMCID: 10205863
• Citations: 19
• Summary: C1GALT1 stably depleted ECC-1 cells mimic an EC aggressive phenotype observed in patients and might be useful for the identification and validation of EC markers of progression.
• Evidence snippets:
• Snippet 1 (score: 0.747)
  > Finally, since LGALS3 (Galectin-3) has been shown to interact with O-glycans in the mucosal epithelium [30], and considering its overexpression observed by proteomics and further confirmed by PCR and WB analyses upon depletion of C1GALT1, we focused on the role of LGALS3 in EC by IHC.
  > A total of 151 out of 178 cores from 79 EC patients were considered adequate for LGALS3 expression assessment by IHC. Morphologic assessment of LGALS3 IHC staining characteristics revealed different staining patterns (Fig. 5 A). Out of the 151 evaluable cores, 45 (29.8%) showed absent LGALS3 expression. LGALS3 positive samples showed variable and low intensity protein expression (mean positive tumor cells per sample = 35.4%). A small subset of cores (13/151, 8.6%) demonstrated diffuse (> 90% positive tumor cells per sample) staining. LGALS3 score varied across histologic types, with serous and undifferentiated tumors displaying the highest protein expression (median IHC LGALS3 score = 10, 20, 50 and 55 for endometrioid, clear cell, serous and undifferentiated tumor types, respectively) (Fig. 5B). Interestingly, the aggressive histologic variants (clear cell, serous and undifferentiated) showed higher LGALS3 IHC scores than endometrioid variants (p value < 0.001). In addition, LGALS3 expression positively correlated with tumor grade. High grade tumors (G3) displayed higher protein expression (median LGALS3 IHC score = 30) compared to low grade tumors (median LGALS3 IHC score for G1/G2 tumors = 10). This finding was independent of histologic type, as similar results were observed when analyzing endometrioid tumors.
  > Finally, we interrogated the correlation between the expression levels of LGALS3 and C1GALT1.

[11] Phenotypic Switching of Vascular Smooth Muscle Cells in Atherosclerosis

• Authors: Runji Chen, D. McVey, D. Shen, Xiaoxin Huang, Shu Ye
• Year: 2023
• Venue: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
• URL: https://www.semanticscholar.org/paper/472c313e2214a97757712ab0a8b39b133bd6a6bc
• DOI: 10.1161/JAHA.123.031121
• PMID: 37815057
• PMCID: 10757534
• Citations: 133
• Influential citations: 2
• Summary: This review article discusses the 9 VSMC phenotypes that have been reported in atherosclerotic lesions and classifies them into differentiated VSMCs, intermediately dedifferentiated VSMCs, and dedifferentiated VSMCs.
• Evidence snippets:
• Snippet 1 (score: 0.744)
  > Lgals3 (also referred to as galectin-3) is considered a marker of macrophage-like cells. 13,31 Rong et al detected a population of VSMCs that expressed Lgals3 following cholesterol loading in vitro. 31 Recently, Alencar et al found that Lgals3 activation is not a specific marker of the differentiation of VSMCs to a macrophage-like state but rather it is a marker of VSMCs entering a transitional state, with increased expression of genes associated with stem cells that are capable of extracellular matrix remodeling. 16 Of note, similar to SEM-like cells, Lgals3 + cells also have increased expression of lymphocyte antigen 6 family member A and vascular cell adhesion molecule 1. Further studies to investigate if SEM-like cells are derived from Lgals3 + cells are warranted.
  > Using mouse, rat, and human models of cholesterolloading in VSMCs, Li et al found that SREBP1 (sterol regulatory-element binding protein-1) and Krüppel-like factor-15 induced up-and downregulation of Lgals3, respectively, via binding to the Lgals3 gene promoter (albeit at different sites). 45 Likewise, Lgals3 promoted SREBP1 gene expression, producing a feedforward loop upregulated by cholesterol loading. 45 Moreover, Lgals3 and SREBP1 downregulated myocardin-related transcription factor A expression in VSMCs. 45 In another study, Owsiany et al used a dual lineage tracing model and found that Lgals3 + VSMCs produce monocyte chemoattractant protein 1, a proinflammatory chemokine. 15 Knockout of monocyte chemoattractant protein 1 specifically in Lgals3 + VSMCs resulted in the formation of atherosclerotic lesions with a greater ACTA2 content in the fibrous cap and decreased Lgals3 + cell content, a feature of stable plaque. 15

[12] Morphological and transcriptional insights into the role of histone phosphorylation-related genes in early development of the chicken duodenum

• Authors: Xiaofeng Li, Bing Yang
• Year: 2025
• Venue: Animal Bioscience
• URL: https://www.semanticscholar.org/paper/b3da4d3a37ec0fae40140d0cf95db98d90b41079
• DOI: 10.5713/ab.25.0108
• PMID: 40506039
• PMCID: 12580959
• Citations: 1
• Summary: A novel paradigm wherein histone phosphorylation coordinates intestinal morphogenesis is established, providing mechanistic insights for optimizing poultry intestinal health and nutritional strategies.
• Evidence snippets:
• Snippet 1 (score: 0.738)
  > LGALS3 Galectin 3
  > LGALS3 encodes a member of the galectin family of carbohydrate binding proteins which play an important role in numerous cellular functions including apoptosis, innate immunity, cell adhesion and T-cell regulation. The protein exhibits antimicrobial activity against bacteria and fungi.

[13] Lysosomal damage is a therapeutic target in Duchenne muscular dystrophy

• Authors: Abbass Jaber, Laura Palmieri, R. Bakour, N. Bourg, A. Hong et al.
• Year: 2025
• Venue: Science Advances
• URL: https://www.semanticscholar.org/paper/3265a29ad8c2d48b294017fd50b6df9188b55ecb
• DOI: 10.1126/sciadv.adv6805
• PMID: 41124255
• PMCID: 12542950
• Citations: 7
• Summary: Lysosomal perturbations in myofibers of patients with DMD and animal models are identified, highlighting lysosomal damage as an important pathomechanism in DMD and suggesting that combining trehalose with gene therapy could enhance therapeutic efficacy.
• Evidence snippets:
• Snippet 1 (score: 0.738)
  > To investigate whether cholesterol accumulation in dystrophic muscle is associated with the impaired lysosomal function, we sought a method to quantify lysosomal damage. Several studies have recently focused on lysosomal dysfunction, in which LMP plays a central role (18). However, very few studies have investigated lysosome damage in muscle. One identified marker of LMP is Gal-3 (or LGALS3), which is part of the galectins, a family of lectins that bind specifically to carbohydrates (19). These lectins are present in the cytosol, nucleus, and extracellular matrix and are translocated to the membrane of damaged lysosomes before their removal by the autophagy machinery (20). To analyze LGALS3 expression in a myogenic environment and its capacity to detect LMP, we differentiated healthy human immortalized myoblasts into elongated myotubes for 7 days and then performed immunostaining for LGALS3 and lysosome-associated membrane protein 2 (LAMP2), which is commonly used as a lysosome marker (21). A diffuse expression of LGALS3 was observed in the cells (fig. S1A). Treatment with l-leucyl-l-leucine methyl ester (LLOMe), a lysomotropic agent that induces lysosome-specific membrane damage (22), for 30 min at 2.5 mM triggered the formation of LGALS3-positive puncta, which colocalized with LAMP2, indicating typical damaged lysosomes. An up-regulation of LGALS3 was also detected by Western blotting after 30 min to 1 hour of LLOMe treatment (fig. S1, B and C). LGALS3 puncta were markedly reduced 3 hours after treatment, and LGALS3 expression was restored to the control level, demonstrating efficient lysosomal repair by the cells. This pattern correlated inversely with the amount of LGALS3 released in the media, detected by an enzyme-linked immunosorbent assay (ELISA) assay (fig.

[14] Mice lacking galectin-3 (Lgals3) function have decreased home cage movement

• Authors: Tammy R. Chaudoin, S. Bonasera
• Year: 2018
• Venue: BMC Neuroscience
• URL: https://www.semanticscholar.org/paper/613a09b176431cdca195e6b3c439b4edbe4f92af
• DOI: 10.1186/s12868-018-0428-x
• Summary: P perturbation of behavioral circadian rhythms in Lgals3−/− mice is noted, with mice at both ages demonstrating greater variability in day-to-day performance of feeding, drinking, and movement compared to wildtype.
• Evidence snippets:
• Snippet 1 (score: 0.736)
  > Galectins are an evolutionarily ancient family of proteins sharing a high binding affinity for carbohydrates with β-galactoside linkages. In the extracellular space, galectins interact (through a conserved carbohydrate recognition domain, aka CRD) with glycosylated proteins to mediate both cell-to-cell interactions and cell-to-matrix adhesion. Galectins are thus pattern recognition molecules specialized to distinguish carbohydrate moieties.
  > Within the galectin family, galectin-3 (also known as Lgals3) has unique properties. Its preferred ligand is N-acetyllactosamine [1]. It is also the only galectin containing a conserved N-domain as well as a single CRD domain. This N-domain allows Lgals3 not bound to a carbohydrate target to form multimeric complexes [2].
  > In this manner, low extracellular Lgals3 concentrations tend to inhibit extracellular interactions and adhesion [3], while high Lgals3 extracellular concentrations facilitate cellular adhesion [4,5]. Lgals3 affinity for ECM substrates is also modulated by phosphorylation at its Ser6 residue [6].
  > Lgals3 is an NFκB target gene [7]; Lgals3 protein is widely distributed throughout most tissue sites (as demonstrated by the TiGER Tissue specific gene expression and regulation database; [8]). Furthermore, within specific tissues, Lgals3 protein expression is widespread, with extracellular [9], membrane bound, cytoplasmic, and nuclear localizations (for review, see [10]).

[15] Mice lacking galectin-3 (Lgals3) function have decreased home cage movement

• Authors: Tammy R. Chaudoin, S. Bonasera
• Year: 2018
• Venue: BMC Neuroscience
• URL: https://www.semanticscholar.org/paper/26255eafb963932be62ecb55d4943930217cb63f
• DOI: 10.1186/s12868-018-0428-x
• PMID: 29716523
• PMCID: 5930520
• Citations: 7
• Influential citations: 1
• Summary: P perturbation of behavioral circadian rhythms in Lgals3−/− mice is noted, with mice at both ages demonstrating greater variability in day-to-day performance of feeding, drinking, and movement compared to wildtype.
• Evidence snippets:
• Snippet 1 (score: 0.733)
  > Galectins are an evolutionarily ancient family of proteins sharing a high binding affinity for carbohydrates with β-galactoside linkages. In the extracellular space, galectins interact (through a conserved carbohydrate recognition domain, aka CRD) with glycosylated proteins to mediate both cell-to-cell interactions and cell-to-matrix adhesion. Galectins are thus pattern recognition molecules specialized to distinguish carbohydrate moieties.
  > Within the galectin family, galectin-3 (also known as Lgals3) has unique properties. Its preferred ligand is N-acetyllactosamine [1]. It is also the only galectin containing a conserved N-domain as well as a single CRD domain. This N-domain allows Lgals3 not bound to a carbohydrate target to form multimeric complexes [2].
  > In this manner, low extracellular Lgals3 concentrations tend to inhibit extracellular interactions and adhesion [3], while high Lgals3 extracellular concentrations facilitate cellular adhesion [4,5]. Lgals3 affinity for ECM substrates is also modulated by phosphorylation at its Ser6 residue [6].
  > Lgals3 is an NFκB target gene [7]; Lgals3 protein is widely distributed throughout most tissue sites (as demonstrated by the TiGER Tissue specific gene expression and regulation database; [8]). Furthermore, within specific tissues, Lgals3 protein expression is widespread, with extracellular [9], membrane bound, cytoplasmic, and nuclear localizations (for review, see [10]).

Notes

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Asta Literature Retrieval: Literature evidence for LGALS3 (Homo sapiens): LGALS3 has eosinophil chemotaxis (GO:0048245). Gene/protein: LGALS3. O...

This report is retrieval-only and is generated directly from Asta results.

• Papers retrieved: 13
• Snippets retrieved: 19

Relevant Papers

[1] High LGALS3 expression induced by HCP5/hsa-miR-27b-3p correlates with poor prognosis and tumor immune infiltration in hepatocellular carcinoma

• Authors: Yinghui Ren, Yongmei Qian, Qicheng Zhang, Xiaoping Li, Mingjiang Li et al.
• Year: 2024
• Venue: Cancer Cell International
• URL: https://www.semanticscholar.org/paper/552bd37c67dea75d0c33a9a0de2acdafcf0dcf6e
• DOI: 10.1186/s12935-024-03309-1
• PMID: 38643145
• PMCID: 11031979
• Citations: 13
• Summary: It is hypothesized that the HCP5/hsa-miR-27b-3p axis could serve as the most promising LGALS3 regulation mechanism in HCC and the upregulation of LGALS3 via the HCP5/hsa-miR-27b-3p axis is associated with unfavorable prognosis and increased tumor immune infiltration in HCC.
• Evidence snippets:
• Snippet 1 (score: 0.894)
  > Chemokines are a group of molecules that are important for the chemotaxis of immune cells [18].According to Table S1, the expression of LGALS3 was statistically positively correlated with several chemokines of immune cells, involving monocytes/macrophages (CCL2, CCL3, CCL5, CCL7, CCL13, CCL17, and CCL22), T lymphocytes (CCL2, CCL1, CCL17, and CCL22), eosinophils (CCL11, CCL26, CCL5, CCL7, CCL13, and CCL3), mast cells (CCR1, CCR2, CCR3, CCR4, CCR5, CXCR2, and CXCR4), and neutrophils (CXCL8).Taken together, these outcomes indicate that LGALS3 is positively associated with immune cell infiltration and cell chemotaxis and could have a crucial function in HCC tumor immune microenvironment.
  > LGALS3 expression correlation and immune cell biomarkers in HCC Next, we wanted to investigate the LGALS3 function in HCC tumor immunity further.Utilizing GEPIA databases, we studied the correlation between LGALS3 expression and immune cell biomarkers within HCC.
• Snippet 2 (score: 0.839)
  > To delineate the driving mechanism of LGALS3 for the malignant progression of HCC, the KEGG and GO analysis was conducted.The volcano plot and heatmap showed significantly differentially expressed genes between LGALS3 high-and low-expression groups (Figure S3A-B).The KEGG pathway analysis revealed that these LGALS3-related genes were enriched in the IL-17 signaling pathway, ECM-receptor interaction pathway, central carbon metabolism in cancer pathway, leukocyte transendothelial migration pathway and PI3K-Akt signaling pathway.Meanwhile, the GO analysis revealed that these genes were strongly associated with cell chemotaxis, leukocyte chemotaxis, regulation of leukocyte migration, as well as regulation of chemotaxis (Fig. 5A).Accumulating evidence has proven the immune system has an essential role in malignancy pathogenesis [17], and LGALS3 is closely correlated with CD163 + tumor-associated macrophages (TAM) in glioma [10].Therefore, we studied the association between LGALS3 level and the immune infiltration level in HCC.There was no statistical difference in immune cell infiltration levels over a number of LGALS3 copy numbers (Fig. 5B).Meanwhile, immune infiltration analysis revealed that expression of LGALS3 showed a significant positive association with several immune cell populations, involving CD4 + T cell, CD8 + T cell, B cell, neutrophil, macrophage, dendritic cell, as well as cancer-associated fibroblasts (CAFs) within HCC (Fig. 5C-E).Based on these results, we further evaluated the immune score in HCC patients with high and low LGALS3 expression.The scores of immune cells, including CD4 + T cell, CD8 + T cell, B cell, neutrophil, macrophage, and dendritic cell, were significantly higher in the high LGALS3 expression groups, as shown in Fig. 5F.Chemokines are a group of molecules that are important for the chemotaxis of immune cells [18].
• Snippet 3 (score: 0.768)
  > analyses highlighted that the LGALS3-related genes were involved in tumor immunity. Furthermore, we detected a significant positive association between LGALS3 and HCP5 with immunological checkpoints, cell chemotaxis, and immune infiltration. In addition, high LGALS3 expression groups had significantly higher immune cell scores and immune checkpoint expression levels. Finally, GSVA analysis was performed to predict potential signaling pathways linked to LGALS3 and HCP5 in immune evasion and metabolic reprogramming of HCC. Our findings indicated that the upregulation of LGALS3 via the HCP5/hsa-miR-27b-3p axis is associated with unfavorable prognosis and increased tumor immune infiltration in HCC.
• Snippet 4 (score: 0.755)
  > Hepatocellular carcinoma (HCC) is widely recognized for its unfavorable prognosis. Increasing evidence has revealed that LGALS3 has an essential function in initiating and developing several malignancies in humans. Nevertheless, thorough analysis of the expression profile, clinical prognosis, pathway prediction, and immune infiltration of LGALS3 has not been fully explored in HCC. In this study, an initial pan-cancer analysis was conducted to investigate the expression and prognosis of LGALS3. Following a comprehensive analysis, which included expression analysis and correlation analysis, noncoding RNAs that contribute to the overexpression of LGALS3 were subsequently identified. This identification was further validated using HCC clinical tissue samples. TIMER2 and GEPIA2 were employed to examine the correlation between LGALS3 and HCP5 with immunological checkpoints, cell chemotaxis, and immune infiltration in HCC. The R program was applied to analyze the expression distribution of immune score in in HCC patients with high and low LGALS3 expression. The expression profiles of immune checkpoints were also analyzed. Use R to perform GSVA analysis in order to explore potential signaling pathways. First, we conducted pan-cancer analysis for LGALS3 expression level through an in-depth analysis of public databases and found that HCC has a high LGALS3 gene and protein expression level, which were then verified in clinical HCC specimens. Meanwhile, high LGALS3 gene expression is related to malignant progression and poor prognosis of HCC. Univariate and multivariate analyses confirmed that LGALS3 could serve as an independent prognostic marker for HCC. Next, by combining comprehensive analysis and validation on HCC clinical tissue samples, we hypothesize that the HCP5/hsa-miR-27b-3p axis could serve as the most promising LGALS3 regulation mechanism in HCC. KEGG and GO analyses highlighted that the LGALS3-related genes were involved in tumor immunity. Furthermore, we detected a significant positive association between LGALS3 and HCP5 with immunological checkpoints, cell chemotaxis, and immune infiltration. In addition, high LGALS3 expression groups had significantly
• Snippet 5 (score: 0.736)
  > Zhang et al. [14] suggested overexpression of LGALS3 promoted HCC bone metastasis and induced associated skeletal complications.Nevertheless, the expression, prognosis, epigenetic, and molecular regulatory mechanisms of LGALS3 in HCC have been incompletely studied.In addition, LGALS3 relation with immune infiltration in HCC TME has yet to be inadequately investigated.
  > This work began with a pan-cancer study of LGALS3 expression and its predictive value in a variety of human malignancies.We further explored the LGALS3 potential upstream regulatory noncoding RNAs (ncRNAs) involving microRNAs (miRNAs) as well as long noncoding RNAs (lncRNAs) throughout HCC.Subsequently, in HCC, a correlation analysis was investigated between LGALS3 and tumor immunity-related indicators involving cell chemotaxis, immune checkpoints, immune cell biomarkers, and infiltration.Eventually, the association between the expression of LGALS3 and signaling pathways was examined in HCC.Findings demonstrated that LGALS3 might have a role in the malignancy of HCC and immune cell infiltration via the HCP5/hsa-miR-27b-3p/ LGALS3 axis, suggesting that a novel HCP5/hsa-miR-27b-3p/LGALS3 axis could be a biomarker for prognosis and treatment target for HCC patients.
• Snippet 6 (score: 0.707)
  > LGALS3 has a crucial function in mediating cell adhesion as well as cell-cell interaction by recognizing complex carbohydrates on the surface of cells [22,23], as well as regulates cell apoptosis, autophagy, and inflammation [24,25].Interestingly, recent studies suggested that LGALS3 involves in essential cancer-related mechanisms, including cellular metabolism, carcinogenesis, metastasis, neoplasia, angiogenesis, as well as immune escape [26][27][28].In addition, LGALS3 is highly expressed and implicated in different cancer types progression such as HCC, gastric, colorectal, pancreatic carcinomas, melanomas or glioblastomas and breast cancer [29,30].Indeed, LGALS3 has been considered a potential marker for these malignancies.Interestingly, LGALS3, which is differentially expressed in different cancers, has been shown to exhibit tumor suppressor activity in certain cancer types.The different roles of LGALS3 may be attributed to different potential mechanisms that appear cancer-type dependent.The different locations and mutations of LGALS3 also contribute to its various functions.However, LGALS3 remains inadequately understood in HCC and requires further investigation.First, we conducted an extensive investigation of the expression profile, clinical prognosis, and pathologic stage of LGALS3 in HCC through an in-depth analysis of the public database.On the basis of TCGA and CPTAC datasets, we found that LGALS3 gene and protein expression was elevated in HCC tissues.Moreover, the OS and DSS were lesser in patients with HCC having higher expression levels of LGALS3 contrasted to those with low expression levels of LGALS3 based on GEPIA2 and Kaplan-Meier plotter datasets.Meanwhile, the expression of LGALS3 within HCC was significantly associated with the advanced tumor stage and grade, indicating that elevated LGALS3 expression could increase tumor progression.Song et al. [31] indicated that galectin-3 promoted HCC tumorigenesis and metastasis via β-catenin signalling in vitro and in vivo.

[2] Identification of systemic biomarkers and potential drug targets for age-related macular degeneration

• Authors: Shizhen Lei, Mang Hu, Zhongtao Wei
• Year: 2024
• Venue: Frontiers in Aging Neuroscience
• URL: https://www.semanticscholar.org/paper/d298311ebc5a23bc38669dd6a0d0878c1197a687
• DOI: 10.3389/fnagi.2024.1322519
• PMID: 38361503
• PMCID: 10867226
• Citations: 7
• Summary: Findings supported that high plasma levels of C3b, CTNNB1, CCL1, and CCL3L1 were associated with increased risk of AMD, thereby highlighting the role of systemic inflammation in AMD pathogenesis and providing the rationale for developing new preventative and therapeutic strategies.
• Evidence snippets:
• Snippet 1 (score: 0.807)
  > Related GO annotations Related diseases CCL1 GO:0090026 positive regulation of monocyte chemotaxis; GO:0048245 eosinophil chemotaxis; GO:0032740 positive regulation of interleukin-17 production.
  > Asthma, allergic rhinitis, rheumatoid arthritis, and multiple sclerosis CCL3L1 GO:0048245 eosinophil chemotaxis; GO:0072677 eosinophil migration; GO:0002548 monocyte chemotaxis.
  > HIV infection/AIDS, rheumatoid arthritis C3b GO:0001970 positive regulation of activation of membrane attack complex; GO:0150064 vertebrate eye-specific patterning; GO:0001798 positive regulation of type IIa hypersensitivity.
  > Atypical hemolytic uremic syndrome (aHUS) and AMD CTNNB1 GO:0007403 glial cell fate determination; GO:0044336 canonical Wnt signaling pathway involved in negative regulation of apoptotic process; GO:0061324 canonical Wnt signaling pathway involved in positive regulation of cardiac outflow tract cell proliferation.
  > Several types of cancer, including uveal melanoma, colorectal cancer, and ovarian cancer SRPs, senescence-related proteins; AMD, age-related macular degeneration; GO, Gene Ontology.
  > In conclusion, we provided the genetic evidence that plasma levels of C3b, CTNNB1, CCL1, and CCL3L1 are causally associated with risk of AMD, which highlights the role of systemic inflammation in the pathophysiology of AMD. Given that the genes encoding these four proteins are all druggable targets, the findings may contribute to understanding the pathogenesis of AMD and the development of new therapeutic or preventive strategy for AMD.

[3] Pregnancy Galectinology: Insights Into a Complex Network of Glycan Binding Proteins

• Authors: S. Blois, G. Dveksler, G. Vasta, N. Freitag, V. Blanchard et al.
• Year: 2019
• Venue: Frontiers in Immunology
• URL: https://www.semanticscholar.org/paper/68fad2b87411701fa708a1f49f8b918370486857
• DOI: 10.3389/fimmu.2019.01166
• PMID: 31231368
• PMCID: 6558399
• Citations: 56
• Influential citations: 7
• Summary: The relevance of galectin-glycan interactions as potential therapeutic targets in pregnancy disorders is discussed and the importance of angiogenesis during decidualization and in placenta formation is discussed.
• Evidence snippets:
• Snippet 1 (score: 0.763)
  > Lgals3 has been implicated in the regulation of innate and adaptive immune responses, where it participates in the activation or differentiation of immune cells and contributes to phagocytic clearance of microorganisms and apoptotic cells by macrophages (117,118). Lgals3 has been reported to promote but also to inhibit T-cell apoptosis depending on whether it binds to glycoproteins on the cell surface (CD45 and CD71) or to intracellular ligands (Bcl-2) (119, 120). In the placenta, Lgals3 was detected in all trophoblastic lineages including villous cytotrophoblasts (CTB) and EVT with a reduction of Lgals3 expression observed from the VT to the trophoblastic cell columns (121). This pattern of Lgals3 expression correlates with the switch from a proliferative to a migratory trophoblast phenotype and while placental Lgals3 dysregulation has been associated with some obstetric complications including spontaneous or recurrent miscarriages, further studies are needed to understand its contribution to trophoblast biology (81,122). In addition to trophoblasts, Lgals3 is expressed by maternal decidual cells (73). While showing a different expression pattern, both Lgals1 and Lgals3 have been proposed to play a role in cell-cell and cell-matrix interactions of trophoblast during placentation (121). Studies of the importance of Lgals3 in murine pregnancy by Yang et al. indicate that Lgals3 is expressed in the luminal and glandular epithelium and that an increase in Lgals3 is required for proper embryo implantation (123). In addition, Lgals3 affects chemotaxis and morphology of endothelial cells and stimulates capillary tube formation and angiogenesis in vivo (124). Therefore, besides its proposed roles in embryo implantation, immune regulation and trophoblast-matrix interactions, Lgals3 has a potential role in placental angiogenesis.

[4] Selective Myeloid Depletion of Galectin-3 Offers Protection Against Acute and Chronic Lung Injury

• Authors: D. Humphries, R. Mills, R. Dobie, N. Henderson, T. Sethi et al.
• Year: 2021
• Venue: Frontiers in Pharmacology
• URL: https://www.semanticscholar.org/paper/a99f52230baf060d40c3fc80a916fafa3ed62d03
• DOI: 10.3389/fphar.2021.715986
• PMID: 34526900
• PMCID: 8435800
• Citations: 30
• Influential citations: 3
• Summary: Myeloid cell derived Gal-3 drives acute and chronic lung inflammation and supports direct targeting of galectin-3 as an attractive new therapy for lung inflammation.
• Evidence snippets:
• Snippet 1 (score: 0.725)
  > Lgals3 flox mice (Lgals3 fl/fl ) were generated as described by Maupin et al. (2018) and crossed with mice expressing either the LysM-cre or the Pdgfrb-cre transgene to obtain mice with a new genomic Lgals3-null allele in the myeloid or mesenchymal compartment. Gal-3 depletion was initially examined in bonemarrow derived cells from LysM-cre + , LysM-cre -and Gal-3 -/- mice (Figures 1A-C). Monocytes and neutrophils obtained from the bone marrow of LysM-cre + mice exhibited a 35 and 75% reduction in surface Gal-3 expression, respectively, when compared to LysM-cre -mice, indicating predominate depletion in neutrophils following recombination. No changes were observed in eosinophils, which displayed low levels of Gal-3. The apparent higher mean fluorescence in Gal-3 −/− eosinophils is due to increased cellular autofluorescence in those cells. There was no difference in the frequency of monocytes, neutrophils or eosinophils between the genotypes (Figure 1D).

[5] The deficiency of galectin-3 in stromal cells leads to enhanced tumor growth and bone marrow metastasis

• Authors: J. X. Pereira, Maria Carolina Braga Azeredo, Felipe Sá Martins, R. Chammas, F. L. Oliveira et al.
• Year: 2016
• Venue: BMC Cancer
• URL: https://www.semanticscholar.org/paper/5f5ef422f3c44fa24a457d97d0c915ae8188a279
• DOI: 10.1186/s12885-016-2679-1
• PMID: 27526676
• PMCID: 4986277
• Citations: 12
• Influential citations: 1
• Summary: It is demonstrated for the first time that the absence of galectin-3 in the host microenvironment favors the growth of the primary tumors, the metastatic spread to the inguinal lymph nodes and bone marrow colonization by metastatic 4T1 tumor cells.
• Evidence snippets:
• Snippet 1 (score: 0.724)
  > We next investigated whether galectin-3 could influence the development of metastasis to the lymph node. Therefore, 28 days post orthotopic injection (p.o.i) of 4T1 cells in Lgals3+/+ or Lgals3−/− mice, the lymph nodes were excised and the presence of CK-19 positive cells was analyzed by immunohistochemistry. We observed that 4T1 cells (CK-19+) were predominantly present in the capsule of the draining lymph node in Lgals3+/+ mice (Fig. 3a) whereas in Lgals3−/− mice, CK-19+ cells were organized as "sheets-like" within the lymph node parenchyma and also found in the capsule (Fig. 3b). Moreover, we evaluated the presence of lymph node metastasis in Lgals3+/+ and Lgals3−/− mice using the 6-thioguanine clonogenic assay and found significant fewer metastasis in Lgals3+/+ mice in comparison to Lgals3−/− mice, both 21 and 28 days p.o.i. (Fig. 3c, p < 0,05). Interestingly though, we also found an increased CK-19 mRNA levels in Lgals3−/− mice at an earlier stage (15 days) p.o.i. (Fig. 3d, p < 0,05). These results suggest that Lgals3−/− mice are more permissive for 4T1 tumor cells dissemination to the inguinal lymph nodes.
  > Galectin-3-deficient bone marrow microenvironment supports more efficiently the growth of metastatic 4T1
  > We have previously described that Lgals3−/− mice presented structural and functional differences in the bone marrow [17]. Likewise, in this study we confirmed differences in terms of cellularity and projections of bone tissue inside the cavity between Balb/c Lgals3+/+ and Lgals3 −/− mice (Fig. 4a and b).

[6] Thyroid malignant neoplasm-associated biomarkers as targets for oncolytic virotherapy

• Authors: Mi Guan, Yanping Ma, S. Shah, G. Romano
• Year: 2016
• Venue: Oncolytic Virotherapy
• URL: https://www.semanticscholar.org/paper/9f79d851e32ad25e83c0a2d64e12919bf81a89f8
• DOI: 10.2147/OV.S99856
• PMID: 27579295
• PMCID: 4996252
• Citations: 4
• Summary: This review focuses on the strategy of biomarkers for the production of novel TMN oncolytic therapeutics, which may improve the specificity of targeting of tumor cells and limit adverse effects in patients.
• Evidence snippets:
• Snippet 1 (score: 0.715)
  > The Galectin-3 (LGALS3) is a protein that is encoded by a single gene, LGALS3, located on chromosome 14, locus q21-q22. 63 The molecular weight of this protein is ∼30 kDa, and it contains a carbohydrate-recognition-binding domain of ∼130 amino acids that enable the specific binding of β-galactosides. This protein localizes to the extracellular matrix, the cytoplasm, and the nucleus. It plays a role in numerous cellular functions including cell adhesion, cell activation and chemoattraction, cell growth, differentiation, cell cycle, apoptosis, innate immunity, cell adhesion, and T-cell regulation. 63,64 It has been known that LGALS3 is distributed widely around the tissues but in a low level.
  > To date, LGALS3 has been extensively studied as an IHC marker of thyroid malignancy, and a high diagnostic accuracy has been reported even for difficult pathological diagnoses. 64 Feilchenfeldt et al reported that the mRNA levels of LGALS3 and thyroglobulin in 28 benign and 31 malignant thyroid samples were quantified by real-time PCR. The LGALS3 expression at the mRNA was 60% (12/20) and the protein level was 100% (8/8), respectively. 65 The positive rate was 84% (41/49) when combined with the LGALS3 and HBME-1 in PTC specimens. 66 Two groups of researchers have detected the LGALS3 by IHC in PTC specimens. Saleh et al have shown that the sensitivity and the specificity for LGALS3 were 92.3% and 77.3%, respectively. 67 Song et al reported that positive expression of LGALS3 was 97% (427/441) in PTC group and 51% (77/151) in the benign thyroid lesions group. 68 These results may further support the notion that the high level of LGALS3 antigen expression occurs in patients with PTC. There are a number of different types of oncolytic viruses that have been altered from natural viruses in the laboratory such as adenovirus, reovirus, measles virus, herpes simplex

[7] Morphological and transcriptional insights into the role of histone phosphorylation-related genes in early development of the chicken duodenum

• Authors: Xiaofeng Li, Bing Yang
• Year: 2025
• Venue: Animal Bioscience
• URL: https://www.semanticscholar.org/paper/b3da4d3a37ec0fae40140d0cf95db98d90b41079
• DOI: 10.5713/ab.25.0108
• PMID: 40506039
• PMCID: 12580959
• Citations: 1
• Summary: A novel paradigm wherein histone phosphorylation coordinates intestinal morphogenesis is established, providing mechanistic insights for optimizing poultry intestinal health and nutritional strategies.
• Evidence snippets:
• Snippet 1 (score: 0.713)
  > Notably, as broilers age (from D0 to D7), the intestinal VH increases accordingly, indicating a positive balance between intestinal cell proliferation and apoptosis (i.e., cell proliferation predominates over apoptosis). Through transcriptional network analysis, we identified eight histone phosphorylation-associated hub genes (LGALS3, ITGB2, IRF7, SOCS3, CSF1R, KIF23, SMC2, and DLGAP5) that mechanistically link epigenetic regulation to developmental programming.
  > LGALS3 (galectin-3) plays critical roles in macrophage chemotaxis, mucosal barrier maintenance, intestinal epithelial cell (IEC) apoptosis regulation, and inflammatory responses [21][22][23]. Our study revealed a 6.59-fold increase in LGALS3 gene expression in the duodenum at D7 compared to D0 (Supplement 6), with functional analysis confirming its involvement in macrophage chemotaxis (Supplement 7). These findings align with Sun et al [21], who reported that LGALS3 silencing in necrotizing enterocolitis models inhibited the TLR4/NF-κB pathway, subsequently reducing IEC apoptosis and inflammation [21]. Emerging evidence further suggests LGALS3' s protective functions through ER stress modulation, autophagy regulation, and inflammasome control in intestinal Behçet' s disease [22], along with its capacity to upregulate key mucosal barrier components (MUC2, Occludin, and ZO-1) [23]. Collectively, these observations suggest LGALS3 promotes duodenal development through: 1) mucosal barrier reinforcement via tight junction protein upregulation, 2) inflammatory control through TLR4/NF-κB-mediated macrophage regulation, and 3) cellular homeostasis maintenance via ER stress/autophagy pathways.

[8] Galectin-3, histone deacetylases, and Hedgehog signaling: Possible convergent targets in schistosomiasis-induced liver fibrosis

• Authors: F. L. de Oliveira, Katia Carneiro, J. Brito, M. Cabanel, J. X. Pereira et al.
• Year: 2017
• Venue: PLoS Neglected Tropical Diseases
• URL: https://www.semanticscholar.org/paper/6dc6d6f3529841361a1ccf76eac911be181636c7
• DOI: 10.1371/journal.pntd.0005137
• PMID: 28231240
• PMCID: 5322873
• Citations: 31
• Summary: A possible involvement of Galectin-3 (Gal-3), histone deacetylases (HDACs), and Hedgehog (Hh) signaling with macrophage activation during Th1/Th2 immune responses, fibrogranuloma reaction, and tissue repair during schistosomiasis is suggested.
• Evidence snippets:
• Snippet 1 (score: 0.710)
  > It is interesting to point out the presence of myeloid progenitor cells in contact with the hepatocytes, indicating a spreading of these cells out of the periovular granulomas in Lgals3-/-mice (Fig 3D and 3F).
  > Another interesting finding of our studies concerning the composition of inflammatory cells around the egg granulomas in Lgals3-/-mice was the predominance of eosinophils in liver granulomas compared with Lgals3+/+ mice [32]. The GR-HSCs of both groups of mice expressed similar levels of IL-5, the critical cytokines for differentiation and proliferation of eosinophils [41]. In contrast, eotaxin, a main chemoatractant chemokine for eosinophils [42], was significantly downregulated in GR-HSCs in the absence of Gal-3 (Fig 3H). In this context, we can suggest that in the absence of Gal-3, the low expression of eotaxin in GR-HSCs, even without alteration in IL-5 expression, favored the local proliferation of myeloid cells instead of the mobilization from bone marrow (Fig 4).

[9] Periplocin suppresses the growth of colorectal cancer cells by triggering LGALS3 (galectin 3)-mediated lysophagy

• Authors: Kui Wang, Shuyue Fu, Lixia Dong, Dingyue Zhang, Mao Wang et al.
• Year: 2023
• Venue: Autophagy
• URL: https://www.semanticscholar.org/paper/3dadfc351823c4e325e65c171ab3765871189c80
• DOI: 10.1080/15548627.2023.2239042
• PMID: 37471054
• Citations: 35
• Influential citations: 2
• Summary: It is shown that periplocin exhibits promising anticancer activity against CRC both in vitro and in vivo, and is indicated as a potential therapeutic option for the treatment of CRC.
• Evidence snippets:
• Snippet 1 (score: 0.708)
  > We next investigated the mechanism underlying periplocinmediated lysophagy. The expression of LGALS3, a key lysophagy marker [46], was found to be upregulated following periplocin treatment as evidenced by immunofluorescent staining (Figure 2M). To this end, we presumed that periplocin-induced lysophagy might be attributable to the upregulation of LGALS3. Indeed, periplocin treatment prominently elevated the protein level of LGALS3 as evidence by immunoblotting analysis (Figure 6A). The increased protein level of LGALS3 was further confirmed in tumor xenografts from periplocin-treated mice (Figure 6B,C). However, no obvious change was observed on the mRNA level of LGALS3 in periplocin-treated cells compared with controls (Figure S6A), suggesting that transcriptional regulation was not involved in increased LGALS3 expression following periplocin treatment. Therefore, we postulated that periplocin might elevate LGALS3 by regulating protein stability. Of note, cycloheximide (CHX, a translational inhibitor) treatment led to an obvious decrease in LGALS3 protein level in control cells, but had no obvious effect on the upregulated protein level of LGALS3 in periplocin-treated cells, suggesting periplocin maintains LGALS3 stability (Figure 6D,E). In support of this, treatment with MG132 (a proteasome inhibitor) failed to further enhance the protein level of LGALS3 in response to periplocin treatment (Figure 6F,G). These data suggest that periplocin may prevent proteasomal degradation of LGALS3.
  > We therefore measured the effect of periplocin on LGALS3 ubiquitination. As shown in Figure 6H, periplocin markedly decreased the ubiquitin-conjugated level of LGALS3.

[10] LGALS3 is connected to CD74 in a previously unknown protein network that is associated with poor survival in patients with AML

• Authors: P. Ruvolo, Chenyue W. Hu, Y. Qiu, V. Ruvolo, Robin L. Go et al.
• Year: 2019
• Venue: EBioMedicine
• URL: https://www.semanticscholar.org/paper/46bbdbcb4660389e13acba24499cc415d75f18e0
• DOI: 10.1016/j.ebiom.2019.05.025
• PMID: 31105032
• PMCID: 6604360
• Citations: 25
• Influential citations: 2
• Summary: The data suggest that the LGALS3 network and the CD74 network each support AML cell survival and the two networks may cooperate in a novel high risk AML population.
• Evidence snippets:
• Snippet 1 (score: 0.701)
  > Thus, potential suppression of the PP2A subunit by LGALS3 could account for elevated AKT and PKC alpha phosphorylation in samples where LGALS3 expression is elevated. Induction of PPP2R2A protein (Fig. 5) but not gene expression (Fig. 7) in THP-1 cells expressing LGALS3 shRNA suggests that LGALS3 acts directly on the PP2A subunits via a post-transcriptional mechanism in these cells. The TCGA data (Table 3) however suggests that there is a positive correlation between gene expression of LGALS3 and PPP2R2A suggesting that a common pathway may regulate the two genes. Fig. 8. Progeny clustering identified an optimal number of 4 distinct protein clusters for this ProFnGrp. Protein networks were generated and showed interactions between "core-proteins" (large nodes) and other probed proteins (small nodes) from the data set. Clustering method has been described in our previous publication (ref. [37]) and further information on these protein networks can be found on our website "Leukemia Profile Atlases", available at https://www.leukemiaatlas.org/. Progeny clustering identified one protein cluster with expression similar to that of the normal CD34+ samples which was designated as "normal-state" while three "leukemia-specific" protein patterns characterized by high expression individually of CD74, LGAL3, and a fourth state with both on. PPP2RA/B/C/D was the only LGALS3 network protein demonstrated to be directly regulated by LGALS3 in the THP-1 cells (Fig. 5). In our previous study we saw potent suppression of AKT signaling by LGALS3 inhibition, so perhaps the mechanism involves LGALS3 suppression of the AKT phosphatase [15]. However, we did not see suppression of LGALS3 affect other network proteins in the THP-1 cells (data not shown). The role of other galectins such as LGALS1 in AML biology is not clear.
• Snippet 2 (score: 0.701)
  > LGALS3 is associated with active Fig. 7. Suppression of LGALS3 does not alter gene expression of LGALS3 network protein genes or CD74 in THP-1 cells. RNA from THP-1 transductant cells with either LKO vector control shRNA or LGALS3 shRNA was isolated, cDNA produced, and mRNA levels of ATG7, LGALS3, ITGAL, CCND3, PRKCA, PARP1, CD74, MYC, CD44, SSBP2, PPP2R2A, CLPP, and B2M were determined by qRT-PCR and levels normalized to ABL-1 as described in "Materials and methods".
  > AKT and MAPK signaling. The protein with the strongest positive correlation with LGALS3 is with ATG7, an autophagy protein that has recently been implicated in maintaining hematopoietic stem cells and serving as a survival factor in AML [46,47]. Recent studies implicate LGALS3 in regulation of autophagy via autophagasome formation, though whether the mechanism involves ATG7 is not clear [48]. Interestingly, phosphorylated PKC delta was positively correlated with LGALS3. PKC delta is viewed as a pro-stress kinase but recent studies suggest that the enzyme has pro-survival properties [49][50][51]. Kinehara and colleagues suggest that PKC delta may act in human pluripotent stem cells as part of a mechanism to regulate stem cell renewal [52]. The data also suggest a novel relationship between LGALS3 and PP2A. The negative correlation of LGALS3 expression with PPP2R2A/B/C/D could reflect LGALS3 suppression of PP2A. The PP2A isoform containing PPP2R2A dephosphorylates both AKT and PKC alpha [53]. Thus, potential suppression of the PP2A subunit by LGALS3 could account for elevated AKT and PKC alpha phosphorylation in samples where LGALS3 expression is elevated.

[11] In-depth quantitative proteomics analysis revealed C1GALT1 depletion in ECC-1 cells mimics an aggressive endometrial cancer phenotype observed in cancer patients with low C1GALT1 expression

• Authors: A. Montero‐Calle, Á. López-Janeiro, Marta L. Mendes, Daniel Perez-Hernandez, Irene Echevarría et al.
• Year: 2023
• Venue: Cellular Oncology
• URL: https://www.semanticscholar.org/paper/92b64e01bcb30f7457ddb8cc4be26de8b0c7cf69
• DOI: 10.1007/s13402-023-00778-w
• PMID: 36745330
• PMCID: 10205863
• Citations: 19
• Summary: C1GALT1 stably depleted ECC-1 cells mimic an EC aggressive phenotype observed in patients and might be useful for the identification and validation of EC markers of progression.
• Evidence snippets:
• Snippet 1 (score: 0.699)
  > Finally, since LGALS3 (Galectin-3) has been shown to interact with O-glycans in the mucosal epithelium [30], and considering its overexpression observed by proteomics and further confirmed by PCR and WB analyses upon depletion of C1GALT1, we focused on the role of LGALS3 in EC by IHC.
  > A total of 151 out of 178 cores from 79 EC patients were considered adequate for LGALS3 expression assessment by IHC. Morphologic assessment of LGALS3 IHC staining characteristics revealed different staining patterns (Fig. 5 A). Out of the 151 evaluable cores, 45 (29.8%) showed absent LGALS3 expression. LGALS3 positive samples showed variable and low intensity protein expression (mean positive tumor cells per sample = 35.4%). A small subset of cores (13/151, 8.6%) demonstrated diffuse (> 90% positive tumor cells per sample) staining. LGALS3 score varied across histologic types, with serous and undifferentiated tumors displaying the highest protein expression (median IHC LGALS3 score = 10, 20, 50 and 55 for endometrioid, clear cell, serous and undifferentiated tumor types, respectively) (Fig. 5B). Interestingly, the aggressive histologic variants (clear cell, serous and undifferentiated) showed higher LGALS3 IHC scores than endometrioid variants (p value < 0.001). In addition, LGALS3 expression positively correlated with tumor grade. High grade tumors (G3) displayed higher protein expression (median LGALS3 IHC score = 30) compared to low grade tumors (median LGALS3 IHC score for G1/G2 tumors = 10). This finding was independent of histologic type, as similar results were observed when analyzing endometrioid tumors.
  > Finally, we interrogated the correlation between the expression levels of LGALS3 and C1GALT1.

[12] Beyond Colonoscopy: Exploring New Cell Surface Biomarkers for Detection of Early, Heterogenous Colorectal Lesions

• Authors: Saleh M. Ramezani, Arianna Parkhideh, P. Bhattacharya, M. Farach-Carson, D. Harrington
• Year: 2021
• Venue: Frontiers in Oncology
• URL: https://www.semanticscholar.org/paper/4b48091d0ad86a2121491218707db23e88605000
• DOI: 10.3389/fonc.2021.657701
• PMID: 34290978
• PMCID: 8287259
• Citations: 13
• Summary: This review contextualizes existing and emergent CRC surface biomarkers and assess each’s potential as a candidate marker for early marker-based detection of CRC lesions and presents an overview of recent advances in imaging techniques useful for visual detection of surface biomarker detection.
• Evidence snippets:
• Snippet 1 (score: 0.696)
  > Galectin 3, or LGALS3, is a member of the galectin family, a group of carbohydrate-binding lectins characterized by their binding affinity for beta-galactosides (85).
  > LGALS3 is expressed at the cell surface, where it interacts with the extracellular matrix, especially with glycoproteins, and has the ability to affect intracellular signaling pathways (42). LGALS3-expressing cells also possess higher ALDH1 activity, which often correlates with a dedifferentiated cancer stem cell phenotype, than do their LGALS3-negative counterparts (86).
  > The correlation of LGALS3 expression in CRC with clinical pathological characteristics has been explored in several immunohistochemical and RT-PCR studies. In one study, the IHC staining of CRC tissue (n=61) and normal adjacent tissue (n=23) samples showed significantly higher LGALS3 expression in cancer tissue (62.5%) versus normal cancer-adjacent tissue (13.0%) (41). In another study, 75% of CRC tissue samples stain high for LGALS3, and ten CRC cell lines were shown to have increased LGALS3 protein levels compared to HeLa cells (42).
  > LGALS3 expression varies according to cancer staging and the degree of differentiation of the adenocarcinoma. LGALS3 mRNA levels were higher in early stage colorectal cancers (58% in stage I) compared to advanced cancers (50% in stage IV) (43). Protein analysis found higher LGALS3 levels in primary adenocarcinomas than in metastatic adenocarcinomas, and stronger LGALS3 staining in well-differentiated tumor areas compared to poorly differentiated tumor areas (43). Conversely, colorectal adenocarcinomas may display higher levels of LGALS3 than do colorectal adenomas; one study sets the rate of colorectal adenocarcinoma expression of LGALS3 at 95% while only 73% of adenomas were positive for LGALS3 (43).

[13] Mutation of the galectin‐3 glycan‐binding domain ( Lgals3‐R200S) enhances cortical bone expansion in male mice and trabecular bone mass in female mice

• Authors: Kevin A. Maupin, Daniel T. Dick, Vari Vivarium, Transgenics Core, B. Williams
• Year: 2020
• Venue: FEBS Open Bio
• URL: https://www.semanticscholar.org/paper/6ab62ea9acc6fef617d0b1f237c1a477f45b05c7
• DOI: 10.1002/2211-5463.13483
• PMID: 36062328
• PMCID: 9527582
• Citations: 2
• Summary: The results suggest that the trabecular bone phenotype of Lgals3-KO mice was driven primarily by loss of extracellular galectin-3, while the cortical bone phenotypeof Lgal3- KO mice may have also been influenced by Loss of intracellular galECTin- 3.
• Evidence snippets:
• Snippet 1 (score: 0.689)
  > The study of galectin-3 is complicated by its ability to function both intracellularly and extracellularly. While the mechanism of galectin-3 secretion is unclear, studies have shown that the mutation of a highly conserved arginine to a serine in human galectin-3 (LGALS3-R186S) blocks glycan binding and secretion. To gain insight into the roles of extracellular and intracellular functions of galectin-3, we generated mice with the equivalent mutation (Lgals3-R200S) using CRISPR/Cas9-directed homologous recombination. Consistent with a reduction in galectin-3 secretion, we observed significantly reduced galectin-3 protein levels in the plasma of heterozygous and homozygous mutant mice. We observed a similar increased bone mass phenotype in Lgals3-R200S mutant mice at 36 weeks as we previously observed in Lgals3-KO mice with slight variation. Like Lgals3-KO mice, Lgals3-R200S females, but not males, had significantly increased trabecular bone mass. However, only male Lgals3-R200S mice showed increased cortical bone expansion, which we had previously observed in both male and female Lgals3-KO mice and only in female mice using a separate Lgals3 null allele (Lgals3). These results suggest that the trabecular bone phenotype of Lgals3-KO mice was driven primarily by loss of extracellular galectin-3. However, the cortical bone phenotype of Lgals3-KO mice may have also been influenced by loss of intracellular galectin-3. Future analyses of these mice will aid in identifying the cellular and molecular mechanisms that contribute to the Lgals3-deficient bone phenotype as well as aid in distinguishing the extracellular vs. intracellular roles of galectin-3 in various signaling pathways.

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Asta Literature Retrieval: Literature evidence for LGALS3 (Homo sapiens): LGALS3 has macrophage chemotaxis (GO:0048246). Gene/protein: LGALS3. O...

This report is retrieval-only and is generated directly from Asta results.

• Papers retrieved: 11
• Snippets retrieved: 20

Relevant Papers

[1] High LGALS3 expression induced by HCP5/hsa-miR-27b-3p correlates with poor prognosis and tumor immune infiltration in hepatocellular carcinoma

• Authors: Yinghui Ren, Yongmei Qian, Qicheng Zhang, Xiaoping Li, Mingjiang Li et al.
• Year: 2024
• Venue: Cancer Cell International
• URL: https://www.semanticscholar.org/paper/552bd37c67dea75d0c33a9a0de2acdafcf0dcf6e
• DOI: 10.1186/s12935-024-03309-1
• PMID: 38643145
• PMCID: 11031979
• Citations: 13
• Summary: It is hypothesized that the HCP5/hsa-miR-27b-3p axis could serve as the most promising LGALS3 regulation mechanism in HCC and the upregulation of LGALS3 via the HCP5/hsa-miR-27b-3p axis is associated with unfavorable prognosis and increased tumor immune infiltration in HCC.
• Evidence snippets:
• Snippet 1 (score: 0.980)
  > To delineate the driving mechanism of LGALS3 for the malignant progression of HCC, the KEGG and GO analysis was conducted.The volcano plot and heatmap showed significantly differentially expressed genes between LGALS3 high-and low-expression groups (Figure S3A-B).The KEGG pathway analysis revealed that these LGALS3-related genes were enriched in the IL-17 signaling pathway, ECM-receptor interaction pathway, central carbon metabolism in cancer pathway, leukocyte transendothelial migration pathway and PI3K-Akt signaling pathway.Meanwhile, the GO analysis revealed that these genes were strongly associated with cell chemotaxis, leukocyte chemotaxis, regulation of leukocyte migration, as well as regulation of chemotaxis (Fig. 5A).Accumulating evidence has proven the immune system has an essential role in malignancy pathogenesis [17], and LGALS3 is closely correlated with CD163 + tumor-associated macrophages (TAM) in glioma [10].Therefore, we studied the association between LGALS3 level and the immune infiltration level in HCC.There was no statistical difference in immune cell infiltration levels over a number of LGALS3 copy numbers (Fig. 5B).Meanwhile, immune infiltration analysis revealed that expression of LGALS3 showed a significant positive association with several immune cell populations, involving CD4 + T cell, CD8 + T cell, B cell, neutrophil, macrophage, dendritic cell, as well as cancer-associated fibroblasts (CAFs) within HCC (Fig. 5C-E).Based on these results, we further evaluated the immune score in HCC patients with high and low LGALS3 expression.The scores of immune cells, including CD4 + T cell, CD8 + T cell, B cell, neutrophil, macrophage, and dendritic cell, were significantly higher in the high LGALS3 expression groups, as shown in Fig. 5F.Chemokines are a group of molecules that are important for the chemotaxis of immune cells [18].
• Snippet 2 (score: 0.947)
  > Chemokines are a group of molecules that are important for the chemotaxis of immune cells [18].According to Table S1, the expression of LGALS3 was statistically positively correlated with several chemokines of immune cells, involving monocytes/macrophages (CCL2, CCL3, CCL5, CCL7, CCL13, CCL17, and CCL22), T lymphocytes (CCL2, CCL1, CCL17, and CCL22), eosinophils (CCL11, CCL26, CCL5, CCL7, CCL13, and CCL3), mast cells (CCR1, CCR2, CCR3, CCR4, CCR5, CXCR2, and CXCR4), and neutrophils (CXCL8).Taken together, these outcomes indicate that LGALS3 is positively associated with immune cell infiltration and cell chemotaxis and could have a crucial function in HCC tumor immune microenvironment.
  > LGALS3 expression correlation and immune cell biomarkers in HCC Next, we wanted to investigate the LGALS3 function in HCC tumor immunity further.Utilizing GEPIA databases, we studied the correlation between LGALS3 expression and immune cell biomarkers within HCC.
• Snippet 3 (score: 0.814)
  > Hepatocellular carcinoma (HCC) is widely recognized for its unfavorable prognosis. Increasing evidence has revealed that LGALS3 has an essential function in initiating and developing several malignancies in humans. Nevertheless, thorough analysis of the expression profile, clinical prognosis, pathway prediction, and immune infiltration of LGALS3 has not been fully explored in HCC. In this study, an initial pan-cancer analysis was conducted to investigate the expression and prognosis of LGALS3. Following a comprehensive analysis, which included expression analysis and correlation analysis, noncoding RNAs that contribute to the overexpression of LGALS3 were subsequently identified. This identification was further validated using HCC clinical tissue samples. TIMER2 and GEPIA2 were employed to examine the correlation between LGALS3 and HCP5 with immunological checkpoints, cell chemotaxis, and immune infiltration in HCC. The R program was applied to analyze the expression distribution of immune score in in HCC patients with high and low LGALS3 expression. The expression profiles of immune checkpoints were also analyzed. Use R to perform GSVA analysis in order to explore potential signaling pathways. First, we conducted pan-cancer analysis for LGALS3 expression level through an in-depth analysis of public databases and found that HCC has a high LGALS3 gene and protein expression level, which were then verified in clinical HCC specimens. Meanwhile, high LGALS3 gene expression is related to malignant progression and poor prognosis of HCC. Univariate and multivariate analyses confirmed that LGALS3 could serve as an independent prognostic marker for HCC. Next, by combining comprehensive analysis and validation on HCC clinical tissue samples, we hypothesize that the HCP5/hsa-miR-27b-3p axis could serve as the most promising LGALS3 regulation mechanism in HCC. KEGG and GO analyses highlighted that the LGALS3-related genes were involved in tumor immunity. Furthermore, we detected a significant positive association between LGALS3 and HCP5 with immunological checkpoints, cell chemotaxis, and immune infiltration. In addition, high LGALS3 expression groups had significantly
• Snippet 4 (score: 0.809)
  > analyses highlighted that the LGALS3-related genes were involved in tumor immunity. Furthermore, we detected a significant positive association between LGALS3 and HCP5 with immunological checkpoints, cell chemotaxis, and immune infiltration. In addition, high LGALS3 expression groups had significantly higher immune cell scores and immune checkpoint expression levels. Finally, GSVA analysis was performed to predict potential signaling pathways linked to LGALS3 and HCP5 in immune evasion and metabolic reprogramming of HCC. Our findings indicated that the upregulation of LGALS3 via the HCP5/hsa-miR-27b-3p axis is associated with unfavorable prognosis and increased tumor immune infiltration in HCC.
• Snippet 5 (score: 0.792)
  > Zhang et al. [14] suggested overexpression of LGALS3 promoted HCC bone metastasis and induced associated skeletal complications.Nevertheless, the expression, prognosis, epigenetic, and molecular regulatory mechanisms of LGALS3 in HCC have been incompletely studied.In addition, LGALS3 relation with immune infiltration in HCC TME has yet to be inadequately investigated.
  > This work began with a pan-cancer study of LGALS3 expression and its predictive value in a variety of human malignancies.We further explored the LGALS3 potential upstream regulatory noncoding RNAs (ncRNAs) involving microRNAs (miRNAs) as well as long noncoding RNAs (lncRNAs) throughout HCC.Subsequently, in HCC, a correlation analysis was investigated between LGALS3 and tumor immunity-related indicators involving cell chemotaxis, immune checkpoints, immune cell biomarkers, and infiltration.Eventually, the association between the expression of LGALS3 and signaling pathways was examined in HCC.Findings demonstrated that LGALS3 might have a role in the malignancy of HCC and immune cell infiltration via the HCP5/hsa-miR-27b-3p/ LGALS3 axis, suggesting that a novel HCP5/hsa-miR-27b-3p/LGALS3 axis could be a biomarker for prognosis and treatment target for HCC patients.
• Snippet 6 (score: 0.766)
  > Utilizing GEPIA databases, we studied the correlation between LGALS3 expression and immune cell biomarkers within HCC.Table S2 lists that LGALS3 demonstrated a significant positive association with various immune cell biomarkers, including B cell (CD19 and CD79A), CD4 + T cell (CD4), CD8 + T cell (CD8A and CD8B), neutrophil (ITGAM and CCR7), M1 macrophage (NOS2, IRF5, and PTGS2), M2 macrophage (CD163, VSIG4, and MS4A4A), dendritic cell (HLA-DPB1, HLA-DQB1, HLA-DRA, HLA-DPA1, CD1C, NRP1, and ITGAX) and CAFs (FAP, ACTA2, S100A4, PDPN, PDGFR, and CD70) in HCC.
  > Our results indicate that LGALS3 has a significant positive connection to the immune infiltration within HCC, especially CAFs.

[2] LGALS3 Is a Poor Prognostic Factor in Diffusely Infiltrating Gliomas and Is Closely Correlated With CD163+ Tumor-Associated Macrophages

• Authors: Wan-Ming Hu, Yuan-Zhong Yang, Tian Zhang, Changling Qin, Xuenong Li
• Year: 2020
• Venue: Frontiers in Medicine
• URL: https://www.semanticscholar.org/paper/53b083f91a08aefebb5f9edaaa95625e2dc98f2b
• DOI: 10.3389/fmed.2020.00182
• PMID: 32528967
• PMCID: 7254797
• Citations: 18
• Influential citations: 1
• Summary: LGALS3 was an independent poor prognostic marker in diffusely infiltrating gliomas and was positively correlated with immune cell infiltration, particularly CD163+ tumor-associated macrophages in the TCGA dataset, Rembrandt dataset, and the SYSUCC cohort.
• Evidence snippets:
• Snippet 1 (score: 0.856)
  > This may explain why LGALS3 positive glioma patients have a significantly shorter OS than LGALS3 negative patients, suggesting that LGALS3 may play a role in malignant progression in glioma through changing the immune microenvironment in glioma. Some studies have also confirmed that LGALS3 played a key role in glioma development through increasing cell motility and invasion (21,22). Vladimirova et al. (23) found that LGALS3 expression was mediated by Runx-2 transcription factors, which contributed to the malignant progression of glial tumors. Conversely, only Gordower et al. (24) reported that LGALS3 expression decreased as the WHO level increased in astrocytic tumors. We think the reason for this difference may be partially due to the small number of patient samples in their study. Moreover, online database analysis also verified our results. Patients with high expression of LGALS3 mRNA had a poor prognosis.
  > LGALS3 was closely related to IDH status, CD163+ TAMs and was mainly expressed in IDH wild-type glioma. It is worth noting that LGALS3 mRNA was highly expressed in the mesenchymal subtype, a more malignant TCGA GBM subtype with a higher tendency for recurrence, metastasis, and increased vascularity.
  > Most importantly, we found that LGALS3 was involved in the regulation of the glioma immune microenvironment, particularly CD163+ TAMs. There is growing evidence that complex tumor microenvironments contribute to the malignant progression of gliomas (25,26). Among the components of the tumor microenvironment, tumor-associated macrophages (TAMs) are considered to provide important support for tumor growth. Macrophages are divided into M1 and M2 subtypes according to their functions. Typically, CD68 is a general marker for macrophages, while CD163 is considered to be a highly specific marker for M2 type macrophages.
• Snippet 2 (score: 0.791)
  > Background: Glioma, the most common brain tumor, is a heterogeneous group of glia-derived tumors, the majority of which have characteristics of diffuse infiltration and immunosuppression. The LGALS protein family is a large class of sugar-binding proteins. Among them, LGALS3 has been reported to promote tumor development and progression in some cancers. However, the clinical significance and biological functions of LGALS3 in glioma remain virtually unknown. The purpose of our research is to detect LGALS3 expression and its prognostic value in glioma and reveal the relationship between its expression and the clinico/molecular-pathological features of patients and immune cell infiltration. Methods: LGALS3 protein expression was examined by immunohistochemistry. The mRNA expression data of LGALS3 was downloaded and analyzed from TCGA and Rembrandt datasets. The association between LGALS3 and glioma clinically relevant diagnostic/molecular markers (IDH, 1p19q, ATRX, MGMT, and TERT) was examined using the Chi-Squared (χ2) test. The correlation between LGALS3 expression and the infiltration of multiple intra-tumoral immune cell types, including B cells (CD20), T cells (CD4 and CD8), macrophages (CD68), and M2 tumor-associated macrophages (CD163), was evaluated by Spearman correlation analysis. Kaplan-Meier analysis and the Cox regression analysis were applied to evaluate the prognostic value of LGALS3 in glioma. The log-rank test was used to evaluate Kaplan-Meier results for significance. Results: Out of all 304 glioma cases, LGALS3 protein was expressed in 125 glioma cases (41.1%, 125/304), with 69.2% (9/13) in WHO I, 9.8% (8/82) in WHO II, 34.2% (26/76) in WHO III, and 61.7% (82/133) in WHO IV. The expression of LGALS3 was correlated with patient age, WHO grade, PHH3 (mitosis), Ki67 index,
• Snippet 3 (score: 0.782)
  > Spearman correlation analysis revealed that CD20+ B cells were not correlated with LGALS3 expression (Figure 3F), but significant positive correlations were found between the infiltration of CD4+ T cells (Figure 3G), CD8+ T cells (Figure 3H), CD68+ macrophages (Figure 3I), CD163+ TAMs (Figure 3J), and the expression of LGALS3. In addition, the number of CD163+ TAMs infiltration was strongly correlated with LGALS3 (R = 0.724) in our cohort (Figure 3J).
• Snippet 4 (score: 0.774)
  > Typically, CD68 is a general marker for macrophages, while CD163 is considered to be a highly specific marker for M2 type macrophages. CD68+ macrophages are usually activated during antigen presentation and inflammatory responses, while CD163+ macrophages have a large number of anti-inflammatory cytokines that contribute to immunosuppression and promote tumor development. Multiple studies have shown that TAMs can actively suppress adaptive immunity, promote tumor growth, and angiogenesis, and are very similar to M2 macrophages (27,28). A previous study (29) confirmed that CD163+ TAMs played an important role in the biological process of glioma and that high expression of CD163 predicted poor prognosis in glioma patients. Another study suggested that the expression level of LGALS3 might affect macrophage infiltration in brain tumors (30), but only 16 GBM samples were used in their study. In the present study, we investigated the relationship between LGALS3 and TAMs in a large sample (304 glioma cases including 133 cases of GBM). We found that CD163+ TAMs were abundant in glioma, particularly in GBM and that LGALS3 was strongly correlated with the number of TAMs. GO and KEGG analyses also revealed that LGALS3 was involved in important inflammation and immune pathways, including cytokine signaling, NF-kappa B, NOD receptor, and the TNF signaling pathway. These results indicated that LGALS3 was involved in inflammatory and immune responses, which further contributed to malignant progression and shorter survival in glioma patients. However, the mechanism by which LGALS3 affects the glioma immune microenvironment and the exact pathways associated with LGALS3 in glioma need to be further explored in future studies.
  > In conclusion, we have shown that LGALS3 is a novel biomarker that is highly expressed in pilocytic astrocytoma, GBM, and IDH wild-type LGG. LGALS3 is associated with poor prognosis in diffusely infiltrating glioma and served as an important prognostic biomarker in LGG and GBM.

[3] Morphological and transcriptional insights into the role of histone phosphorylation-related genes in early development of the chicken duodenum

• Authors: Xiaofeng Li, Bing Yang
• Year: 2025
• Venue: Animal Bioscience
• URL: https://www.semanticscholar.org/paper/b3da4d3a37ec0fae40140d0cf95db98d90b41079
• DOI: 10.5713/ab.25.0108
• PMID: 40506039
• PMCID: 12580959
• Citations: 1
• Summary: A novel paradigm wherein histone phosphorylation coordinates intestinal morphogenesis is established, providing mechanistic insights for optimizing poultry intestinal health and nutritional strategies.
• Evidence snippets:
• Snippet 1 (score: 0.838)
  > Notably, as broilers age (from D0 to D7), the intestinal VH increases accordingly, indicating a positive balance between intestinal cell proliferation and apoptosis (i.e., cell proliferation predominates over apoptosis). Through transcriptional network analysis, we identified eight histone phosphorylation-associated hub genes (LGALS3, ITGB2, IRF7, SOCS3, CSF1R, KIF23, SMC2, and DLGAP5) that mechanistically link epigenetic regulation to developmental programming.
  > LGALS3 (galectin-3) plays critical roles in macrophage chemotaxis, mucosal barrier maintenance, intestinal epithelial cell (IEC) apoptosis regulation, and inflammatory responses [21][22][23]. Our study revealed a 6.59-fold increase in LGALS3 gene expression in the duodenum at D7 compared to D0 (Supplement 6), with functional analysis confirming its involvement in macrophage chemotaxis (Supplement 7). These findings align with Sun et al [21], who reported that LGALS3 silencing in necrotizing enterocolitis models inhibited the TLR4/NF-κB pathway, subsequently reducing IEC apoptosis and inflammation [21]. Emerging evidence further suggests LGALS3' s protective functions through ER stress modulation, autophagy regulation, and inflammasome control in intestinal Behçet' s disease [22], along with its capacity to upregulate key mucosal barrier components (MUC2, Occludin, and ZO-1) [23]. Collectively, these observations suggest LGALS3 promotes duodenal development through: 1) mucosal barrier reinforcement via tight junction protein upregulation, 2) inflammatory control through TLR4/NF-κB-mediated macrophage regulation, and 3) cellular homeostasis maintenance via ER stress/autophagy pathways.

[4] Phenotypic Switching of Vascular Smooth Muscle Cells in Atherosclerosis

• Authors: Runji Chen, D. McVey, D. Shen, Xiaoxin Huang, Shu Ye
• Year: 2023
• Venue: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
• URL: https://www.semanticscholar.org/paper/472c313e2214a97757712ab0a8b39b133bd6a6bc
• DOI: 10.1161/JAHA.123.031121
• PMID: 37815057
• PMCID: 10757534
• Citations: 133
• Influential citations: 2
• Summary: This review article discusses the 9 VSMC phenotypes that have been reported in atherosclerotic lesions and classifies them into differentiated VSMCs, intermediately dedifferentiated VSMCs, and dedifferentiated VSMCs.
• Evidence snippets:
• Snippet 1 (score: 0.835)
  > Lgals3 (also referred to as galectin-3) is considered a marker of macrophage-like cells. 13,31 Rong et al detected a population of VSMCs that expressed Lgals3 following cholesterol loading in vitro. 31 Recently, Alencar et al found that Lgals3 activation is not a specific marker of the differentiation of VSMCs to a macrophage-like state but rather it is a marker of VSMCs entering a transitional state, with increased expression of genes associated with stem cells that are capable of extracellular matrix remodeling. 16 Of note, similar to SEM-like cells, Lgals3 + cells also have increased expression of lymphocyte antigen 6 family member A and vascular cell adhesion molecule 1. Further studies to investigate if SEM-like cells are derived from Lgals3 + cells are warranted.
  > Using mouse, rat, and human models of cholesterolloading in VSMCs, Li et al found that SREBP1 (sterol regulatory-element binding protein-1) and Krüppel-like factor-15 induced up-and downregulation of Lgals3, respectively, via binding to the Lgals3 gene promoter (albeit at different sites). 45 Likewise, Lgals3 promoted SREBP1 gene expression, producing a feedforward loop upregulated by cholesterol loading. 45 Moreover, Lgals3 and SREBP1 downregulated myocardin-related transcription factor A expression in VSMCs. 45 In another study, Owsiany et al used a dual lineage tracing model and found that Lgals3 + VSMCs produce monocyte chemoattractant protein 1, a proinflammatory chemokine. 15 Knockout of monocyte chemoattractant protein 1 specifically in Lgals3 + VSMCs resulted in the formation of atherosclerotic lesions with a greater ACTA2 content in the fibrous cap and decreased Lgals3 + cell content, a feature of stable plaque. 15

[5] Pregnancy Galectinology: Insights Into a Complex Network of Glycan Binding Proteins

• Authors: S. Blois, G. Dveksler, G. Vasta, N. Freitag, V. Blanchard et al.
• Year: 2019
• Venue: Frontiers in Immunology
• URL: https://www.semanticscholar.org/paper/68fad2b87411701fa708a1f49f8b918370486857
• DOI: 10.3389/fimmu.2019.01166
• PMID: 31231368
• PMCID: 6558399
• Citations: 56
• Influential citations: 7
• Summary: The relevance of galectin-glycan interactions as potential therapeutic targets in pregnancy disorders is discussed and the importance of angiogenesis during decidualization and in placenta formation is discussed.
• Evidence snippets:
• Snippet 1 (score: 0.794)
  > Lgals3 has been implicated in the regulation of innate and adaptive immune responses, where it participates in the activation or differentiation of immune cells and contributes to phagocytic clearance of microorganisms and apoptotic cells by macrophages (117,118). Lgals3 has been reported to promote but also to inhibit T-cell apoptosis depending on whether it binds to glycoproteins on the cell surface (CD45 and CD71) or to intracellular ligands (Bcl-2) (119, 120). In the placenta, Lgals3 was detected in all trophoblastic lineages including villous cytotrophoblasts (CTB) and EVT with a reduction of Lgals3 expression observed from the VT to the trophoblastic cell columns (121). This pattern of Lgals3 expression correlates with the switch from a proliferative to a migratory trophoblast phenotype and while placental Lgals3 dysregulation has been associated with some obstetric complications including spontaneous or recurrent miscarriages, further studies are needed to understand its contribution to trophoblast biology (81,122). In addition to trophoblasts, Lgals3 is expressed by maternal decidual cells (73). While showing a different expression pattern, both Lgals1 and Lgals3 have been proposed to play a role in cell-cell and cell-matrix interactions of trophoblast during placentation (121). Studies of the importance of Lgals3 in murine pregnancy by Yang et al. indicate that Lgals3 is expressed in the luminal and glandular epithelium and that an increase in Lgals3 is required for proper embryo implantation (123). In addition, Lgals3 affects chemotaxis and morphology of endothelial cells and stimulates capillary tube formation and angiogenesis in vivo (124). Therefore, besides its proposed roles in embryo implantation, immune regulation and trophoblast-matrix interactions, Lgals3 has a potential role in placental angiogenesis.

[6] Secreted Factors and EV-miRNAs Orchestrate the Healing Capacity of Adipose Mesenchymal Stem Cells for the Treatment of Knee Osteoarthritis

• Authors: E. Ragni, C. Perucca Orfei, P. De Luca, A. Colombini, M. Viganò et al.
• Year: 2020
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/7d8d9d140ae309da10710f17dc979236a67fb966
• DOI: 10.3390/ijms21051582
• PMID: 32111031
• PMCID: 7084308
• Citations: 67
• Influential citations: 1
• Summary: Light is shed about the way ASCs regulate cell homeostasis and regenerative pathways in an OA-resembling environment, therefore suggesting a rationale for the use of MSC-enriched clinical products, such as stromal vascular fraction and microfragmented adipose tissue, in joint pathologies.
• Evidence snippets:
• Snippet 1 (score: 0.788)
  > 903, seven) and regulation of protein secretion (GO:0050708, 19) and, for the (ii) response to stimulus cascade-inflammatory response (GO:0006954, 31). Further, due to the reported role of ASCs in modulating synovial macrophages, the inflammatory response list was sifted through a Panther algorithm to identify specific and macrophage-related GO terms. A few terms emerged: macrophage chemotaxis (GO:0048246, two factors) and migration (GO:1905517), both defined by CCL3 and CCL5; the positive regulation of macrophage differentiation (GO:0045651) and regulation of macrophage differentiation (GO:0045649), both defined by CSF1 and TGFB1; the positive regulation of macrophage chemotaxis (GO:0010759, CCL5 and CSF1) and regulation of macrophage chemotaxis (GO:0010758, CSF1, CCL5 and MIF) and the positive regulation of macrophage activation (GO:0043032, CCL3 and IL13) and regulation of macrophage activation (GO:0043030, CCL3, IL13 and MIF). Eventually, to have a comprehensive overview of the entire dataset, in the inflammatory response terms, nine proteins of the > 10 ng group also fell (CCL2, CXCL10, CXCL5, EGFR, ICAM1, IGFBP4, IL6, TIMP1 and TNFRSF1A). CCL2 belonged to macrophage chemotaxis, LIF to the regulation of macrophage differentiation and IL1RL1 and IL6 to macrophage activation. Related to macrophages and their ability to migrate, monocyte chemotaxis (GO:0002548, IL6 and CCL2) emerged. Interestingly, other GO terms related with motility were identified, like leukocyte chemotaxis (GO:0030595, IL6, CCL2, CXCL5 and CXCL10); lymphoc

[7] Macrophage-derived Spp1 promotes intramuscular fat in dystrophic muscle

• Authors: Philip K Farahat, Chino Kumagai-Cresse, Raquel L. Aragón, Feiyang Ma, Justin K. Amakor et al.
• Year: 2025
• Venue: JCI Insight
• URL: https://www.semanticscholar.org/paper/25c265aed44730ce4b23491cd7ac24d8c3fcf94b
• DOI: 10.1172/jci.insight.181946
• PMID: 40626359
• PMCID: 12288893
• Citations: 7
• Summary: A role for myeloid-derived Spp1 in the differentiation of stromal cells towards an adipogenic fate, leading to accumulation of intramuscular fat in dystrophic muscles is suggested.
• Evidence snippets:
• Snippet 1 (score: 0.786)
  > Lgals3 clusters 2 and 3 expressed the highest Spp1. All Spp1-expressing clusters showed a drastic reduction in Spp1 in the cKO (Figure 2B, compare blue and green) (8). Lgals3-2 cells also expressed Arg1 while Lgals3-3 expressed Igf1 (11). The proportion of different monocyte/macrophage subtypes was evaluated in the 2 genotypes (Figure 2, C and D). While the proportion of Lgals3-3 and Lgals3-2 remained similar in the 2 genotypes, a mild increase in Lgals3-1 was observed in the cKO, while both monocyte subclusters slightly decreased in the cKO (Figure 2C). Although the overall number of macrophages increased in the cKO (mdx:969 vs cKO 4,028), cKO macrophages did not show large changes in the cellular frequency of subtypes (Figure 2D). Inflammatory genes were either unchanged or slightly reduced in the cKO, including the chemokines Ccl3 and Ccl4 (Figure 2F) and Tgfb1 (Supplemental Figure 2B). However, IFN genes such as Ifi207, Ifi204, and Isg15 were slightly increased in cKO monocytes (Figure 2F).

[8] Macrophages secrete murinoglobulin-1 and galectin-3 to regulate neutrophil degranulation after myocardial infarction

• Authors: Upendra Chalise, M. Daseke, William J. Kalusche, Shelby R. Konfrst, Jocelyn R. Rodriguez-Paar et al.
• Year: 2022
• Venue: Molecular Omics
• URL: https://www.semanticscholar.org/paper/446873a6222f1a5c4299cb80c95f7f9ff792e9f8
• DOI: 10.1039/d1mo00519g
• PMID: 35230372
• PMCID: 8963000
• Citations: 18
• Summary: In conclusion, macrophages at MI day 1 secrete MUG1 to limit and Lgals3 to accentuate neutrophil degranulation to regulate infarct wall thinning.
• Evidence snippets:
• Snippet 1 (score: 0.765)
  > Inflammation presides early after myocardial infarction (MI) as a key event in cardiac wound healing. Ischemic cardiomyocytes secrete inflammatory cues to stimulate infiltration of leukocytes, predominantly macrophages and neutrophils. Infiltrating neutrophils degranulate to release a series of proteases including matrix metalloproteinase (MMP)-9 to break down extracellular matrix and remove necrotic myocytes to create space for the infarct scar to form. While neutrophil to macrophage communication has been explored, the reverse has been understudied. We used a proteomics approach to catalogue the macrophage secretome at MI day 1. Murinoglobulin-1 (MUG1) was the highest-ranked secreted protein (4.1-fold upregulated at MI day 1 vs. day 0 pre-MI cardiac macrophages, p = 0.004). By transcriptomics evaluation, galectin-3 (Lgals3) was 2.2-fold upregulated (p = 0.008) in MI day 1 macrophages. We explored the direct roles of MUG1 and Lgals3 on neutrophil degranulation. MUG1 blunted while Lgals3 amplified neutrophil degranulation in response to phorbol 12-myristate 13-acetate or interleukin-1β, as measured by MMP-9 secretion. Lgals3 itself also stimulated MMP-9 secretion. To determine if MUG1 regulated Lgals3, we co-stimulated neutrophils with MUG1 and Lgals3. MUG1 limited degranulation stimulated by Lgals3 by 64% (p < 0.001). In vivo, MUG1 was elevated in the infarct region at MI days 1 and 3, while Lgals3 increased at MI day 7. The ratio of MUG1 to Lgals3 positively correlated with infarct wall thickness, revealing that MUG1 attenuated infarct wall thinning. In conclusion, macrophages at MI day 1 secrete MUG1 to limit and Lgals
• Snippet 2 (score: 0.755)
  > while Lgals3 increased at MI day 7. The ratio of MUG1 to Lgals3 positively correlated with infarct wall thickness, revealing that MUG1 attenuated infarct wall thinning. In conclusion, macrophages at MI day 1 secrete MUG1 to limit and Lgals3 to accentuate neutrophil degranulation to regulate infarct wall thinning.

[9] Galectin-3, histone deacetylases, and Hedgehog signaling: Possible convergent targets in schistosomiasis-induced liver fibrosis

• Authors: F. L. de Oliveira, Katia Carneiro, J. Brito, M. Cabanel, J. X. Pereira et al.
• Year: 2017
• Venue: PLoS Neglected Tropical Diseases
• URL: https://www.semanticscholar.org/paper/6dc6d6f3529841361a1ccf76eac911be181636c7
• DOI: 10.1371/journal.pntd.0005137
• PMID: 28231240
• PMCID: 5322873
• Citations: 31
• Summary: A possible involvement of Galectin-3 (Gal-3), histone deacetylases (HDACs), and Hedgehog (Hh) signaling with macrophage activation during Th1/Th2 immune responses, fibrogranuloma reaction, and tissue repair during schistosomiasis is suggested.
• Evidence snippets:
• Snippet 1 (score: 0.756)
  > Indeed, considering that the first step of the infection is under the control of a macrophage, the outcome of the disease needs to be further investigated, including in the Lgals3-/-infected mice. The downmodulation of macrophages in Lgals3-/-infected mice during the first step of the infection could be directly associated with a type of fibrogranulomatous reaction in the liver and, consequently, drive profibrotic events during schistosomiasis.

[10] Galectin-3 Identifies a Subset of Macrophages With a Potential Beneficial Role in Atherosclerosis

• Authors: K. Di Gregoli, M. Somerville, Rosaria Bianco, Anita C. Thomas, Aleksandra Frankow et al.
• Year: 2020
• Venue: Arteriosclerosis, Thrombosis, and Vascular Biology
• URL: https://www.semanticscholar.org/paper/7cc49f01469f15e073d249c35f5b1deb45262ade
• DOI: 10.1161/ATVBAHA.120.314252
• PMID: 32295421
• PMCID: 7253188
• Citations: 79
• Summary: A prominent protective role is revealed for galectin-3 in regulating macrophage polarization and invasive capacity and, therefore, delaying plaque progression.
• Evidence snippets:
• Snippet 1 (score: 0.749)
  > Macrophage buildup within atherosclerotic lesions is at least, in part, due to enhanced monocyte/macrophage recruitment and is associated with the progression of plaques. 35 As macrophage (CD68-positive cells) content was increased within plaques of galectin-3 mice, we assessed galectin-3 modulation on macrophage accumulation in vitro and in vivo, as a surrogate indicator of steady-state invasion. The in vitro invasive capacity of macrophages from Lgals3 −/− mice was significantly increased in comparison to cells from Lgals3 +/+ wild-type mice (2.2-fold increase; P<0.001; Figure 3A). Conversely, the number of invading Lgals3 −/− macrophages was diminished through addition of exogenous recombinant galectin-3 compared with untreated cells (69%; P<0.001; Figure 3B). Furthermore, and consistent with our in vitro data, the number of macrophages recruited and accrued within implanted Matrigel-infused sponges was significantly increased within Lgals3 −/− mice in comparison to Lgals3 +/+ animals (1.6-fold increase; P<0.001; Figure 3C). These data support a key role for galectin-3 in retarding macrophage invasive capacity and may explain the observed increase in (CD68 positive) macrophage numbers within brachiocephalic plaques of Lgals 3 −/− :Apoe −/− mice.

[11] Physical Activity Attenuates the Obesity-Induced Dysregulated Expression of Brown Adipokines in Murine Interscapular Brown Adipose Tissue

• Authors: T. Sakurai, Toshiyuki Fukutomi, Sachiko Yamamoto, Eriko Nozaki, T. Kizaki
• Year: 2021
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/c62f909c1038a72ef7c427bfa9914983c22b5422
• DOI: 10.3390/ijms221910391
• PMID: 34638731
• PMCID: 8508858
• Citations: 2
• Summary: Results indicate that PA attenuates the obesity-induced dysregulated expression of brown adipokines and suggests that Lgals3 and Lgal3bp are involved in brown adipocyte differentiation.
• Evidence snippets:
• Snippet 1 (score: 0.748)
  > In the present study, we identified humoral factors from HB2 brown adipocytes similar to those reported by Villarroya et al. [30] using murine brown preadipocytes in BAT. Among these humoral factors, Ccl9, Lgals3, and Lgals3bp were found to be brown adipokines with gene expressions that were largely influenced by obesity and PA. Ccl9, which is also known as macrophage inflammatory protein 1-γ, is a chemokine belonging to the CC chemokine family [45] and is known to play an important role in anti-leukemia and bone resorption procedures. Although there are very few reports of the effect of Ccl9 on adipocytes, it is known to inhibit the differentiation of white adipocytes [46].
  > The Lgals3 protein (galectin-3) is involved in biological processes such as cell adhesion, inflammation, and apoptosis. Lgals3 is upregulated in the WAT and the BAT of obese mice and can attenuate insulin signaling in white adipocytes [41]. Furthermore, obese and diabetic individuals were shown to have higher blood levels of the Lgals3 protein, which parallels the deterioration of glucose homeostasis and suggests that Lgals3 may be involved in the development of obesity and type 2 diabetes [41]. In addition, studies using Lgals3 KO mice reported decreases in body and fat masses in HFD-fed Lgals3 KO mice by comparison with control mice [47]. However, another study using Lgals3 KO mice demonstrated that Lgals3 deficiency accelerates adiposity, levels of adipose tissue, and systemic inflammation associated with altered glucose homeostasis [48,49]. Additionally, Lgals3 is known to stimulate the differentiation of preadipocytes into mature white adipocytes in vitro [47]. On the other hand, human Lgals3bp has long been regarded as an important clinical tumor biomarker associated with disease diagnosis, negative prognosis, and poor response to therapy [50].

Notes

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Asta Literature Retrieval: Literature evidence for LGALS3 (Homo sapiens): LGALS3 has positive chemotaxis (GO:0050918). Gene/protein: LGALS3. Org...

This report is retrieval-only and is generated directly from Asta results.

• Papers retrieved: 11
• Snippets retrieved: 19

Relevant Papers

[1] High LGALS3 expression induced by HCP5/hsa-miR-27b-3p correlates with poor prognosis and tumor immune infiltration in hepatocellular carcinoma

• Authors: Yinghui Ren, Yongmei Qian, Qicheng Zhang, Xiaoping Li, Mingjiang Li et al.
• Year: 2024
• Venue: Cancer Cell International
• URL: https://www.semanticscholar.org/paper/552bd37c67dea75d0c33a9a0de2acdafcf0dcf6e
• DOI: 10.1186/s12935-024-03309-1
• PMID: 38643145
• PMCID: 11031979
• Citations: 13
• Summary: It is hypothesized that the HCP5/hsa-miR-27b-3p axis could serve as the most promising LGALS3 regulation mechanism in HCC and the upregulation of LGALS3 via the HCP5/hsa-miR-27b-3p axis is associated with unfavorable prognosis and increased tumor immune infiltration in HCC.
• Evidence snippets:
• Snippet 1 (score: 0.826)
  > To delineate the driving mechanism of LGALS3 for the malignant progression of HCC, the KEGG and GO analysis was conducted.The volcano plot and heatmap showed significantly differentially expressed genes between LGALS3 high-and low-expression groups (Figure S3A-B).The KEGG pathway analysis revealed that these LGALS3-related genes were enriched in the IL-17 signaling pathway, ECM-receptor interaction pathway, central carbon metabolism in cancer pathway, leukocyte transendothelial migration pathway and PI3K-Akt signaling pathway.Meanwhile, the GO analysis revealed that these genes were strongly associated with cell chemotaxis, leukocyte chemotaxis, regulation of leukocyte migration, as well as regulation of chemotaxis (Fig. 5A).Accumulating evidence has proven the immune system has an essential role in malignancy pathogenesis [17], and LGALS3 is closely correlated with CD163 + tumor-associated macrophages (TAM) in glioma [10].Therefore, we studied the association between LGALS3 level and the immune infiltration level in HCC.There was no statistical difference in immune cell infiltration levels over a number of LGALS3 copy numbers (Fig. 5B).Meanwhile, immune infiltration analysis revealed that expression of LGALS3 showed a significant positive association with several immune cell populations, involving CD4 + T cell, CD8 + T cell, B cell, neutrophil, macrophage, dendritic cell, as well as cancer-associated fibroblasts (CAFs) within HCC (Fig. 5C-E).Based on these results, we further evaluated the immune score in HCC patients with high and low LGALS3 expression.The scores of immune cells, including CD4 + T cell, CD8 + T cell, B cell, neutrophil, macrophage, and dendritic cell, were significantly higher in the high LGALS3 expression groups, as shown in Fig. 5F.Chemokines are a group of molecules that are important for the chemotaxis of immune cells [18].
• Snippet 2 (score: 0.810)
  > Chemokines are a group of molecules that are important for the chemotaxis of immune cells [18].According to Table S1, the expression of LGALS3 was statistically positively correlated with several chemokines of immune cells, involving monocytes/macrophages (CCL2, CCL3, CCL5, CCL7, CCL13, CCL17, and CCL22), T lymphocytes (CCL2, CCL1, CCL17, and CCL22), eosinophils (CCL11, CCL26, CCL5, CCL7, CCL13, and CCL3), mast cells (CCR1, CCR2, CCR3, CCR4, CCR5, CXCR2, and CXCR4), and neutrophils (CXCL8).Taken together, these outcomes indicate that LGALS3 is positively associated with immune cell infiltration and cell chemotaxis and could have a crucial function in HCC tumor immune microenvironment.
  > LGALS3 expression correlation and immune cell biomarkers in HCC Next, we wanted to investigate the LGALS3 function in HCC tumor immunity further.Utilizing GEPIA databases, we studied the correlation between LGALS3 expression and immune cell biomarkers within HCC.
• Snippet 3 (score: 0.777)
  > Hepatocellular carcinoma (HCC) is widely recognized for its unfavorable prognosis. Increasing evidence has revealed that LGALS3 has an essential function in initiating and developing several malignancies in humans. Nevertheless, thorough analysis of the expression profile, clinical prognosis, pathway prediction, and immune infiltration of LGALS3 has not been fully explored in HCC. In this study, an initial pan-cancer analysis was conducted to investigate the expression and prognosis of LGALS3. Following a comprehensive analysis, which included expression analysis and correlation analysis, noncoding RNAs that contribute to the overexpression of LGALS3 were subsequently identified. This identification was further validated using HCC clinical tissue samples. TIMER2 and GEPIA2 were employed to examine the correlation between LGALS3 and HCP5 with immunological checkpoints, cell chemotaxis, and immune infiltration in HCC. The R program was applied to analyze the expression distribution of immune score in in HCC patients with high and low LGALS3 expression. The expression profiles of immune checkpoints were also analyzed. Use R to perform GSVA analysis in order to explore potential signaling pathways. First, we conducted pan-cancer analysis for LGALS3 expression level through an in-depth analysis of public databases and found that HCC has a high LGALS3 gene and protein expression level, which were then verified in clinical HCC specimens. Meanwhile, high LGALS3 gene expression is related to malignant progression and poor prognosis of HCC. Univariate and multivariate analyses confirmed that LGALS3 could serve as an independent prognostic marker for HCC. Next, by combining comprehensive analysis and validation on HCC clinical tissue samples, we hypothesize that the HCP5/hsa-miR-27b-3p axis could serve as the most promising LGALS3 regulation mechanism in HCC. KEGG and GO analyses highlighted that the LGALS3-related genes were involved in tumor immunity. Furthermore, we detected a significant positive association between LGALS3 and HCP5 with immunological checkpoints, cell chemotaxis, and immune infiltration. In addition, high LGALS3 expression groups had significantly
• Snippet 4 (score: 0.774)
  > analyses highlighted that the LGALS3-related genes were involved in tumor immunity. Furthermore, we detected a significant positive association between LGALS3 and HCP5 with immunological checkpoints, cell chemotaxis, and immune infiltration. In addition, high LGALS3 expression groups had significantly higher immune cell scores and immune checkpoint expression levels. Finally, GSVA analysis was performed to predict potential signaling pathways linked to LGALS3 and HCP5 in immune evasion and metabolic reprogramming of HCC. Our findings indicated that the upregulation of LGALS3 via the HCP5/hsa-miR-27b-3p axis is associated with unfavorable prognosis and increased tumor immune infiltration in HCC.
• Snippet 5 (score: 0.750)
  > Zhang et al. [14] suggested overexpression of LGALS3 promoted HCC bone metastasis and induced associated skeletal complications.Nevertheless, the expression, prognosis, epigenetic, and molecular regulatory mechanisms of LGALS3 in HCC have been incompletely studied.In addition, LGALS3 relation with immune infiltration in HCC TME has yet to be inadequately investigated.
  > This work began with a pan-cancer study of LGALS3 expression and its predictive value in a variety of human malignancies.We further explored the LGALS3 potential upstream regulatory noncoding RNAs (ncRNAs) involving microRNAs (miRNAs) as well as long noncoding RNAs (lncRNAs) throughout HCC.Subsequently, in HCC, a correlation analysis was investigated between LGALS3 and tumor immunity-related indicators involving cell chemotaxis, immune checkpoints, immune cell biomarkers, and infiltration.Eventually, the association between the expression of LGALS3 and signaling pathways was examined in HCC.Findings demonstrated that LGALS3 might have a role in the malignancy of HCC and immune cell infiltration via the HCP5/hsa-miR-27b-3p/ LGALS3 axis, suggesting that a novel HCP5/hsa-miR-27b-3p/LGALS3 axis could be a biomarker for prognosis and treatment target for HCC patients.
• Snippet 6 (score: 0.707)
  > LGALS3 has a crucial function in mediating cell adhesion as well as cell-cell interaction by recognizing complex carbohydrates on the surface of cells [22,23], as well as regulates cell apoptosis, autophagy, and inflammation [24,25].Interestingly, recent studies suggested that LGALS3 involves in essential cancer-related mechanisms, including cellular metabolism, carcinogenesis, metastasis, neoplasia, angiogenesis, as well as immune escape [26][27][28].In addition, LGALS3 is highly expressed and implicated in different cancer types progression such as HCC, gastric, colorectal, pancreatic carcinomas, melanomas or glioblastomas and breast cancer [29,30].Indeed, LGALS3 has been considered a potential marker for these malignancies.Interestingly, LGALS3, which is differentially expressed in different cancers, has been shown to exhibit tumor suppressor activity in certain cancer types.The different roles of LGALS3 may be attributed to different potential mechanisms that appear cancer-type dependent.The different locations and mutations of LGALS3 also contribute to its various functions.However, LGALS3 remains inadequately understood in HCC and requires further investigation.First, we conducted an extensive investigation of the expression profile, clinical prognosis, and pathologic stage of LGALS3 in HCC through an in-depth analysis of the public database.On the basis of TCGA and CPTAC datasets, we found that LGALS3 gene and protein expression was elevated in HCC tissues.Moreover, the OS and DSS were lesser in patients with HCC having higher expression levels of LGALS3 contrasted to those with low expression levels of LGALS3 based on GEPIA2 and Kaplan-Meier plotter datasets.Meanwhile, the expression of LGALS3 within HCC was significantly associated with the advanced tumor stage and grade, indicating that elevated LGALS3 expression could increase tumor progression.Song et al. [31] indicated that galectin-3 promoted HCC tumorigenesis and metastasis via β-catenin signalling in vitro and in vivo.

[2] Increased LGALS3 expression independently predicts shorter overall survival in patients with the proneural subtype of glioblastoma

• Authors: Xia He, Sunfu Zhang, Jun-chen Chen, Dekang Li
• Year: 2019
• Venue: Cancer Medicine
• URL: https://www.semanticscholar.org/paper/e5ebda3eeb9ae3c62aaea1ded13f19ca3632de24
• DOI: 10.1002/cam4.2075
• PMID: 30848102
• PMCID: 6536958
• Citations: 23
• Influential citations: 1
• Summary: It is inferred that LGALS3 expression serves as an independent biomarker of shorter OS in the proneural subtype of GBM, the expression of which might be regulated in an epigenetic manner.
• Evidence snippets:
• Snippet 1 (score: 0.761)
  > Using IHC staining images and protein expression scoring in the HPA, we examined LGALS3 and LGALS3BP protein expression in normal brain and GBM tissues. According to the data in the HPA, LGALS3 and LGALS3BP protein expression was not detectable in glial cells in normal brain tissues (Figure 2 with LGALS3 examined, 8 cases showed positive LGALS3 staining (3 low and 5 medium) (Figure 2, right). In addition, 8 out of 10 GBM cases had positive LGALS3BP staining (1 low, 2 medium and 5 high). These findings confirmed that LGALS3 and LGALS3BP were expressed at the protein level in GBM tissues.

[3] In-depth quantitative proteomics analysis revealed C1GALT1 depletion in ECC-1 cells mimics an aggressive endometrial cancer phenotype observed in cancer patients with low C1GALT1 expression

• Authors: A. Montero‐Calle, Á. López-Janeiro, Marta L. Mendes, Daniel Perez-Hernandez, Irene Echevarría et al.
• Year: 2023
• Venue: Cellular Oncology
• URL: https://www.semanticscholar.org/paper/92b64e01bcb30f7457ddb8cc4be26de8b0c7cf69
• DOI: 10.1007/s13402-023-00778-w
• PMID: 36745330
• PMCID: 10205863
• Citations: 19
• Summary: C1GALT1 stably depleted ECC-1 cells mimic an EC aggressive phenotype observed in patients and might be useful for the identification and validation of EC markers of progression.
• Evidence snippets:
• Snippet 1 (score: 0.744)
  > Finally, since LGALS3 (Galectin-3) has been shown to interact with O-glycans in the mucosal epithelium [30], and considering its overexpression observed by proteomics and further confirmed by PCR and WB analyses upon depletion of C1GALT1, we focused on the role of LGALS3 in EC by IHC.
  > A total of 151 out of 178 cores from 79 EC patients were considered adequate for LGALS3 expression assessment by IHC. Morphologic assessment of LGALS3 IHC staining characteristics revealed different staining patterns (Fig. 5 A). Out of the 151 evaluable cores, 45 (29.8%) showed absent LGALS3 expression. LGALS3 positive samples showed variable and low intensity protein expression (mean positive tumor cells per sample = 35.4%). A small subset of cores (13/151, 8.6%) demonstrated diffuse (> 90% positive tumor cells per sample) staining. LGALS3 score varied across histologic types, with serous and undifferentiated tumors displaying the highest protein expression (median IHC LGALS3 score = 10, 20, 50 and 55 for endometrioid, clear cell, serous and undifferentiated tumor types, respectively) (Fig. 5B). Interestingly, the aggressive histologic variants (clear cell, serous and undifferentiated) showed higher LGALS3 IHC scores than endometrioid variants (p value < 0.001). In addition, LGALS3 expression positively correlated with tumor grade. High grade tumors (G3) displayed higher protein expression (median LGALS3 IHC score = 30) compared to low grade tumors (median LGALS3 IHC score for G1/G2 tumors = 10). This finding was independent of histologic type, as similar results were observed when analyzing endometrioid tumors.
  > Finally, we interrogated the correlation between the expression levels of LGALS3 and C1GALT1.

[4] Periplocin suppresses the growth of colorectal cancer cells by triggering LGALS3 (galectin 3)-mediated lysophagy

• Authors: Kui Wang, Shuyue Fu, Lixia Dong, Dingyue Zhang, Mao Wang et al.
• Year: 2023
• Venue: Autophagy
• URL: https://www.semanticscholar.org/paper/3dadfc351823c4e325e65c171ab3765871189c80
• DOI: 10.1080/15548627.2023.2239042
• PMID: 37471054
• Citations: 35
• Influential citations: 2
• Summary: It is shown that periplocin exhibits promising anticancer activity against CRC both in vitro and in vivo, and is indicated as a potential therapeutic option for the treatment of CRC.
• Evidence snippets:
• Snippet 1 (score: 0.740)
  > We next investigated the mechanism underlying periplocinmediated lysophagy. The expression of LGALS3, a key lysophagy marker [46], was found to be upregulated following periplocin treatment as evidenced by immunofluorescent staining (Figure 2M). To this end, we presumed that periplocin-induced lysophagy might be attributable to the upregulation of LGALS3. Indeed, periplocin treatment prominently elevated the protein level of LGALS3 as evidence by immunoblotting analysis (Figure 6A). The increased protein level of LGALS3 was further confirmed in tumor xenografts from periplocin-treated mice (Figure 6B,C). However, no obvious change was observed on the mRNA level of LGALS3 in periplocin-treated cells compared with controls (Figure S6A), suggesting that transcriptional regulation was not involved in increased LGALS3 expression following periplocin treatment. Therefore, we postulated that periplocin might elevate LGALS3 by regulating protein stability. Of note, cycloheximide (CHX, a translational inhibitor) treatment led to an obvious decrease in LGALS3 protein level in control cells, but had no obvious effect on the upregulated protein level of LGALS3 in periplocin-treated cells, suggesting periplocin maintains LGALS3 stability (Figure 6D,E). In support of this, treatment with MG132 (a proteasome inhibitor) failed to further enhance the protein level of LGALS3 in response to periplocin treatment (Figure 6F,G). These data suggest that periplocin may prevent proteasomal degradation of LGALS3.
  > We therefore measured the effect of periplocin on LGALS3 ubiquitination. As shown in Figure 6H, periplocin markedly decreased the ubiquitin-conjugated level of LGALS3.
• Snippet 2 (score: 0.712)
  > Scale bar: 10 μm. (I) Immunofluorescent analysis of the colocalization of LGALS3 with ubiquitin in CRC cells treated with or without 0.50 μM periplocin for 24 h. Scale bar: 10 μm. (J) Representative fluorescent images of CRC cells transiently expressing Mrfp-GFP-tandem fluorescent-tagged LGALS3 (tfGal3) followed by 0.50 μM periplocin treatment for 24 h. Scale bar: 10 μm. (K) Quantitative analysis of the GFP + RFP + or GFP − RFP + LGALS3 puncta in (J). (L) the relative decreased ratio of Magic Red intensity, relative increased ratio of LysoSensor Blue intensity, relative increased ratio of the interaction between LGALS3 and TRIM16, and relative increased ratio of LC3B-II protein level in DLD-1 cells following 0.50 μM periplocin treatment at different time periods. Results are representative of three independent experiments. Data are presented as mean ± SD. P < 0.05, P < 0.01, **P < 0.001. for LGALS3 degradation, we generated lysine to arginine mutants of LGALS3 at K196 or Lys210 (LGALS3 K196R or LGALS3 K210R ). As shown in Figure 6I, the ubiquitinconjugated level of LGALS3 K196R mutant was comparable to the wild type (WT), whereas K210 mutation significantly decreased LGALS3 ubiquitination. These results suggest that periplocin elevates LGALS3 level by preventing K210 ubiquitination and proteasomal degradation. In addition, periplocin was found to stabilize the protein level of LGALS3 against thermal changes using a cellular thermal shift assay (CETSA) (Figure 6J,K), implying the binding of periplocin with LGALS3.
• Snippet 3 (score: 0.711)
  > In addition, periplocin was found to stabilize the protein level of LGALS3 against thermal changes using a cellular thermal shift assay (CETSA) (Figure 6J,K), implying the binding of periplocin with LGALS3. The interaction between periplocin and LGALS3 was further confirmed by drug affinity responsive target stability (DARTS) analysis, as evidenced by a more stable property of LGALS3 protein against pronase digestion in response to periplocin treatment (Figure 6L,M). Moreover, using semiflexible docking analysis, we found that LGALS3 showed a good binding activity for periplocin, with a binding energy of −6.689 kcal/mol. Glu165, Arg162, Gly152, Gln150, Arg144, and Asn143 of LGALS3 were identified as possible sites for periplocin binding (Figure 6N,O), which required further experimental investigation. Together, these data suggest that periplocin binds and prevents ubiquitin-mediated degradation of LGALS3 in CRC cells.

[5] Pregnancy Galectinology: Insights Into a Complex Network of Glycan Binding Proteins

• Authors: S. Blois, G. Dveksler, G. Vasta, N. Freitag, V. Blanchard et al.
• Year: 2019
• Venue: Frontiers in Immunology
• URL: https://www.semanticscholar.org/paper/68fad2b87411701fa708a1f49f8b918370486857
• DOI: 10.3389/fimmu.2019.01166
• PMID: 31231368
• PMCID: 6558399
• Citations: 56
• Influential citations: 7
• Summary: The relevance of galectin-glycan interactions as potential therapeutic targets in pregnancy disorders is discussed and the importance of angiogenesis during decidualization and in placenta formation is discussed.
• Evidence snippets:
• Snippet 1 (score: 0.739)
  > Lgals3 has been implicated in the regulation of innate and adaptive immune responses, where it participates in the activation or differentiation of immune cells and contributes to phagocytic clearance of microorganisms and apoptotic cells by macrophages (117,118). Lgals3 has been reported to promote but also to inhibit T-cell apoptosis depending on whether it binds to glycoproteins on the cell surface (CD45 and CD71) or to intracellular ligands (Bcl-2) (119, 120). In the placenta, Lgals3 was detected in all trophoblastic lineages including villous cytotrophoblasts (CTB) and EVT with a reduction of Lgals3 expression observed from the VT to the trophoblastic cell columns (121). This pattern of Lgals3 expression correlates with the switch from a proliferative to a migratory trophoblast phenotype and while placental Lgals3 dysregulation has been associated with some obstetric complications including spontaneous or recurrent miscarriages, further studies are needed to understand its contribution to trophoblast biology (81,122). In addition to trophoblasts, Lgals3 is expressed by maternal decidual cells (73). While showing a different expression pattern, both Lgals1 and Lgals3 have been proposed to play a role in cell-cell and cell-matrix interactions of trophoblast during placentation (121). Studies of the importance of Lgals3 in murine pregnancy by Yang et al. indicate that Lgals3 is expressed in the luminal and glandular epithelium and that an increase in Lgals3 is required for proper embryo implantation (123). In addition, Lgals3 affects chemotaxis and morphology of endothelial cells and stimulates capillary tube formation and angiogenesis in vivo (124). Therefore, besides its proposed roles in embryo implantation, immune regulation and trophoblast-matrix interactions, Lgals3 has a potential role in placental angiogenesis.

[6] LGALS3 is connected to CD74 in a previously unknown protein network that is associated with poor survival in patients with AML

• Authors: P. Ruvolo, Chenyue W. Hu, Y. Qiu, V. Ruvolo, Robin L. Go et al.
• Year: 2019
• Venue: EBioMedicine
• URL: https://www.semanticscholar.org/paper/46bbdbcb4660389e13acba24499cc415d75f18e0
• DOI: 10.1016/j.ebiom.2019.05.025
• PMID: 31105032
• PMCID: 6604360
• Citations: 25
• Influential citations: 2
• Summary: The data suggest that the LGALS3 network and the CD74 network each support AML cell survival and the two networks may cooperate in a novel high risk AML population.
• Evidence snippets:
• Snippet 1 (score: 0.731)
  > LGALS3 is associated with active Fig. 7. Suppression of LGALS3 does not alter gene expression of LGALS3 network protein genes or CD74 in THP-1 cells. RNA from THP-1 transductant cells with either LKO vector control shRNA or LGALS3 shRNA was isolated, cDNA produced, and mRNA levels of ATG7, LGALS3, ITGAL, CCND3, PRKCA, PARP1, CD74, MYC, CD44, SSBP2, PPP2R2A, CLPP, and B2M were determined by qRT-PCR and levels normalized to ABL-1 as described in "Materials and methods".
  > AKT and MAPK signaling. The protein with the strongest positive correlation with LGALS3 is with ATG7, an autophagy protein that has recently been implicated in maintaining hematopoietic stem cells and serving as a survival factor in AML [46,47]. Recent studies implicate LGALS3 in regulation of autophagy via autophagasome formation, though whether the mechanism involves ATG7 is not clear [48]. Interestingly, phosphorylated PKC delta was positively correlated with LGALS3. PKC delta is viewed as a pro-stress kinase but recent studies suggest that the enzyme has pro-survival properties [49][50][51]. Kinehara and colleagues suggest that PKC delta may act in human pluripotent stem cells as part of a mechanism to regulate stem cell renewal [52]. The data also suggest a novel relationship between LGALS3 and PP2A. The negative correlation of LGALS3 expression with PPP2R2A/B/C/D could reflect LGALS3 suppression of PP2A. The PP2A isoform containing PPP2R2A dephosphorylates both AKT and PKC alpha [53]. Thus, potential suppression of the PP2A subunit by LGALS3 could account for elevated AKT and PKC alpha phosphorylation in samples where LGALS3 expression is elevated.
• Snippet 2 (score: 0.716)
  > Thus, potential suppression of the PP2A subunit by LGALS3 could account for elevated AKT and PKC alpha phosphorylation in samples where LGALS3 expression is elevated. Induction of PPP2R2A protein (Fig. 5) but not gene expression (Fig. 7) in THP-1 cells expressing LGALS3 shRNA suggests that LGALS3 acts directly on the PP2A subunits via a post-transcriptional mechanism in these cells. The TCGA data (Table 3) however suggests that there is a positive correlation between gene expression of LGALS3 and PPP2R2A suggesting that a common pathway may regulate the two genes. Fig. 8. Progeny clustering identified an optimal number of 4 distinct protein clusters for this ProFnGrp. Protein networks were generated and showed interactions between "core-proteins" (large nodes) and other probed proteins (small nodes) from the data set. Clustering method has been described in our previous publication (ref. [37]) and further information on these protein networks can be found on our website "Leukemia Profile Atlases", available at https://www.leukemiaatlas.org/. Progeny clustering identified one protein cluster with expression similar to that of the normal CD34+ samples which was designated as "normal-state" while three "leukemia-specific" protein patterns characterized by high expression individually of CD74, LGAL3, and a fourth state with both on. PPP2RA/B/C/D was the only LGALS3 network protein demonstrated to be directly regulated by LGALS3 in the THP-1 cells (Fig. 5). In our previous study we saw potent suppression of AKT signaling by LGALS3 inhibition, so perhaps the mechanism involves LGALS3 suppression of the AKT phosphatase [15]. However, we did not see suppression of LGALS3 affect other network proteins in the THP-1 cells (data not shown). The role of other galectins such as LGALS1 in AML biology is not clear.

[7] The deficiency of galectin-3 in stromal cells leads to enhanced tumor growth and bone marrow metastasis

• Authors: J. X. Pereira, Maria Carolina Braga Azeredo, Felipe Sá Martins, R. Chammas, F. L. Oliveira et al.
• Year: 2016
• Venue: BMC Cancer
• URL: https://www.semanticscholar.org/paper/5f5ef422f3c44fa24a457d97d0c915ae8188a279
• DOI: 10.1186/s12885-016-2679-1
• PMID: 27526676
• PMCID: 4986277
• Citations: 12
• Influential citations: 1
• Summary: It is demonstrated for the first time that the absence of galectin-3 in the host microenvironment favors the growth of the primary tumors, the metastatic spread to the inguinal lymph nodes and bone marrow colonization by metastatic 4T1 tumor cells.
• Evidence snippets:
• Snippet 1 (score: 0.725)
  > We next investigated whether galectin-3 could influence the development of metastasis to the lymph node. Therefore, 28 days post orthotopic injection (p.o.i) of 4T1 cells in Lgals3+/+ or Lgals3−/− mice, the lymph nodes were excised and the presence of CK-19 positive cells was analyzed by immunohistochemistry. We observed that 4T1 cells (CK-19+) were predominantly present in the capsule of the draining lymph node in Lgals3+/+ mice (Fig. 3a) whereas in Lgals3−/− mice, CK-19+ cells were organized as "sheets-like" within the lymph node parenchyma and also found in the capsule (Fig. 3b). Moreover, we evaluated the presence of lymph node metastasis in Lgals3+/+ and Lgals3−/− mice using the 6-thioguanine clonogenic assay and found significant fewer metastasis in Lgals3+/+ mice in comparison to Lgals3−/− mice, both 21 and 28 days p.o.i. (Fig. 3c, p < 0,05). Interestingly though, we also found an increased CK-19 mRNA levels in Lgals3−/− mice at an earlier stage (15 days) p.o.i. (Fig. 3d, p < 0,05). These results suggest that Lgals3−/− mice are more permissive for 4T1 tumor cells dissemination to the inguinal lymph nodes.
  > Galectin-3-deficient bone marrow microenvironment supports more efficiently the growth of metastatic 4T1
  > We have previously described that Lgals3−/− mice presented structural and functional differences in the bone marrow [17]. Likewise, in this study we confirmed differences in terms of cellularity and projections of bone tissue inside the cavity between Balb/c Lgals3+/+ and Lgals3 −/− mice (Fig. 4a and b).

[8] Thyroid malignant neoplasm-associated biomarkers as targets for oncolytic virotherapy

• Authors: Mi Guan, Yanping Ma, S. Shah, G. Romano
• Year: 2016
• Venue: Oncolytic Virotherapy
• URL: https://www.semanticscholar.org/paper/9f79d851e32ad25e83c0a2d64e12919bf81a89f8
• DOI: 10.2147/OV.S99856
• PMID: 27579295
• PMCID: 4996252
• Citations: 4
• Summary: This review focuses on the strategy of biomarkers for the production of novel TMN oncolytic therapeutics, which may improve the specificity of targeting of tumor cells and limit adverse effects in patients.
• Evidence snippets:
• Snippet 1 (score: 0.724)
  > The Galectin-3 (LGALS3) is a protein that is encoded by a single gene, LGALS3, located on chromosome 14, locus q21-q22. 63 The molecular weight of this protein is ∼30 kDa, and it contains a carbohydrate-recognition-binding domain of ∼130 amino acids that enable the specific binding of β-galactosides. This protein localizes to the extracellular matrix, the cytoplasm, and the nucleus. It plays a role in numerous cellular functions including cell adhesion, cell activation and chemoattraction, cell growth, differentiation, cell cycle, apoptosis, innate immunity, cell adhesion, and T-cell regulation. 63,64 It has been known that LGALS3 is distributed widely around the tissues but in a low level.
  > To date, LGALS3 has been extensively studied as an IHC marker of thyroid malignancy, and a high diagnostic accuracy has been reported even for difficult pathological diagnoses. 64 Feilchenfeldt et al reported that the mRNA levels of LGALS3 and thyroglobulin in 28 benign and 31 malignant thyroid samples were quantified by real-time PCR. The LGALS3 expression at the mRNA was 60% (12/20) and the protein level was 100% (8/8), respectively. 65 The positive rate was 84% (41/49) when combined with the LGALS3 and HBME-1 in PTC specimens. 66 Two groups of researchers have detected the LGALS3 by IHC in PTC specimens. Saleh et al have shown that the sensitivity and the specificity for LGALS3 were 92.3% and 77.3%, respectively. 67 Song et al reported that positive expression of LGALS3 was 97% (427/441) in PTC group and 51% (77/151) in the benign thyroid lesions group. 68 These results may further support the notion that the high level of LGALS3 antigen expression occurs in patients with PTC. There are a number of different types of oncolytic viruses that have been altered from natural viruses in the laboratory such as adenovirus, reovirus, measles virus, herpes simplex

[9] Mutation of the galectin‐3 glycan‐binding domain ( Lgals3‐R200S) enhances cortical bone expansion in male mice and trabecular bone mass in female mice

• Authors: Kevin A. Maupin, Daniel T. Dick, Vari Vivarium, Transgenics Core, B. Williams
• Year: 2020
• Venue: FEBS Open Bio
• URL: https://www.semanticscholar.org/paper/6ab62ea9acc6fef617d0b1f237c1a477f45b05c7
• DOI: 10.1002/2211-5463.13483
• PMID: 36062328
• PMCID: 9527582
• Citations: 2
• Summary: The results suggest that the trabecular bone phenotype of Lgals3-KO mice was driven primarily by loss of extracellular galectin-3, while the cortical bone phenotypeof Lgal3- KO mice may have also been influenced by Loss of intracellular galECTin- 3.
• Evidence snippets:
• Snippet 1 (score: 0.714)
  > The study of galectin-3 is complicated by its ability to function both intracellularly and extracellularly. While the mechanism of galectin-3 secretion is unclear, studies have shown that the mutation of a highly conserved arginine to a serine in human galectin-3 (LGALS3-R186S) blocks glycan binding and secretion. To gain insight into the roles of extracellular and intracellular functions of galectin-3, we generated mice with the equivalent mutation (Lgals3-R200S) using CRISPR/Cas9-directed homologous recombination. Consistent with a reduction in galectin-3 secretion, we observed significantly reduced galectin-3 protein levels in the plasma of heterozygous and homozygous mutant mice. We observed a similar increased bone mass phenotype in Lgals3-R200S mutant mice at 36 weeks as we previously observed in Lgals3-KO mice with slight variation. Like Lgals3-KO mice, Lgals3-R200S females, but not males, had significantly increased trabecular bone mass. However, only male Lgals3-R200S mice showed increased cortical bone expansion, which we had previously observed in both male and female Lgals3-KO mice and only in female mice using a separate Lgals3 null allele (Lgals3). These results suggest that the trabecular bone phenotype of Lgals3-KO mice was driven primarily by loss of extracellular galectin-3. However, the cortical bone phenotype of Lgals3-KO mice may have also been influenced by loss of intracellular galectin-3. Future analyses of these mice will aid in identifying the cellular and molecular mechanisms that contribute to the Lgals3-deficient bone phenotype as well as aid in distinguishing the extracellular vs. intracellular roles of galectin-3 in various signaling pathways.

[10] Impairment of lysosomal quality control in Huntington disease

• Authors: P. Rusmini, F. Mina, M. Valenza, Martina Vitali, V. Ferrari et al.
• Year: 2025
• Venue: Cell Death & Disease
• URL: https://www.semanticscholar.org/paper/c874bbb3c9e6aa0a3f74519c022f3fa822daf4a8
• DOI: 10.1038/s41419-025-08103-z
• PMID: 41145409
• PMCID: 12559425
• Citations: 4
• Influential citations: 1
• Summary: TFEB and TFE3 are sequestered in muHTT aggregates, and muHTT proteins associates with LMP triggering the translocation of LGALS3 to the lumen of lysosomes, with a close relation between polyQ size and severity of these events.
• Evidence snippets:
• Snippet 1 (score: 0.704)
  > In HD, high levels of LGALS3 have been found in plasma and brain of patients and mice. LGALS3 upregulation was observed in HD mice before the motor symptoms, in the microglia LGALS3 was found associated to damaged lysosomes and its suppression in microglia ameliorated the HD mice phenotype [36].
  > LGALS3 is emerging as a key factor for NDs for its intracellular role in lysosomal damage, but also for its functions linked to its secretion in the extracellular space. Many pieces of evidence suggest its detrimental role in neurodegeneration, even if a protective role of LGALS3 has been reported (reviewed in ref. [75]). LGALS3 mechanisms of action need further investigation but its pharmacological modulation might represent a valuable target for intervention for NDs. LGALS3 inhibitors have already been tested in metabolic and fibrotic diseases, and these approaches might be applied to NDs. 3′-bis-(4aryltriazol-1-yl) thiodigalactoside (GB039, formerly named TD139), a synthetic small molecule that antagonizes LGALS3 activity by binding to the carbohydrate recognition domain, was effective in idiopathic pulmonary fibrosis and retinal degeneration [76,77]. Pectins, plant cell wall polysaccharides, mostly obtained from citrus and apples, represent natural LGALS3 inhibitors [78,79].
  > In summary, our experiments suggest that LQC impairment might contribute to HD. Indeed, the LGALS3 accumulation observed in HD cellular models due to TFEB and TFE3 sequestration by muHTT inclusions causes LMP and lysophagy impairment, in turn, influences LQC.
  > Fig. 8 TFEB and TFE3 sequestration affects the LQC. A, B NSC-34 cells were transfected with wt or muHTT.

[11] Identification of an Internal Gene to the Human Galectin-3 Gene with Two Different Overlapping Reading Frames That Do Not Encode Galectin-3*

• Authors: M. Guittaut, Stéphane Charpentier, Thierry Normand, Martine Dubois, J. Raimond et al.
• Year: 2001
• Venue: The Journal of Biological Chemistry
• URL: https://www.semanticscholar.org/paper/75ca62f4b6eb66b3bcdac062664da410941fdcaa
• DOI: 10.1074/JBC.M002523200
• PMID: 11160123
• Citations: 37
• Influential citations: 6
• Summary: It is demonstrated that these transcripts arise from an internal gene embedded within LGALS3 and named galig (Galectin-3 internal gene), which appears to be tightly regulated and principally activated in leukocytes from peripheral blood.
• Evidence snippets:
• Snippet 1 (score: 0.702)
  > Human Rapid-Scan Gene Expression Panel was used to detect the alternative transcripts in various human tissues using RT-PCR. The primers used were designed to amplify a 923-or 629-bp fragment.
  > LGALS3 transcripts were detected as a 457-bp DNA and actin transcripts as a 640-bp DNA. PCR was performed using 0.25 ng or 2.5 ng (10ϫ) template cDNA.
  > average of other human proteins is 10 times lower. This rich content in tryptophans confers hydrophobic properties that may account for the membrane localization of the ORF2⅐EGFP protein (Fig. 6). Consistent with the mitochondrial localization of the ORF2⅐EGFP fusion protein, this sequence exhibits the common properties of mitochondrial-imported proteins such as the enrichment of arginine, leucine, and serine residues (36).
  > Tissue Specificity of galig Expression-Detection of galig transcripts in HOS cells and colon tumor cells revealed a low expression level. Based on this observation, the rationale that the appearance of galig transcripts may have resulted from a leaky transcription of a cryptic promoter rather than from an independently functioning promoter could not be excluded. Screening of several human tissues indicated clearly that galig is a tightly regulated gene whose expression is most efficient in leukocytes from peripheral blood. The low level of transcription in bone marrow indicates that galig is specifically expressed in mature forms of leukocytes. Whereas the precise quantification of galig mRNA has not been addressed in these experiments, it is clear that these transcripts are much less abundant than LGALS3 transcripts. This may not be surprising considering that LGALS3 is known to be highly expressed when activated (37,38). Indeed, the amount of LGALS3 transcripts appeared as abundant as those from actin genes. This shows a different type of regulation by the galig and LGALS3 promoters. In particular, muscle, stomach, and uterus, although expressing low levels of galig transcripts, revealed no LGALS3 transcripts, thus indicating an independent functioning of the two promoters.

Notes

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Asta Literature Retrieval: Literature evidence for LGALS3 (Homo sapiens): LGALS3 has positive regulation of calcium ion import (GO:0090280). Gen...

This report is retrieval-only and is generated directly from Asta results.

• Papers retrieved: 12
• Snippets retrieved: 20

Relevant Papers

[1] Identification of an Internal Gene to the Human Galectin-3 Gene with Two Different Overlapping Reading Frames That Do Not Encode Galectin-3*

• Authors: M. Guittaut, Stéphane Charpentier, Thierry Normand, Martine Dubois, J. Raimond et al.
• Year: 2001
• Venue: The Journal of Biological Chemistry
• URL: https://www.semanticscholar.org/paper/75ca62f4b6eb66b3bcdac062664da410941fdcaa
• DOI: 10.1074/JBC.M002523200
• PMID: 11160123
• Citations: 37
• Influential citations: 6
• Summary: It is demonstrated that these transcripts arise from an internal gene embedded within LGALS3 and named galig (Galectin-3 internal gene), which appears to be tightly regulated and principally activated in leukocytes from peripheral blood.
• Evidence snippets:
• Snippet 1 (score: 0.733)
  > Human Rapid-Scan Gene Expression Panel was used to detect the alternative transcripts in various human tissues using RT-PCR. The primers used were designed to amplify a 923-or 629-bp fragment.
  > LGALS3 transcripts were detected as a 457-bp DNA and actin transcripts as a 640-bp DNA. PCR was performed using 0.25 ng or 2.5 ng (10ϫ) template cDNA.
  > average of other human proteins is 10 times lower. This rich content in tryptophans confers hydrophobic properties that may account for the membrane localization of the ORF2⅐EGFP protein (Fig. 6). Consistent with the mitochondrial localization of the ORF2⅐EGFP fusion protein, this sequence exhibits the common properties of mitochondrial-imported proteins such as the enrichment of arginine, leucine, and serine residues (36).
  > Tissue Specificity of galig Expression-Detection of galig transcripts in HOS cells and colon tumor cells revealed a low expression level. Based on this observation, the rationale that the appearance of galig transcripts may have resulted from a leaky transcription of a cryptic promoter rather than from an independently functioning promoter could not be excluded. Screening of several human tissues indicated clearly that galig is a tightly regulated gene whose expression is most efficient in leukocytes from peripheral blood. The low level of transcription in bone marrow indicates that galig is specifically expressed in mature forms of leukocytes. Whereas the precise quantification of galig mRNA has not been addressed in these experiments, it is clear that these transcripts are much less abundant than LGALS3 transcripts. This may not be surprising considering that LGALS3 is known to be highly expressed when activated (37,38). Indeed, the amount of LGALS3 transcripts appeared as abundant as those from actin genes. This shows a different type of regulation by the galig and LGALS3 promoters. In particular, muscle, stomach, and uterus, although expressing low levels of galig transcripts, revealed no LGALS3 transcripts, thus indicating an independent functioning of the two promoters.

[2] LGALS3 is connected to CD74 in a previously unknown protein network that is associated with poor survival in patients with AML

• Authors: P. Ruvolo, Chenyue W. Hu, Y. Qiu, V. Ruvolo, Robin L. Go et al.
• Year: 2019
• Venue: EBioMedicine
• URL: https://www.semanticscholar.org/paper/46bbdbcb4660389e13acba24499cc415d75f18e0
• DOI: 10.1016/j.ebiom.2019.05.025
• PMID: 31105032
• PMCID: 6604360
• Citations: 25
• Influential citations: 2
• Summary: The data suggest that the LGALS3 network and the CD74 network each support AML cell survival and the two networks may cooperate in a novel high risk AML population.
• Evidence snippets:
• Snippet 1 (score: 0.721)
  > LGALS3 is associated with active Fig. 7. Suppression of LGALS3 does not alter gene expression of LGALS3 network protein genes or CD74 in THP-1 cells. RNA from THP-1 transductant cells with either LKO vector control shRNA or LGALS3 shRNA was isolated, cDNA produced, and mRNA levels of ATG7, LGALS3, ITGAL, CCND3, PRKCA, PARP1, CD74, MYC, CD44, SSBP2, PPP2R2A, CLPP, and B2M were determined by qRT-PCR and levels normalized to ABL-1 as described in "Materials and methods".
  > AKT and MAPK signaling. The protein with the strongest positive correlation with LGALS3 is with ATG7, an autophagy protein that has recently been implicated in maintaining hematopoietic stem cells and serving as a survival factor in AML [46,47]. Recent studies implicate LGALS3 in regulation of autophagy via autophagasome formation, though whether the mechanism involves ATG7 is not clear [48]. Interestingly, phosphorylated PKC delta was positively correlated with LGALS3. PKC delta is viewed as a pro-stress kinase but recent studies suggest that the enzyme has pro-survival properties [49][50][51]. Kinehara and colleagues suggest that PKC delta may act in human pluripotent stem cells as part of a mechanism to regulate stem cell renewal [52]. The data also suggest a novel relationship between LGALS3 and PP2A. The negative correlation of LGALS3 expression with PPP2R2A/B/C/D could reflect LGALS3 suppression of PP2A. The PP2A isoform containing PPP2R2A dephosphorylates both AKT and PKC alpha [53]. Thus, potential suppression of the PP2A subunit by LGALS3 could account for elevated AKT and PKC alpha phosphorylation in samples where LGALS3 expression is elevated.
• Snippet 2 (score: 0.640)
  > The role of other galectins such as LGALS1 in AML biology is not clear.
  > LGALS1 may substitute for some LGALS3 functions particularly those involved in survival pathways as knock down of either LGALS1 or LGALS3 sensitized AML cells to BH3 mimetic drugs [15]. The failure of LGALS3 suppression to affect many of the RPPA identified proteins with the exception of PPP2R2A/B/C/D (Fig. 5) may reflect LGALS1 activity in these cells that may not be present in the primary AML cells. It is possible that many of the LGALS3 network proteins act to regulate LGALS3 rather than being regulated by the galectin. It is also possible that LGALS3 and some of the LGALS3 network proteins are subject to regulation by a yet unidentified common regulator(s). Further examination of the mechanism regulating the LGALS3 network is ongoing.
  > Network analysis from the data identifies a new extremely poor prognosis group based on the interaction between the LGALS3 and CD74 associated protein networks revealing potential biological pathways that may be critical in supporting AML cell survival. AML patients with both networks active are 8.5% of patients in the study (Fig. 9A) and thus this group may represent a sizeable population of AML patients. It is possible the two proteins regulate independent survival pathways that may have a synergistic effect on survival when both are active. The top ten biological processes associated with LGALS3 network include processes associated with cell metabolism (GO:0031325; GO:0032268; and GO:0032270), cell migration (GO:0030355), and response to growth factor stimulus (GO:0071363) and response to chemical stimulus (GO:0070887) (Supplemental Table 1). While it is unclear how LGALS3 might mechanistically influence leukemic cell recovery and growth after therapy, perhaps regulation of these cellular processes are important in addition to the well documented role of LGALS3 in regulation of cell cycle and cell proliferation [1,2,13,14].
• Snippet 3 (score: 0.626)
  > Thus, potential suppression of the PP2A subunit by LGALS3 could account for elevated AKT and PKC alpha phosphorylation in samples where LGALS3 expression is elevated. Induction of PPP2R2A protein (Fig. 5) but not gene expression (Fig. 7) in THP-1 cells expressing LGALS3 shRNA suggests that LGALS3 acts directly on the PP2A subunits via a post-transcriptional mechanism in these cells. The TCGA data (Table 3) however suggests that there is a positive correlation between gene expression of LGALS3 and PPP2R2A suggesting that a common pathway may regulate the two genes. Fig. 8. Progeny clustering identified an optimal number of 4 distinct protein clusters for this ProFnGrp. Protein networks were generated and showed interactions between "core-proteins" (large nodes) and other probed proteins (small nodes) from the data set. Clustering method has been described in our previous publication (ref. [37]) and further information on these protein networks can be found on our website "Leukemia Profile Atlases", available at https://www.leukemiaatlas.org/. Progeny clustering identified one protein cluster with expression similar to that of the normal CD34+ samples which was designated as "normal-state" while three "leukemia-specific" protein patterns characterized by high expression individually of CD74, LGAL3, and a fourth state with both on. PPP2RA/B/C/D was the only LGALS3 network protein demonstrated to be directly regulated by LGALS3 in the THP-1 cells (Fig. 5). In our previous study we saw potent suppression of AKT signaling by LGALS3 inhibition, so perhaps the mechanism involves LGALS3 suppression of the AKT phosphatase [15]. However, we did not see suppression of LGALS3 affect other network proteins in the THP-1 cells (data not shown). The role of other galectins such as LGALS1 in AML biology is not clear.
• Snippet 4 (score: 0.623)
  > While it is unclear how LGALS3 might mechanistically influence leukemic cell recovery and growth after therapy, perhaps regulation of these cellular processes are important in addition to the well documented role of LGALS3 in regulation of cell cycle and cell proliferation [1,2,13,14]. Many of the CD74 network associated biological processes involved immune regulation (Supplemental Table 3) though it is unclear if CD74 network regulates potential immune response in AML. Many of the CD74 network associated biological processes did include those involved in regulation of cell death and apoptosis (Supplemental Table 3). Of the 31 proteins correlated with CD74 expression, 19 are associated with the biological pathway regulation of cell death (GO.0010941) and 16 are associated with the biological pathway negative regulation of apoptotic process (GO.0043066). The raises the question of what the cross-talk is between the LGALS3 and CD74 networks? Gene expression analysis of CD74, CD44, and CLPP in the THP-1 LKO cells versus THP-1 cells with LGALS3 shRNA showed no or only slight changes in these genes (Fig. 7). Protein expression of CD74, CD44, and CLPP were similar in THP-1 LKO and THP-1 LGALS3 shRNA cells (data not shown). While LGALS3 supports AKT activation via RAS, CD74 would be expected to support AKT via MIF mediated signaling involving CD44 and/or CXCR4 [19][20][21][22][23][24][25][26][27]. Though the functional roles of LGALS3 and CD74 in this process are very different, each network would contribute to activation and perhaps may explain why patients with both active networks do so poorly (Fig. 9A and B). Unfortunately, CXCR4 is not represented in the RPPA panel due to lack of validated antibody. However, CD44 is present and interestingly is most elevated in patients with active LGALS3 network and CD74 network (Fig. 8).

[3] Systematic identification of potential key microRNAs and circRNAs in the dorsal root ganglia of mice with sciatic nerve injury

• Authors: Youfen Yu, Xueru Xu, Chunshui Lin, Rongguo Liu
• Year: 2023
• Venue: Frontiers in Molecular Neuroscience
• URL: https://www.semanticscholar.org/paper/bb63dc0bb6c65149c674451492fc049ff2f4ce8f
• DOI: 10.3389/fnmol.2023.1119164
• PMID: 36998510
• PMCID: 10043392
• Citations: 4
• Summary: Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis demonstrated that these differentially expressed mRNAs and targeting miRNAs were involved in signal transduction, positive regulation of receptor-mediated endocytosis and regulation of neuronal synaptic plasticity in NeP.
• Evidence snippets:
• Snippet 1 (score: 0.719)
  > The metabolic processes included positive regulation of apoptotic process (GO:0043065), negative regulation of neuron death (GO:1901215), regulation of angiogenesis (GO:0045765), positive regulation of calcium ion import (GO:0090280), positive regulation of receptor-mediated endocytosis (GO:0048260), positive regulation of serotonin secretion (GO:0014064), positive regulation of chemokine production (GO:0032722), etc. For CC, almost all of the enriched terms were related to cellular metabolic processes, intracellular organelles and signal transmission, such as neuronal cell body (GO:0043025), glial cell projection (GO:0097386), neuron projection (GO:0043005), glutamatergic synapse (GO:0098978), Golgi apparatus (GO:0005794), axon cytoplasm (GO:1904115), and postsynaptic density (GO:0014069). Regarding MF, the enriched terms were almost all associated with protein binding, sequence-specific binding and ion channel activity, including chemokine receptor binding (GO:0048020), neuropeptide hormone activity (GO:0005184), calmodulin binding (GO:0005516), transcription factor activity (GO:0003700), sequence-specific DNA binding (GO:0043565), transmembrane transporter activity (GO:0022857), extracellular-glutamate-gated ion channel activity (GO:0005234), and ligand-gated ion channel activity (GO:0015276).
  > In summary, the involvement of intracellular and extracellular signaling pathways in immune, inflammatory and oxidative stress processes as well as endocrine metabolic processes may be closely related to the onset and development of NeP.
• Snippet 2 (score: 0.675)
  > KEGG functional analysis of DEmRNAs showed the top 17 representative enrichment pathways, including the MAPK signaling pathway, calcium signaling pathway, p53 signaling pathway, HIF-1 signaling pathway, and cytokine-cytokine receptor interaction (Figure 2A; Supplementary Table S2).
  > Furthermore, we performed GO analysis of DEGs, and the enriched results were highly significant, including 131 entries enriched in biological process (BP), 36 entries in cellular component (CC) and 34 entries in molecular function (MF) (Figures 2B-D; Supplementary Table S2). For BP, DEmRNAs were mainly enriched in inflammatory and immune processes as well as endocrine metabolism processes. The inflammatory and immune processes included inflammatory response The construction of protein-protein interaction network and identification of hub genes. (GO:0006954), neutrophil chemotaxis (GO:0030593), cellular response to interleukin-1 (GO:0071347), macrophage chemotaxis (GO:0048246), cytokine-mediated signaling pathway (GO:0019221), positive regulation of tumor necrosis factor production (GO:0032760), immune system process (GO:0002376), etc. The metabolic processes included positive regulation of apoptotic process (GO:0043065), negative regulation of neuron death (GO:1901215), regulation of angiogenesis (GO:0045765), positive regulation of calcium ion import (GO:0090280), positive regulation of receptor-mediated endocytosis (GO:0048260), positive regulation of serotonin secretion (GO:0014064), positive regulation of chemokine production (GO:0032722), etc.

[4] Comparative transcriptome analysis provides clues to molecular mechanisms underlying blue-green eggshell color in the Jinding duck (Anas platyrhynchos)

• Authors: Zhepeng Wang, Guohua Meng, Yun Bai, Ruifang Liu, Yu Du et al.
• Year: 2017
• Venue: BMC Genomics
• URL: https://www.semanticscholar.org/paper/9d37ba3b57ef695a83d1039fe094ded0df9f4b38
• DOI: 10.1186/s12864-017-4135-2
• PMID: 28899357
• PMCID: 5596863
• Citations: 28
• Summary: Given the involvement of membrane cholesterol contents, ions and ATP levels in modulating the transport activity of bile pigment transporters, the data suggest a potential association between duck BGEC and the transportActivity of the related transporter.
• Evidence snippets:
• Snippet 1 (score: 0.698)
  > During eggshell formation, a series of ions, including Ca 2+ , HCO 3 − , Na + , K + , H + , and Cl − participate in the mineralization process [40]. Here, a total of 13 Ca 2+ , 10 Na + , 8 K + , 5 H + , and 1 Cl − transporter and two HCO 3 − synthesis genes were identified among the candidate genes (Additional files 2, and 4). Among the 13 Ca 2+ transport genes, ATP2C2, HTP1B, PKD2, RASA3, CACNB2, TRPC1, TRPC4, and TRPV2 were further annotated as calcium ion import (GO:0070509) and positive regulation of calcium ion import (GO:0090280) (Additional file 5). These Ca 2+ import genes were almost all downregulated in the BSD groups, with the exception of HTR1B and ATP2C2 (Fig. 5). In contrast, three Ca 2+ pumps (ATP2A2, ATP2B2, and ATP2C2) were all upregulated (Fig. 5). Genes mediating Na + , K + , H + , and Cl − transport were almost all upregulated, with the exception of one Na + (PKD2) and two K + (PKD2 and KCNF1) transport genes (Fig. 5). In addition, two HCO 3 − synthesis genes (CA2 and CA8) were upregulated in the BSD groups (Fig. 5).
  > We identified a considerable number of candidate genes involved in ion transport coupled ATP hydrolysis (i.e. Ca 2+ pumps and Na + /K + exchangers) and synthesis (i.e. H + transporters).

[5] Lgals3 Promotes Calcium Oxalate Crystal Formation and Kidney Injury Through Histone Lactylation‐Mediated FGFR4 Activation

• Authors: Zehua Ye, Yushi Sun, Songyuan Yang, Lei Li, Bojun Li et al.
• Year: 2025
• Venue: Advanced Science
• URL: https://www.semanticscholar.org/paper/adbfa30b5832407d200a5eade9196d41be08050e
• DOI: 10.1002/advs.202413937
• PMID: 39903812
• PMCID: 11947994
• Citations: 18
• Summary: Findings suggest that Lgals3 may play a key role in CaOx stone formation and kidney injury by interacting with PKM2 and promoting both H3K18la‐mediated gene transcription and activation.
• Evidence snippets:
• Snippet 1 (score: 0.695)
  > The incidence of kidney stones is increasing worldwide. However, the underlying mechanism of the process of kidney stone formation and the kidney damage caused are not well understood. Here, it is observed that Lgals3, a β‐galactoside‐binding protein, is significantly increased in tissues with calcium oxalate (CaOx) stones, and in both in vivo and in vitro models. Lgals3 expression is positively correlated with the deposition of CaOx crystals. Knockout of Lgals3 markedly reduces the deposition of CaOx crystal and renal fibrosis in vivo. Furthermore, Lgals3 deficiency decrease the glycolytic rate and lactate production during the process of CaOx deposition and inhibited histone lactylation of H3K18la. Mechanistic studies shows that Lgals3 directly interacted with the key glycolysis protein pyruvate kinase M2 (PKM2) and promoted its expression by modulating E3 ligase Trim21, preventing the ubiquitination of PKM2. Furthermore, H3K18 lactylation promoted CaOx crystal deposition and kidney injury in vivo and in vitro. Lgals3 deficiency inhibites the transcription, activation, and expression of FGFR4 through inhibition of H3K18la. These findings suggest that Lgals3 may play a key role in CaOx stone formation and kidney injury by interacting with PKM2 and promoting both H3K18la‐mediated gene transcription and activation.
• Snippet 2 (score: 0.661)
  > [23] The result of the present study revealed that Lgals3 exhibited several novel functions and mechanisms in the formation of kidney stones and the development of renal fibrosis (Figure 13). It was found that Lgals3 was highly expressed in CaOx crystal deposition and stimulated the activation of glycolysis during crystal deposition and renal fibrosis. Knockout or pharmacological inhibition of Lgals3 demonstrated a significant reduction of crystal deposition and renal fibrosis. In addition, IP-MS analysis identified PKM2, a key molecule in the regulation of glycolytic function, as the direct binding target of Lgals3. Furthermore, this study integrated analyses of CUT&Tag and RNA-seq and demonstrated that Lgals3mediated histone lactylation promoted FGFR4 expression during the formation of CaOx stones and renal fibrosis. [24] Lgals3 is considered a disease-associated biomarker and it is significantly increased in cases of acute myocardial infarction or AKI. [25,26] urthermore, recent investigations have shown that it has significant potential as a therapeutic target for various inflammatory and fibrotic illnesses, including lung or kidney fibrosis. [27] n this study, it was found that Lgals3 expression was increased in both mouse and human CaOx crystal kidney tissues. This study utilized Lgals3 −/-mice and demonstrated that Lgals3 deficiency alleviated CaOx crystal deposition and renal fibrosis. The deposition of CaOx crystals and the development of renal fibrosis are complex processes regulated by numerous genes and signaling pathways. RNA-seq and 4D-DIA proteomics were performed to detect alterations in mRNA and protein expression in Lgals3-deficient cells under COM stimulation. The KEGG analysis showed that Lgals3 deficiency primarily enriched metabolicrelated pathways, specifically glycolysis. When cells are exposed to various stimuli, the mitochondrial energy metabolism undergoes alterations, leading to significant activation of glycolysis, which in turn increases the overall energy supply. [28]
• Snippet 3 (score: 0.653)
  > To explore the role of Lgals3 in kidney injury caused by CaOx crystal, Lgals3 knockout (Lgals3 −/− ) mice were generated (Figure S3A,B, Supporting Information). qPCR, Western blot and immunohistochemistry staining were used to verify knockout efficiency (Figure S3C-E, Supporting Information). Subsequently, a CaOx kidney stone model was established (Figure 2A). CaOx crystal deposition markedly elevated blood urea nitrogen (BUN) and creatinine levels, whereas Lgals3 knockout ameliorated kidney function (Figure 2B,C). Histological assessment of kidney pathology by hematoxylin and eosin (HE) and Von Kossa staining showed that tubular injury and CaOx crystal deposition were significantly increased in the model group, whereas knockout of Lgals3 alleviated kidney injury and CaOx crystal formation (Figure 2D). Meanwhile, renal fibrotic structural alterations were evaluated, and Lgals3 knockout reduced collagen fiber deposition (Figure 2E,F). In addition, Inflammatory responses play a crucial role in the formation of calcium oxalate kidney stones. We found that CaOx crystals leads to an increase in the expression of inflammatory cytokines such as IL-1,IL-6 and TNF- (Figure S3F, Supporting Information). Conversely, the knockout of Lgals3 results in a significant decrease in the expression of these inflammatory factors.
  > To identify the role of Lgals3 in vitro, a Lgals3-knockdown HK-2 cell line was established and western blot analysis confirmed that Lgals3 knockdown was successful (Figure S4A, Supporting Information). The HK-2 cells were treated with COM for 48h to established the cell model. Immunofluorescence staining found that Lgals3 knockdown alleviated -SMA expression in COM-treated HK-2 cells (Figure S4C, Supporting Information). Western blot analysis showed a significant decrease in fibrosis-related protein expression under the stimulation of COM in vitro (Figure S4D, Supporting Information).

[6] Periplocin suppresses the growth of colorectal cancer cells by triggering LGALS3 (galectin 3)-mediated lysophagy

• Authors: Kui Wang, Shuyue Fu, Lixia Dong, Dingyue Zhang, Mao Wang et al.
• Year: 2023
• Venue: Autophagy
• URL: https://www.semanticscholar.org/paper/3dadfc351823c4e325e65c171ab3765871189c80
• DOI: 10.1080/15548627.2023.2239042
• PMID: 37471054
• Citations: 35
• Influential citations: 2
• Summary: It is shown that periplocin exhibits promising anticancer activity against CRC both in vitro and in vivo, and is indicated as a potential therapeutic option for the treatment of CRC.
• Evidence snippets:
• Snippet 1 (score: 0.658)
  > We next investigated the mechanism underlying periplocinmediated lysophagy. The expression of LGALS3, a key lysophagy marker [46], was found to be upregulated following periplocin treatment as evidenced by immunofluorescent staining (Figure 2M). To this end, we presumed that periplocin-induced lysophagy might be attributable to the upregulation of LGALS3. Indeed, periplocin treatment prominently elevated the protein level of LGALS3 as evidence by immunoblotting analysis (Figure 6A). The increased protein level of LGALS3 was further confirmed in tumor xenografts from periplocin-treated mice (Figure 6B,C). However, no obvious change was observed on the mRNA level of LGALS3 in periplocin-treated cells compared with controls (Figure S6A), suggesting that transcriptional regulation was not involved in increased LGALS3 expression following periplocin treatment. Therefore, we postulated that periplocin might elevate LGALS3 by regulating protein stability. Of note, cycloheximide (CHX, a translational inhibitor) treatment led to an obvious decrease in LGALS3 protein level in control cells, but had no obvious effect on the upregulated protein level of LGALS3 in periplocin-treated cells, suggesting periplocin maintains LGALS3 stability (Figure 6D,E). In support of this, treatment with MG132 (a proteasome inhibitor) failed to further enhance the protein level of LGALS3 in response to periplocin treatment (Figure 6F,G). These data suggest that periplocin may prevent proteasomal degradation of LGALS3.
  > We therefore measured the effect of periplocin on LGALS3 ubiquitination. As shown in Figure 6H, periplocin markedly decreased the ubiquitin-conjugated level of LGALS3.
• Snippet 2 (score: 0.651)
  > In addition, periplocin was found to stabilize the protein level of LGALS3 against thermal changes using a cellular thermal shift assay (CETSA) (Figure 6J,K), implying the binding of periplocin with LGALS3. The interaction between periplocin and LGALS3 was further confirmed by drug affinity responsive target stability (DARTS) analysis, as evidenced by a more stable property of LGALS3 protein against pronase digestion in response to periplocin treatment (Figure 6L,M). Moreover, using semiflexible docking analysis, we found that LGALS3 showed a good binding activity for periplocin, with a binding energy of −6.689 kcal/mol. Glu165, Arg162, Gly152, Gln150, Arg144, and Asn143 of LGALS3 were identified as possible sites for periplocin binding (Figure 6N,O), which required further experimental investigation. Together, these data suggest that periplocin binds and prevents ubiquitin-mediated degradation of LGALS3 in CRC cells.

[7] Lysosomal damage is a therapeutic target in Duchenne muscular dystrophy

• Authors: Abbass Jaber, Laura Palmieri, R. Bakour, N. Bourg, A. Hong et al.
• Year: 2025
• Venue: Science Advances
• URL: https://www.semanticscholar.org/paper/3265a29ad8c2d48b294017fd50b6df9188b55ecb
• DOI: 10.1126/sciadv.adv6805
• PMID: 41124255
• PMCID: 12542950
• Citations: 7
• Summary: Lysosomal perturbations in myofibers of patients with DMD and animal models are identified, highlighting lysosomal damage as an important pathomechanism in DMD and suggesting that combining trehalose with gene therapy could enhance therapeutic efficacy.
• Evidence snippets:
• Snippet 1 (score: 0.642)
  > To confirm the inflammatory origin of these regions, coimmunostaining for LGALS3 and CD11b was performed on serial TA muscle cross sections (Fig. 1F). An overlay of both staining (CD11b and LGALS3) was observed between the myofibers, confirming the presence of infiltrating macrophages, while LGALS3 staining was also evident within myofibers. This indicates that the up-regulation of Gal-3 in muscle lysates reflects contributions from both immune infiltrates and myogenic sources.
  > To specifically quantify LMP in myofibers, we measured the number of LAMP2 + LGALS3 + puncta within myofibers, excluding inflammatory areas using a segmentation method (fig. S2A). This analysis revealed a significant increase in LAMP2 + LGALS3 + puncta in dystrophic muscle compared to WT controls (mean puncta = 9 for Dmd mdx-4Cv versus 1 in WT) (Fig. 1G), confirming that LGALS3 upregulation in Dmd mdx-4Cv muscles is not solely due to macrophage infiltration but also reflects myogenic up-regulation and recruitment to the lysosome, suggesting substantial LMP in dystrophic myofibers.
  > To validate these findings in human and large animal models, we analyzed muscle biopsies from patients with DMD and golden retriever muscular dystrophy (GRMD) dogs. LGALS3 up-regulation within myofibers was consistently observed in biopsies of patients with DMD from children aged 2 and nearly 4 years (Fig. 1H and fig. S2B) and in 6-month-old GRMD dogs (Fig. 1H). In all cases, LGALS3 colocalized with LAMP2 in most myofibers, further supporting the presence of LMP and myofiber-intrinsic Gal-3 up-regulation across species.

[8] High LGALS3 expression induced by HCP5/hsa-miR-27b-3p correlates with poor prognosis and tumor immune infiltration in hepatocellular carcinoma

• Authors: Yinghui Ren, Yongmei Qian, Qicheng Zhang, Xiaoping Li, Mingjiang Li et al.
• Year: 2024
• Venue: Cancer Cell International
• URL: https://www.semanticscholar.org/paper/552bd37c67dea75d0c33a9a0de2acdafcf0dcf6e
• DOI: 10.1186/s12935-024-03309-1
• PMID: 38643145
• PMCID: 11031979
• Citations: 13
• Summary: It is hypothesized that the HCP5/hsa-miR-27b-3p axis could serve as the most promising LGALS3 regulation mechanism in HCC and the upregulation of LGALS3 via the HCP5/hsa-miR-27b-3p axis is associated with unfavorable prognosis and increased tumor immune infiltration in HCC.
• Evidence snippets:
• Snippet 1 (score: 0.642)
  > Hepatocellular carcinoma (HCC) is widely recognized for its unfavorable prognosis. Increasing evidence has revealed that LGALS3 has an essential function in initiating and developing several malignancies in humans. Nevertheless, thorough analysis of the expression profile, clinical prognosis, pathway prediction, and immune infiltration of LGALS3 has not been fully explored in HCC. In this study, an initial pan-cancer analysis was conducted to investigate the expression and prognosis of LGALS3. Following a comprehensive analysis, which included expression analysis and correlation analysis, noncoding RNAs that contribute to the overexpression of LGALS3 were subsequently identified. This identification was further validated using HCC clinical tissue samples. TIMER2 and GEPIA2 were employed to examine the correlation between LGALS3 and HCP5 with immunological checkpoints, cell chemotaxis, and immune infiltration in HCC. The R program was applied to analyze the expression distribution of immune score in in HCC patients with high and low LGALS3 expression. The expression profiles of immune checkpoints were also analyzed. Use R to perform GSVA analysis in order to explore potential signaling pathways. First, we conducted pan-cancer analysis for LGALS3 expression level through an in-depth analysis of public databases and found that HCC has a high LGALS3 gene and protein expression level, which were then verified in clinical HCC specimens. Meanwhile, high LGALS3 gene expression is related to malignant progression and poor prognosis of HCC. Univariate and multivariate analyses confirmed that LGALS3 could serve as an independent prognostic marker for HCC. Next, by combining comprehensive analysis and validation on HCC clinical tissue samples, we hypothesize that the HCP5/hsa-miR-27b-3p axis could serve as the most promising LGALS3 regulation mechanism in HCC. KEGG and GO analyses highlighted that the LGALS3-related genes were involved in tumor immunity. Furthermore, we detected a significant positive association between LGALS3 and HCP5 with immunological checkpoints, cell chemotaxis, and immune infiltration. In addition, high LGALS3 expression groups had significantly
• Snippet 2 (score: 0.616)
  > To delineate the driving mechanism of LGALS3 for the malignant progression of HCC, the KEGG and GO analysis was conducted.The volcano plot and heatmap showed significantly differentially expressed genes between LGALS3 high-and low-expression groups (Figure S3A-B).The KEGG pathway analysis revealed that these LGALS3-related genes were enriched in the IL-17 signaling pathway, ECM-receptor interaction pathway, central carbon metabolism in cancer pathway, leukocyte transendothelial migration pathway and PI3K-Akt signaling pathway.Meanwhile, the GO analysis revealed that these genes were strongly associated with cell chemotaxis, leukocyte chemotaxis, regulation of leukocyte migration, as well as regulation of chemotaxis (Fig. 5A).Accumulating evidence has proven the immune system has an essential role in malignancy pathogenesis [17], and LGALS3 is closely correlated with CD163 + tumor-associated macrophages (TAM) in glioma [10].Therefore, we studied the association between LGALS3 level and the immune infiltration level in HCC.There was no statistical difference in immune cell infiltration levels over a number of LGALS3 copy numbers (Fig. 5B).Meanwhile, immune infiltration analysis revealed that expression of LGALS3 showed a significant positive association with several immune cell populations, involving CD4 + T cell, CD8 + T cell, B cell, neutrophil, macrophage, dendritic cell, as well as cancer-associated fibroblasts (CAFs) within HCC (Fig. 5C-E).Based on these results, we further evaluated the immune score in HCC patients with high and low LGALS3 expression.The scores of immune cells, including CD4 + T cell, CD8 + T cell, B cell, neutrophil, macrophage, and dendritic cell, were significantly higher in the high LGALS3 expression groups, as shown in Fig. 5F.Chemokines are a group of molecules that are important for the chemotaxis of immune cells [18].

[9] Microarray assay of circular RNAs reveals cicRNA.7079 as a new anti-apoptotic molecule in spinal cord injury in mice.

• Authors: Ying Yao, Jingyu Wang, T. He, Heyangzi Li, Jue Hu et al.
• Year: 2020
• Venue: Brain research bulletin
• URL: https://www.semanticscholar.org/paper/8e327ffbb4c66488f7c21b3dc5f8bcd5321ffdae
• DOI: 10.1016/j.brainresbull.2020.08.004
• PMID: 32882320
• Citations: 24
• Summary: The anticipation of anti-apoptosis circRNA 7079 may provide potential research targets for SCI in mice and contribute to new insights into the mechanism of apoptosis after SCI.
• Evidence snippets:
• Snippet 1 (score: 0.627)
  > the expression of downstream target genes. Our current study Our current study verified that lgals3 is the downstream target of the cicRNA.7079-mmu-miR-6953-5p axis. To date, the mechanisms of the regulation of lgals3 expression in CNS were barely known. In this study, we identified a new regulatory mechanism of lgals3 expression in motor neurons. The previous study reported that lgals3 was increased on day 14 after SCI in rats' spinal cord (Chih-Yen et al., 2011). In line with that, lgals3 was increased at day 3 after SCI in mice spinal cord in our study. Lgals3, has been described as a mediator of apoptosis. The anti-apoptotic role of lgals3 has been was demonstrated in peritoneal macrophages (Hsu et al., 2000), myocardial cells (Al-Salam et al., 2020), and melanoma cells (Wang et al., 2019a). Our study provided evidence that the anti-apoptotic effect of cicRNA.7079 was mediated by mmu-miR-6953-5p -lgals3 axis in motor neurons. Lgals3 containing the anti-death Asp-Trp-Gly-Arg (NWGR) motif, plays an anti-apoptotic effect possibly through its interaction with Bcl-2 family members, Akt-1, NF kappa-B, beta-cateninn, and cathepsin D proteins (Yang et al., 1996;Al-Salam et al., 2020;Akahani et al., 1997). Therefore, the detailed mechanism by which lgals3 regulates apoptosis in motor neurons needs to be further investigated.
  > Recently, circRNA expression profile in rat spinal cord at 6 h after SCI was identified by RNA-seq finding out that 99 circRNAs were up- Fig. 6. The apoptosis-related ceRNA network analysis. The top 30 apoptosis-related circRNAs were plotted as triangles. LncRNAs were plotted as rectangles. miRNAs were plotted as V-shapes.

[10] SREBP1 regulates Lgals3 activation in response to cholesterol loading

• Authors: Jing Li, Hongtao Shen, G. Owens, Lian‐Wang Guo
• Year: 2022
• Venue: Molecular Therapy. Nucleic Acids
• URL: https://www.semanticscholar.org/paper/6c55d666855233ff0e7035d46075997924da854c
• DOI: 10.1016/j.omtn.2022.05.028
• PMID: 35694209
• PMCID: 9168384
• Citations: 13
• Summary: Results identify a previously uncharacterized cholesterol-responsive dyad—SREBP1 and LGALS3, constituting a feedforward circuit that can be blocked by BETs inhibition in SMC phenotypic transition and potential interventional targets.
• Evidence snippets:
• Snippet 1 (score: 0.623)
  > Thus far, our data have shown transcriptional control of LGALS3 by SREBP1, likely in combination with BRD2. Of note, LGALS3 was initially used as a macrophage marker reciprocally regulating SREBP1 levels (Figure 5). In fact, increasing evidence in the literature supports the notion that LGALS3 is not merely a marker, but it actively participates in various cellular events while distributed broadly in intra-or extra-cellular locations of different cell types. 30 e were thus prompted to examine its possible influence on cholesterol-induced SMC phenotype. The data in Figure 7A show that LGALS3 silencing and overexpression potently mitigated and pro-moted an SMC migratory behavior, respectively, and LGALS3 knockdown without cholesterol loading appeared to be pro-apoptotic (Figure S6). These results agree with previous reports. 30,36 Consistent with SREBP1 regulation of LGALS3 (Figure 1), silencing SREBP1 reduced SMC migration as well (Figure 7B). Because cholesterol loading resulted in remarkable lipid accumulation inside SMCs (Figure 7C), we were curious as to whether this treatment had turned SMCs into an adipocyte-like phenotype, a question not previously addressed. We found that although three lipid-storage factors, SREBP1 (Figure 1), FABP4, and ACC1, were elevated after cholesterol loading, other adipogenic factors including CEBPA, PPARg, adiponectin, and ACAT2, decreased (Figure 7D). This result was confirmed by experiments with rat primary SMCs (Figure S7). Indicative of a specific role for LGALS3, its silencing significantly inhibited cholesterolinduced upregulation of SREBP1 (Figure 5), FABP4, and ACC1, albeit without a significant effect on other markers (Figure 7E). Accordingly, the effects of SREBP1 silencing on these markers largely followed the pattern that resulted from LGALS3 silencing (Figure 7F).

[11] Thyroid malignant neoplasm-associated biomarkers as targets for oncolytic virotherapy

• Authors: Mi Guan, Yanping Ma, S. Shah, G. Romano
• Year: 2016
• Venue: Oncolytic Virotherapy
• URL: https://www.semanticscholar.org/paper/9f79d851e32ad25e83c0a2d64e12919bf81a89f8
• DOI: 10.2147/OV.S99856
• PMID: 27579295
• PMCID: 4996252
• Citations: 4
• Summary: This review focuses on the strategy of biomarkers for the production of novel TMN oncolytic therapeutics, which may improve the specificity of targeting of tumor cells and limit adverse effects in patients.
• Evidence snippets:
• Snippet 1 (score: 0.620)
  > The Galectin-3 (LGALS3) is a protein that is encoded by a single gene, LGALS3, located on chromosome 14, locus q21-q22. 63 The molecular weight of this protein is ∼30 kDa, and it contains a carbohydrate-recognition-binding domain of ∼130 amino acids that enable the specific binding of β-galactosides. This protein localizes to the extracellular matrix, the cytoplasm, and the nucleus. It plays a role in numerous cellular functions including cell adhesion, cell activation and chemoattraction, cell growth, differentiation, cell cycle, apoptosis, innate immunity, cell adhesion, and T-cell regulation. 63,64 It has been known that LGALS3 is distributed widely around the tissues but in a low level.
  > To date, LGALS3 has been extensively studied as an IHC marker of thyroid malignancy, and a high diagnostic accuracy has been reported even for difficult pathological diagnoses. 64 Feilchenfeldt et al reported that the mRNA levels of LGALS3 and thyroglobulin in 28 benign and 31 malignant thyroid samples were quantified by real-time PCR. The LGALS3 expression at the mRNA was 60% (12/20) and the protein level was 100% (8/8), respectively. 65 The positive rate was 84% (41/49) when combined with the LGALS3 and HBME-1 in PTC specimens. 66 Two groups of researchers have detected the LGALS3 by IHC in PTC specimens. Saleh et al have shown that the sensitivity and the specificity for LGALS3 were 92.3% and 77.3%, respectively. 67 Song et al reported that positive expression of LGALS3 was 97% (427/441) in PTC group and 51% (77/151) in the benign thyroid lesions group. 68 These results may further support the notion that the high level of LGALS3 antigen expression occurs in patients with PTC. There are a number of different types of oncolytic viruses that have been altered from natural viruses in the laboratory such as adenovirus, reovirus, measles virus, herpes simplex

[12] Extracellular Vesicles from iPSC-Derived Glial Progenitor Cells Prevent Glutamate-Induced Excitotoxicity by Stabilising Calcium Oscillations and Mitochondrial Depolarisation

• Authors: M. Shedenkova, Anastasiia A. Gurianova, I. Krasilnikova, A. Sudina, E. Karpulevich et al.
• Year: 2025
• Venue: Cells
• URL: https://www.semanticscholar.org/paper/6a7fa01a0c5294235731390acdd5215a4a803f13
• DOI: 10.3390/cells14231915
• PMID: 41369405
• PMCID: 12691032
• Citations: 1
• Summary: The obtaining results demonstrated the improvement of neuronal survival by reducing intracellular calcium levels and stabilising mitochondrial membrane potential under glutamate-induced excitotoxicity via PI3K-Akt signalling pathway activation.
• Evidence snippets:
• Snippet 1 (score: 0.619)
  > The final category of identified processes involved the maintenance of intracellular homeostasis, which encompassed the following pathways: regulation of metal ion transport, positive regulation of transmembrane transport, positive regulation of secretion by cell, peptide hormone secretion, neuropeptide signalling pathway, positive regulation of ion transmembrane transporter activity, receptor recycling, and regulation of membrane depolarisation (Figure 12A).
  > Analysis of down-regulated pathways revealed significant enrichment of processes associated with neuronal physiology, including axonogenesis, regulation of cellular response to stress, dendrite development, regulation of synapse organisation, calcium ion transport, regulation of synapse structure or activity, axon guidance, neuron projection guidance, regulation of calcium ion transport, calcium ion transmembrane import into cytosol, negative regulation of epigenetic gene expression, neuron projection organisation, actin-mediated cell contraction, regulation of calcium ion transmembrane transport via high voltage-gated calcium channel, and axo-dendritic protein transport (Figure 12B).
  > For deeper functional insights, we performed KEGG pathway enrichment analysis, consistent with our previous experimental approach. Additionally, Figure 13A displays a heatmap of selected differentially expressed genes, illustrating specific expression patterns across experimental conditions. Up-regulated DEGs showed significant enrichment in several signalling pathways, including focal adhesion, PI3K-Akt signalling pathway, ECM-receptor interaction, motor proteins, phagosome, regulation of actin cytoskeleton, and glutathione metabolism (Figure 13A). Down-regulated DEGs were significantly associated with pathways, including cAMP signalling pathway, MAPK signalling pathway, calcium signalling pathway, dopaminergic synapse, cGMP-PKG signalling pathway, Ras signalling pathway, cellular senescence, Wnt signalling pathway, axon guidance, long-term potentiation, cholinergic synapse, Apelin signalling pathway, glutamatergic synapse, and GABAergic synapse (Figure 13B). Gene set enrichment analysis (GSEA) identified coordinated gene expression patterns distinguishing the glutamate (GL) and extracellular vesicle-treated (GL_EV) groups.

Notes

• This provider combines search_papers_by_relevance with snippet_search.
• No synthesis or second-stage model call is performed.

Asta Literature Retrieval: Literature evidence for LGALS3 (Homo sapiens): LGALS3 has negative regulation of extrinsic apoptotic signaling pathwa...

This report is retrieval-only and is generated directly from Asta results.

• Papers retrieved: 15
• Snippets retrieved: 20

Relevant Papers

[1] LGALS3 is connected to CD74 in a previously unknown protein network that is associated with poor survival in patients with AML

• Authors: P. Ruvolo, Chenyue W. Hu, Y. Qiu, V. Ruvolo, Robin L. Go et al.
• Year: 2019
• Venue: EBioMedicine
• URL: https://www.semanticscholar.org/paper/46bbdbcb4660389e13acba24499cc415d75f18e0
• DOI: 10.1016/j.ebiom.2019.05.025
• PMID: 31105032
• PMCID: 6604360
• Citations: 25
• Influential citations: 2
• Summary: The data suggest that the LGALS3 network and the CD74 network each support AML cell survival and the two networks may cooperate in a novel high risk AML population.
• Evidence snippets:
• Snippet 1 (score: 0.870)
  > LGALS3 is associated with active Fig. 7. Suppression of LGALS3 does not alter gene expression of LGALS3 network protein genes or CD74 in THP-1 cells. RNA from THP-1 transductant cells with either LKO vector control shRNA or LGALS3 shRNA was isolated, cDNA produced, and mRNA levels of ATG7, LGALS3, ITGAL, CCND3, PRKCA, PARP1, CD74, MYC, CD44, SSBP2, PPP2R2A, CLPP, and B2M were determined by qRT-PCR and levels normalized to ABL-1 as described in "Materials and methods".
  > AKT and MAPK signaling. The protein with the strongest positive correlation with LGALS3 is with ATG7, an autophagy protein that has recently been implicated in maintaining hematopoietic stem cells and serving as a survival factor in AML [46,47]. Recent studies implicate LGALS3 in regulation of autophagy via autophagasome formation, though whether the mechanism involves ATG7 is not clear [48]. Interestingly, phosphorylated PKC delta was positively correlated with LGALS3. PKC delta is viewed as a pro-stress kinase but recent studies suggest that the enzyme has pro-survival properties [49][50][51]. Kinehara and colleagues suggest that PKC delta may act in human pluripotent stem cells as part of a mechanism to regulate stem cell renewal [52]. The data also suggest a novel relationship between LGALS3 and PP2A. The negative correlation of LGALS3 expression with PPP2R2A/B/C/D could reflect LGALS3 suppression of PP2A. The PP2A isoform containing PPP2R2A dephosphorylates both AKT and PKC alpha [53]. Thus, potential suppression of the PP2A subunit by LGALS3 could account for elevated AKT and PKC alpha phosphorylation in samples where LGALS3 expression is elevated.
• Snippet 2 (score: 0.777)
  > While it is unclear how LGALS3 might mechanistically influence leukemic cell recovery and growth after therapy, perhaps regulation of these cellular processes are important in addition to the well documented role of LGALS3 in regulation of cell cycle and cell proliferation [1,2,13,14]. Many of the CD74 network associated biological processes involved immune regulation (Supplemental Table 3) though it is unclear if CD74 network regulates potential immune response in AML. Many of the CD74 network associated biological processes did include those involved in regulation of cell death and apoptosis (Supplemental Table 3). Of the 31 proteins correlated with CD74 expression, 19 are associated with the biological pathway regulation of cell death (GO.0010941) and 16 are associated with the biological pathway negative regulation of apoptotic process (GO.0043066). The raises the question of what the cross-talk is between the LGALS3 and CD74 networks? Gene expression analysis of CD74, CD44, and CLPP in the THP-1 LKO cells versus THP-1 cells with LGALS3 shRNA showed no or only slight changes in these genes (Fig. 7). Protein expression of CD74, CD44, and CLPP were similar in THP-1 LKO and THP-1 LGALS3 shRNA cells (data not shown). While LGALS3 supports AKT activation via RAS, CD74 would be expected to support AKT via MIF mediated signaling involving CD44 and/or CXCR4 [19][20][21][22][23][24][25][26][27]. Though the functional roles of LGALS3 and CD74 in this process are very different, each network would contribute to activation and perhaps may explain why patients with both active networks do so poorly (Fig. 9A and B). Unfortunately, CXCR4 is not represented in the RPPA panel due to lack of validated antibody. However, CD44 is present and interestingly is most elevated in patients with active LGALS3 network and CD74 network (Fig. 8).
• Snippet 3 (score: 0.755)
  > Galectin 3 (LGALS3) is a beta-galactoside binding protein that participates in diverse cellular processes that support cell growth and cell survival [1][2][3][4][5][6][7][8][9]. There are at least fourteen known galectin family members of which ten are found in mammalian cells [1]. There are three families of galectins based on structure but LGALS3 is unique in that it is the only member of the chimeric group [1]. LGALS3 is the only galectin which can form pentamers and this enables the galectin to form lattices and thus participate in endocytotic processes [1].
  > LGALS3 is an excellent example of a molecule that acts as a tumor promoter in the context of the entire tumor microenvironment by promoting survival of malignant cells, supporting metastasis, suppressing immune surveillance, and modulating inflammatory expression of chemokines/cytokines [1][2][3][4][5][6][7][8][9].
  > LGALS3 supports cell survival by diverse mechanisms. The galectin has been shown to associate with BCL2 via a NWGR motif common to both proteins to help the anti-apoptotic molecule support mitochondrial integrity during stress challenge [7][8][9]. LGALS3 also supports cell proliferation via the WNT signaling pathway. LGALS3 can bind beta Catenin and Axin and also supports beta catenin protein stability by promoting Protein Kinase B (AKT) suppression of GSK3 beta [10][11][12].
  > LGALS3 is critical for RAS signaling and thus supports Mitogen Activated Protein Kinase (MAPK) and AKT cascades [1,2,[12][13][14][15][16][17]. LGALS3 positively regulates BCL2 and MCL-1 gene and protein expression in AML cells by supporting both ERK and AKT pathways [1,2,[12][13][14][15][16][17].
• Snippet 4 (score: 0.755)
  > LGALS3 positively regulates BCL2 and MCL-1 gene and protein expression in AML cells by supporting both ERK and AKT pathways [1,2,[12][13][14][15][16][17]. Suppression of LGALS3 by shRNA or with GCS-100 (an inhibitor of LGALS1 and LGALS3) blocks both AKT and ERK signaling pathways [15,17].
  > LGALS3 regulated pathways are involved in expression of genes and protein associated with cancer stem cells (CSC) and thus the galectin likely supports CSC [9]. Recent data suggests that LGALS3 supports malignant cell survival in AML [6,15,18]. In a cohort of Taiwanese AML patients, Cheng and colleagues reported that elevated LGALS3 mRNA was prognostic for poor survival outcome [18]. However, in that study the impact of LGALS3 protein expression or associations of the galectin with potential LGALS3 target proteins was not examined.
  > CD74 (also known as the invariant chain protein) is best known as a chaperone for major histocompatibility (MHC) Class II molecules involved in antigen presentation [19,20]. In addition to mediating MHC Class II molecule endocytosis, CD74 protects these molecules from proteolysis [19][20][21]. CD74 also has MHC Class II independent functions that involve the pro-inflammatory cytokine macrophage inhibitory factor (MIF) and cell surface signaling molecules CD44 and CXCR4 [19][20][21]. CD74 was found to bind MIF but CD74 alone is unable to initiate MIF signaling which requires either CD44 or CXCR4 [19][20][21][22][23]. CD74 dependent MIF signaling pathways include ERK, JNK, and AKT [24][25][26][27]. CD74 dependent MIF signaling has been shown to suppress p53 function and to activate NF kappa B [26,28].
• Snippet 5 (score: 0.754)
  > The role of other galectins such as LGALS1 in AML biology is not clear.
  > LGALS1 may substitute for some LGALS3 functions particularly those involved in survival pathways as knock down of either LGALS1 or LGALS3 sensitized AML cells to BH3 mimetic drugs [15]. The failure of LGALS3 suppression to affect many of the RPPA identified proteins with the exception of PPP2R2A/B/C/D (Fig. 5) may reflect LGALS1 activity in these cells that may not be present in the primary AML cells. It is possible that many of the LGALS3 network proteins act to regulate LGALS3 rather than being regulated by the galectin. It is also possible that LGALS3 and some of the LGALS3 network proteins are subject to regulation by a yet unidentified common regulator(s). Further examination of the mechanism regulating the LGALS3 network is ongoing.
  > Network analysis from the data identifies a new extremely poor prognosis group based on the interaction between the LGALS3 and CD74 associated protein networks revealing potential biological pathways that may be critical in supporting AML cell survival. AML patients with both networks active are 8.5% of patients in the study (Fig. 9A) and thus this group may represent a sizeable population of AML patients. It is possible the two proteins regulate independent survival pathways that may have a synergistic effect on survival when both are active. The top ten biological processes associated with LGALS3 network include processes associated with cell metabolism (GO:0031325; GO:0032268; and GO:0032270), cell migration (GO:0030355), and response to growth factor stimulus (GO:0071363) and response to chemical stimulus (GO:0070887) (Supplemental Table 1). While it is unclear how LGALS3 might mechanistically influence leukemic cell recovery and growth after therapy, perhaps regulation of these cellular processes are important in addition to the well documented role of LGALS3 in regulation of cell cycle and cell proliferation [1,2,13,14].

[2] Parthenolide leads to proteomic differences in thyroid cancer cells and promotes apoptosis

• Authors: Meng Cui, Zhe Wang, Letao Huang, Jia-He Wang
• Year: 2022
• Venue: BMC Complementary Medicine and Therapies
• URL: https://www.semanticscholar.org/paper/7f36ac62e89f19c15f02a3e0b01306e4f458dd67
• DOI: 10.1186/s12906-022-03579-0
• PMID: 35366876
• PMCID: 8977004
• Citations: 11
• Summary: Parthenolide may influence the biological behavior of human thyroid cancer cells by affecting the expression of proteins related to cell metabolism and DNA replication, leading to an anti-proliferative effect.
• Evidence snippets:
• Snippet 1 (score: 0.830)
  > The above experiments confirmed that PTL can induce apoptosis of BCPAP cells, and in the proteomics clustering results, 6 proteins (IL1B, ITGA6, CASP8, GCLM, HMOX1 and HSPA1A) were classified into 'negative regulation of extrinsic apoptotic signaling pathway' (GO: 2001237). After bioinformatics screening, three were selected to further verify expression differences by PRM. HMOX1 and GCLM were up-regulated and IL1B was down-regulated in BCPAP cells treated with PTL (Fig. 7).

[3] Dual RNA Sequencing Reveals Key Events When Different Giardia Life Cycle Stages Interact With Human Intestinal Epithelial Cells In Vitro

• Authors: L. Rojas, Jana Grüttner, S. Ma'ayeh, Feifei Xu, S. Svärd
• Year: 2022
• Venue: Frontiers in Cellular and Infection Microbiology
• URL: https://www.semanticscholar.org/paper/a07b7add52e16b284f33a3757df71a8f8338df7b
• DOI: 10.3389/fcimb.2022.862211
• PMID: 35573800
• PMCID: 9094438
• Citations: 12
• Influential citations: 1
• Summary: It is shown that different life cycle stages of Giardia induce different gene expression responses in the host cells and that the IECs in turn differentially affect the gene expression in trophozoites and early encysting cells.
• Evidence snippets:
• Snippet 1 (score: 0.816)
  > Studies of giardiasis patients have shown an increased number of apoptotic cells in the duodenum (Troeger et al., 2007). Recent studies of Giardia-host cell interactions using 3D stem cellenriched organoid cultures from human duodenal biopsies and WB trophozoites show induction of apoptosis after 48 h interaction (Holthaus et al., 2021). WB parasites of all life-cycle stages up-regulate pro-apoptotic and anti-apoptotic genes (Table S1). This ambiguity was first observed when Giardia WB trophozoite-Caco-2 interactions were studied using microarrays (Roxström-Lindquist et al., 2005), and it was also observed during GS trophozoite infection of Caco-2 cells (Ma'ayeh et al., 2018). Differentially transcribed apoptosis-related genes are listed in Figure S4. Both intrinsic and extrinsic apoptosis pathway genes were identified as DEGs during infection. GO term enrichment analysis showed that the regulation of apoptotic process (GO:0042981) was enriched in up-regulated DEGs during all 3 time-points from all three life cycle stages. Extrinsic apoptosis pathway genes were differentially expressed (e.g., TNFRSF10A, B, and D) and GO term enrichment showed that tumor necrosis factor-mediated signaling pathway (GO:0033209) and negative regulation of extrinsic apoptotic signaling pathway (GO:2001237) were enriched for in the DEGs. This is in line with a recent report (Liu et al., 2020b) showing that Giardia trophozoites can activate CASP3/8 signaling pathways via activation of TNFR1 and K63 deubiquitination of RIP1, which in turn is caused by up-regulation of CYLD and A20. GO term enrichment analysis also detected the term intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress (GO:0070059).

[4] Microarray assay of circular RNAs reveals cicRNA.7079 as a new anti-apoptotic molecule in spinal cord injury in mice.

• Authors: Ying Yao, Jingyu Wang, T. He, Heyangzi Li, Jue Hu et al.
• Year: 2020
• Venue: Brain research bulletin
• URL: https://www.semanticscholar.org/paper/8e327ffbb4c66488f7c21b3dc5f8bcd5321ffdae
• DOI: 10.1016/j.brainresbull.2020.08.004
• PMID: 32882320
• Citations: 24
• Summary: The anticipation of anti-apoptosis circRNA 7079 may provide potential research targets for SCI in mice and contribute to new insights into the mechanism of apoptosis after SCI.
• Evidence snippets:
• Snippet 1 (score: 0.773)
  > the expression of downstream target genes. Our current study Our current study verified that lgals3 is the downstream target of the cicRNA.7079-mmu-miR-6953-5p axis. To date, the mechanisms of the regulation of lgals3 expression in CNS were barely known. In this study, we identified a new regulatory mechanism of lgals3 expression in motor neurons. The previous study reported that lgals3 was increased on day 14 after SCI in rats' spinal cord (Chih-Yen et al., 2011). In line with that, lgals3 was increased at day 3 after SCI in mice spinal cord in our study. Lgals3, has been described as a mediator of apoptosis. The anti-apoptotic role of lgals3 has been was demonstrated in peritoneal macrophages (Hsu et al., 2000), myocardial cells (Al-Salam et al., 2020), and melanoma cells (Wang et al., 2019a). Our study provided evidence that the anti-apoptotic effect of cicRNA.7079 was mediated by mmu-miR-6953-5p -lgals3 axis in motor neurons. Lgals3 containing the anti-death Asp-Trp-Gly-Arg (NWGR) motif, plays an anti-apoptotic effect possibly through its interaction with Bcl-2 family members, Akt-1, NF kappa-B, beta-cateninn, and cathepsin D proteins (Yang et al., 1996;Al-Salam et al., 2020;Akahani et al., 1997). Therefore, the detailed mechanism by which lgals3 regulates apoptosis in motor neurons needs to be further investigated.
  > Recently, circRNA expression profile in rat spinal cord at 6 h after SCI was identified by RNA-seq finding out that 99 circRNAs were up- Fig. 6. The apoptosis-related ceRNA network analysis. The top 30 apoptosis-related circRNAs were plotted as triangles. LncRNAs were plotted as rectangles. miRNAs were plotted as V-shapes.

[5] Identification of programmed cell death-related genes and diagnostic biomarkers in endometriosis using a machine learning and Mendelian randomization approach

• Authors: Ziwei Xie, Yue He, Yuxin Feng, Xiaohong Wang
• Year: 2024
• Venue: Frontiers in Endocrinology
• URL: https://www.semanticscholar.org/paper/a437f1ce179ac605a4b4d5733d5e488db5fbabe5
• DOI: 10.3389/fendo.2024.1372221
• PMID: 39149122
• PMCID: 11324423
• Citations: 15
• Influential citations: 3
• Summary: This study systematically elucidated the molecular characteristics of PCD in EM and identified TNFSF12, AP3M1, and PDK2 as key biomarkers, providing new directions for the early diagnosis and personalized treatment of EM.
• Evidence snippets:
• Snippet 1 (score: 0.748)
  > Functional annotation and pathway enrichment analyses were performed on the DPGs. The results of the GO enrichment analysis indicate that these genes are involved in multiple signaling pathways associated with PCD (Figure 2D). The pathways encompassed are the intrinsic apoptotic signaling pathway, regulation of apoptotic signaling pathway, regulation of autophagy, macroautophagy, intrinsic apoptotic signaling pathway triggered by DNA damage, extrinsic apoptotic signaling pathway, mitochondrial structure organization, apoptotic mitochondrial changes, negative regulation of apoptotic signaling pathway, and regulation of intrinsic apoptotic signaling pathway. The KEGG pathway enrichment analysis (Figure 2E) indicated that these genes are involved in pathways, such as lysosome, apoptosis, autophagy, and necroptosis.

[6] Identification and Characterization of Non-Coding RNAs in Thymoma

• Authors: Guanglei Ji, R. Ren, Xichao Fang
• Year: 2021
• Venue: Medical Science Monitor : International Medical Journal of Experimental and Clinical Research
• URL: https://www.semanticscholar.org/paper/e0ad5ef5a9e860f17008417de010a1dc1b91e301
• DOI: 10.12659/MSM.929727
• PMID: 34219124
• PMCID: 8268976
• Citations: 15
• Influential citations: 2
• Summary: A network analysis of the lncRNA-mRNA-miRNA regulation axes identified a cluster of miRNAs upregulated in thymomas, that can trigger the expression of target protein-coding genes, and lead to the disruption of several biological pathways, including the PI3K-Akt signaling pathway, FoxO signaling pathways, and HIF-1 signaling pathway.
• Evidence snippets:
• Snippet 1 (score: 0.740)
  > We constructed an lncRNA-mRNA-miRNA regulation network based on the gene co-expression correlation analysis between DELs, mRNAs, and DEMs identified in thymomas (Figure 7). In this network, the upregulated miRNA hsa-let-7a-3 exhibits interactions with 8 protein-coding genes (INSR, IGF1, IL10, IGF1R, ITGB3, COL5A2, ZNF322, PXDN, TGFBR1) and can increase their expressions. The majority of target genes of DELs and DEMs are enriched in several biological pathways, including the PI3K-Akt signaling pathway (P value=0.0), the FoxO signaling pathway (P value=0.0), the HIF-1 signaling pathway (P value=0.0), the proteoglycans in cancer (P value=0.01), and other cancer pathways (P value=0.01), the Supplementary Table 2 shows these details. Most target genes were associated with various GO terms, including immune response (GO: 0006955), hepatic immune response (GO: 0002384), positive regulation of DNA replication (GO: 0045740), positive regulation of cell proliferation (GO: 0008284), positive regulation of MAPK cascade (GO: 0043410), positive regulation of DNA replication (GO: 0045740), positive regulation of cell proliferation (GO: 0008284), negative regulation of extrinsic apoptotic signaling pathway (GO: 2001237), and negative regulation of apoptotic process (GO: 0043066). Supplementary Table 3 shows these details. Our network and pathway analyses show the overexpression of miRNA clusters activates the PI3K-Akt/FoxO/HIF-1/Rap-1 signaling pathway, suggesting that PI3K/Akt/HIF-1/ Rap-1 inhibitors may be therapeutic targets for thymoma patients. The hsa-let-7a family of miRNAs is thought to inhibit migration, invasion, and tumor growth by targeting the AKT2 e929727-12

[7] High LGALS3 expression induced by HCP5/hsa-miR-27b-3p correlates with poor prognosis and tumor immune infiltration in hepatocellular carcinoma

• Authors: Yinghui Ren, Yongmei Qian, Qicheng Zhang, Xiaoping Li, Mingjiang Li et al.
• Year: 2024
• Venue: Cancer Cell International
• URL: https://www.semanticscholar.org/paper/552bd37c67dea75d0c33a9a0de2acdafcf0dcf6e
• DOI: 10.1186/s12935-024-03309-1
• PMID: 38643145
• PMCID: 11031979
• Citations: 13
• Summary: It is hypothesized that the HCP5/hsa-miR-27b-3p axis could serve as the most promising LGALS3 regulation mechanism in HCC and the upregulation of LGALS3 via the HCP5/hsa-miR-27b-3p axis is associated with unfavorable prognosis and increased tumor immune infiltration in HCC.
• Evidence snippets:
• Snippet 1 (score: 0.738)
  > Hepatocellular carcinoma (HCC) is widely recognized for its unfavorable prognosis. Increasing evidence has revealed that LGALS3 has an essential function in initiating and developing several malignancies in humans. Nevertheless, thorough analysis of the expression profile, clinical prognosis, pathway prediction, and immune infiltration of LGALS3 has not been fully explored in HCC. In this study, an initial pan-cancer analysis was conducted to investigate the expression and prognosis of LGALS3. Following a comprehensive analysis, which included expression analysis and correlation analysis, noncoding RNAs that contribute to the overexpression of LGALS3 were subsequently identified. This identification was further validated using HCC clinical tissue samples. TIMER2 and GEPIA2 were employed to examine the correlation between LGALS3 and HCP5 with immunological checkpoints, cell chemotaxis, and immune infiltration in HCC. The R program was applied to analyze the expression distribution of immune score in in HCC patients with high and low LGALS3 expression. The expression profiles of immune checkpoints were also analyzed. Use R to perform GSVA analysis in order to explore potential signaling pathways. First, we conducted pan-cancer analysis for LGALS3 expression level through an in-depth analysis of public databases and found that HCC has a high LGALS3 gene and protein expression level, which were then verified in clinical HCC specimens. Meanwhile, high LGALS3 gene expression is related to malignant progression and poor prognosis of HCC. Univariate and multivariate analyses confirmed that LGALS3 could serve as an independent prognostic marker for HCC. Next, by combining comprehensive analysis and validation on HCC clinical tissue samples, we hypothesize that the HCP5/hsa-miR-27b-3p axis could serve as the most promising LGALS3 regulation mechanism in HCC. KEGG and GO analyses highlighted that the LGALS3-related genes were involved in tumor immunity. Furthermore, we detected a significant positive association between LGALS3 and HCP5 with immunological checkpoints, cell chemotaxis, and immune infiltration. In addition, high LGALS3 expression groups had significantly
• Snippet 2 (score: 0.723)
  > To delineate the driving mechanism of LGALS3 for the malignant progression of HCC, the KEGG and GO analysis was conducted.The volcano plot and heatmap showed significantly differentially expressed genes between LGALS3 high-and low-expression groups (Figure S3A-B).The KEGG pathway analysis revealed that these LGALS3-related genes were enriched in the IL-17 signaling pathway, ECM-receptor interaction pathway, central carbon metabolism in cancer pathway, leukocyte transendothelial migration pathway and PI3K-Akt signaling pathway.Meanwhile, the GO analysis revealed that these genes were strongly associated with cell chemotaxis, leukocyte chemotaxis, regulation of leukocyte migration, as well as regulation of chemotaxis (Fig. 5A).Accumulating evidence has proven the immune system has an essential role in malignancy pathogenesis [17], and LGALS3 is closely correlated with CD163 + tumor-associated macrophages (TAM) in glioma [10].Therefore, we studied the association between LGALS3 level and the immune infiltration level in HCC.There was no statistical difference in immune cell infiltration levels over a number of LGALS3 copy numbers (Fig. 5B).Meanwhile, immune infiltration analysis revealed that expression of LGALS3 showed a significant positive association with several immune cell populations, involving CD4 + T cell, CD8 + T cell, B cell, neutrophil, macrophage, dendritic cell, as well as cancer-associated fibroblasts (CAFs) within HCC (Fig. 5C-E).Based on these results, we further evaluated the immune score in HCC patients with high and low LGALS3 expression.The scores of immune cells, including CD4 + T cell, CD8 + T cell, B cell, neutrophil, macrophage, and dendritic cell, were significantly higher in the high LGALS3 expression groups, as shown in Fig. 5F.Chemokines are a group of molecules that are important for the chemotaxis of immune cells [18].

[8] Pregnancy Galectinology: Insights Into a Complex Network of Glycan Binding Proteins

• Authors: S. Blois, G. Dveksler, G. Vasta, N. Freitag, V. Blanchard et al.
• Year: 2019
• Venue: Frontiers in Immunology
• URL: https://www.semanticscholar.org/paper/68fad2b87411701fa708a1f49f8b918370486857
• DOI: 10.3389/fimmu.2019.01166
• PMID: 31231368
• PMCID: 6558399
• Citations: 56
• Influential citations: 7
• Summary: The relevance of galectin-glycan interactions as potential therapeutic targets in pregnancy disorders is discussed and the importance of angiogenesis during decidualization and in placenta formation is discussed.
• Evidence snippets:
• Snippet 1 (score: 0.731)
  > Lgals3 has been implicated in the regulation of innate and adaptive immune responses, where it participates in the activation or differentiation of immune cells and contributes to phagocytic clearance of microorganisms and apoptotic cells by macrophages (117,118). Lgals3 has been reported to promote but also to inhibit T-cell apoptosis depending on whether it binds to glycoproteins on the cell surface (CD45 and CD71) or to intracellular ligands (Bcl-2) (119, 120). In the placenta, Lgals3 was detected in all trophoblastic lineages including villous cytotrophoblasts (CTB) and EVT with a reduction of Lgals3 expression observed from the VT to the trophoblastic cell columns (121). This pattern of Lgals3 expression correlates with the switch from a proliferative to a migratory trophoblast phenotype and while placental Lgals3 dysregulation has been associated with some obstetric complications including spontaneous or recurrent miscarriages, further studies are needed to understand its contribution to trophoblast biology (81,122). In addition to trophoblasts, Lgals3 is expressed by maternal decidual cells (73). While showing a different expression pattern, both Lgals1 and Lgals3 have been proposed to play a role in cell-cell and cell-matrix interactions of trophoblast during placentation (121). Studies of the importance of Lgals3 in murine pregnancy by Yang et al. indicate that Lgals3 is expressed in the luminal and glandular epithelium and that an increase in Lgals3 is required for proper embryo implantation (123). In addition, Lgals3 affects chemotaxis and morphology of endothelial cells and stimulates capillary tube formation and angiogenesis in vivo (124). Therefore, besides its proposed roles in embryo implantation, immune regulation and trophoblast-matrix interactions, Lgals3 has a potential role in placental angiogenesis.

[9] Identification of Oncosuppressing Effects of Seven Selenoproteins in Thyroid Cancer: Implications for Distinct Roles of Selenoproteins in Tumorigenesis

• Authors: Yang Zhao, Pu Chen, Hong-jun Lv, Yuan Wu, Shu Liu et al.
• Year: 2021
• Venue: Unknown venue
• URL: https://www.semanticscholar.org/paper/13df7e615ebc2fa71ed470d2f3a02f8a65b931ef
• DOI: 10.21203/RS.3.RS-402154/V1
• Summary: This study confirms the distinct roles of the 25 selenoproteins in thyroid cancer pathogenesis, providing useful information to uncover the currently unknown functions of seleniproteins and open up the possibility for targeted regulation of individual selenobroteins for treatment of thyroid cancer.
• Evidence snippets:
• Snippet 1 (score: 0.730)
  > KEGG analysis identi ed 8 pathways related to SELENOO in thyroid cancers, including hsa03013: RNA transport, hsa04668: TNF signaling pathway, hsa04550:
  > Signaling pathways regulating pluripotency of stem cells, hsa04141: Protein processing in endoplasmic reticulum, hsa04110: Cell cycle, hsa04144: Endocytosis, hsa00240: Pyrimidine metabolism, and hsa00230: Purine metabolism (Table 2).
  > With regards to SELENOV, 22 biological processes including GO:0055085 (transmembrane transport) and GO:0055114 (oxidation-reduction process) were enriched in the top 200 SELENOV-positive-correlated genes and 35 biological processes including GO: 0098609 (cell-cell adhesion), GO:0042060 (wound healing), GO: 0007155 (cell adhesion) and GO: 2001237 (negative regulation of extrinsic apoptotic signaling pathway) were enriched in the top 200 SELENOV-negatively-correlated genes by GO analysis (Table S13). The top 5 processes on each list were shown in Fig. 4F. In addition, 8 pathways including hsa04931: Insulin resistance, hsa04920: Adipocytokine signaling pathway, hsa04520: Adherens junction, hsa05205: Proteoglycans in cancer, hsa04512: ECM-receptor interaction, hsa05200: Pathways in cancer, hsa04390: Hippo signaling pathway, and hsa05412: Arrhythmogenic right ventricular cardiomyopathy (ARVC) were identi ed to be correlated with SELENOV (Table 2).

[10] Bioinformatics-Based Identification of a circRNA-miRNA-mRNA Axis in Esophageal Squamous Cell Carcinomas

• Authors: Zhaojun Wang, Haifeng Li, Fajun Li, Xin Su, Junhang Zhang
• Year: 2020
• Venue: Journal of Oncology
• URL: https://www.semanticscholar.org/paper/d2dff21c189100a75d23e26ee2a4eef452807b2d
• DOI: 10.1155/2020/8813800
• PMID: 33061972
• PMCID: 7542503
• Citations: 13
• Influential citations: 1
• Summary: Support is provided for the possible mechanisms of disease progression in ESCC by discovering differentially expressed nonprotein-coding RNAs and genes with potential prognostic relevance in ES CC.
• Evidence snippets:
• Snippet 1 (score: 0.711)
  > Genes.KEGG enrichment and GO analyses were performed for the target genes of the two DEMs (Figure 2).In the BP category, the "extrinsic apoptotic signaling pathway in absence of ligand," "negative regulation of anoikis," and "negative regulation of apoptotic process" were enriched.While "protein binding" was enriched according to the MF category, enrichment of the "nucleoplasm," "nucleus," and "cytosol" was shown in the CC category (Figure 3(b)).e KEGG pathway analysis revealed enrichment of the "focal adhesion," "estrogen signaling," "sphingolipid signaling," and "PI3K-Akt signaling" pathways (Figure 3(a)).

[11] A Network Pharmacology Approach to Understanding the Mechanisms of Action of Traditional Medicine: Rheum L. for Diabetic Kidney Disease

• Authors: Jin Luo, C. Piao, De Jin, Li Wang, Xiaohua Zhao et al.
• Year: 2020
• Venue: Unknown venue
• URL: https://www.semanticscholar.org/paper/97072294d3d8475989fea00468baf914f0e68111
• DOI: 10.21203/rs.3.rs-76167/v1
• Summary: A network pharmacology-based strategy was proposed to elucidate the underlying multi-component, multi-target, and multi-pathway mode of action of Rheum L. in the treatment of diabetic kidney disease using a systems pharmacology approach.
• Evidence snippets:
• Snippet 1 (score: 0.710)
  > The 11 biological processes were mainly involved in in ammatory response, apoptosis, brosis, and peripheral circulation. The details are shown in Fig. 7. The processes were, in the aspect of cell proliferation: positive regulation of transcription from RNA polymerase II promoter (GO:0045944), positive regulation of cell proliferation (GO:0008284), transmembrane receptor protein tyrosine kinase signaling pathway (GO:0007169), and transcription, DNA-templated (GO:0006351);in the aspect of protein metabolism: negative regulation of protein binding (GO:0032091) and positive regulation of protein binding (GO:0032092); in the aspect of in ammatory response: response to oxidative stress (GO:0006979); in the aspect of apoptosis: negative regulation of extrinsic apoptotic signaling pathway (GO:2001237); and in the aspect of peripheral circulation regulation: glucose homeostasis(GO:0042593), regulation of blood pressure(GO:0008217), and blood coagulation(GO:0007596). Based on these ve main aspects, a complex multi-path synergetic effect may be the cause of the effect of Rheum L. on DKD.

[12] Galectin-3 aggravates microglial activation and tau transmission in tauopathy

• Authors: Jian-Jing Siew, Hui-Mei Chen, Feng‐Lan Chiu, Chia-Wei Lee, Yao-Ming Chang et al.
• Year: 2023
• Venue: The Journal of Clinical Investigation
• URL: https://www.semanticscholar.org/paper/8c77eea796475aa4e26a4051432bc4d4c021d847
• DOI: 10.1172/JCI165523
• PMID: 37988169
• PMCID: 10786694
• Citations: 24
• Influential citations: 1
• Summary: It is shown that Gal3 was upregulated in the microglia of humans and mice with tauopathy, and is a potential therapeutic target for tauopathy.
• Evidence snippets:
• Snippet 1 (score: 0.710)
  > Interestingly, the 812 GAM genes shared 172 genes with the AD DAM genes (23) (Supplemental Figure 17A), including upregulated microglial activation genes (such as Clec7a, Cd68, Csf1, Apoe, and Cybb) and downregulated microglial homeostatic genes (such as P2ry12, TMEM119, Csf1r, Hexb, and Slc2a5). Collectively, GAM is a subset of microglia with several features similar to those of DAM (e.g., the enhanced inflammatory responses and protein translation processes) and some unique only to GAM (including the protein folding process, energy metabolism, transcription, and specific translation processes) (Figure 4L and Supplemental Figure 17, B-F). Additionally, we conducted a comparative analysis between GAM in Tau22 mice and the DEGs in pTau-induced iMGLs, as well as the effects of Gal3 inhibition with TD139, to explore their potential relevance for future cross-species studies. Among the identified conservation of canonical pathways, pathways such as hepatic fibrosis signaling, Rho family GTPases, neuroinflammation, integrin, and IL8 signaling, were suppressed in the presence of TD139 (Supplemental Figure 18, A and B).
  > Loss of Gal3 protects against tauopathy. To assess the importance of Gal3 in tauopathies in vivo, we crossed Tau22 mice with Gal3 knockout mice (Tau22/Lgals3 -/-, Figure 5A). The knockout of findings suggest that the Lgals3-enriched Cluster 9 may play a pivotal role in pathways associated with EVs as evidenced by the iMGL study, and may potentially contribute to the intricate interplay between microglial activity and tau transmission.
  > Because not all microglia express Lgals3, we aimed to specifically characterize the Lgals3-positive and Lgals3-negative microglia. We define Lgals3-positive microglia as cells with Lgals3 expression levels greater than or equal to 1 average log Unique Molecular Identifier (UMI) count, which serves as a reference point.

[13] Lgals3 Promotes Calcium Oxalate Crystal Formation and Kidney Injury Through Histone Lactylation‐Mediated FGFR4 Activation

• Authors: Zehua Ye, Yushi Sun, Songyuan Yang, Lei Li, Bojun Li et al.
• Year: 2025
• Venue: Advanced Science
• URL: https://www.semanticscholar.org/paper/adbfa30b5832407d200a5eade9196d41be08050e
• DOI: 10.1002/advs.202413937
• PMID: 39903812
• PMCID: 11947994
• Citations: 18
• Summary: Findings suggest that Lgals3 may play a key role in CaOx stone formation and kidney injury by interacting with PKM2 and promoting both H3K18la‐mediated gene transcription and activation.
• Evidence snippets:
• Snippet 1 (score: 0.710)
  > [23] The result of the present study revealed that Lgals3 exhibited several novel functions and mechanisms in the formation of kidney stones and the development of renal fibrosis (Figure 13). It was found that Lgals3 was highly expressed in CaOx crystal deposition and stimulated the activation of glycolysis during crystal deposition and renal fibrosis. Knockout or pharmacological inhibition of Lgals3 demonstrated a significant reduction of crystal deposition and renal fibrosis. In addition, IP-MS analysis identified PKM2, a key molecule in the regulation of glycolytic function, as the direct binding target of Lgals3. Furthermore, this study integrated analyses of CUT&Tag and RNA-seq and demonstrated that Lgals3mediated histone lactylation promoted FGFR4 expression during the formation of CaOx stones and renal fibrosis. [24] Lgals3 is considered a disease-associated biomarker and it is significantly increased in cases of acute myocardial infarction or AKI. [25,26] urthermore, recent investigations have shown that it has significant potential as a therapeutic target for various inflammatory and fibrotic illnesses, including lung or kidney fibrosis. [27] n this study, it was found that Lgals3 expression was increased in both mouse and human CaOx crystal kidney tissues. This study utilized Lgals3 −/-mice and demonstrated that Lgals3 deficiency alleviated CaOx crystal deposition and renal fibrosis. The deposition of CaOx crystals and the development of renal fibrosis are complex processes regulated by numerous genes and signaling pathways. RNA-seq and 4D-DIA proteomics were performed to detect alterations in mRNA and protein expression in Lgals3-deficient cells under COM stimulation. The KEGG analysis showed that Lgals3 deficiency primarily enriched metabolicrelated pathways, specifically glycolysis. When cells are exposed to various stimuli, the mitochondrial energy metabolism undergoes alterations, leading to significant activation of glycolysis, which in turn increases the overall energy supply. [28]

[14] Characteristics of the PI3K/AKT and MAPK/ERK pathways involved in the maintenance of self-renewal in lung cancer stem-like cells

• Authors: Jingyuan Li, Jianyu Wang, D. Xie, Qin Pei, Xue Wan et al.
• Year: 2021
• Venue: International Journal of Biological Sciences
• URL: https://www.semanticscholar.org/paper/9302948464800646b146c0b29b812d6771909340
• DOI: 10.7150/ijbs.57871
• PMID: 33867839
• PMCID: 8040472
• Citations: 38
• Influential citations: 2
• Summary: A clinically relevant CSCs enrichment recognition model is constructed and a new insight is uncovered that PI3K/AKT and MAPK/ERK pathways as oncogenic signaling pathway and/or stem cell signaling pathway act distinctively and synergistically to regulate lung C SCs self-renewal.
• Evidence snippets:
• Snippet 1 (score: 0.703)
  > We firstly evaluated the enrichment relationship between the stemness score and key molecules of PI3K/AKT pathway involving PIK3CA, AKT1, mTOR and MAPK/ERK pathway involving MAP2K1, MAP2K2, MAPK1 and MAPK3 (Figure 3A-B). The KEGG enrichment analysis revealed that PI3K/AKT pathway was markedly enriched in high stemness score group (Figure 3B, P < 0.05). Moreover, we conducted GO analysis to uncover the most valuable 10 clusters of enriched sets closely associated with proliferation, differentiation, apoptosis, as well as stemness and carcinogenicity characteristics. Notably, in the high stemness score group, the PI3K/AKT was significantly enriched in the biological process categories of negative regulation of stem cell differentiation, apoptotic process involved in morphogenesis, stem cell division, etc. (Figure 3C). And the MAPK/ERK pathway was enriched in positive regulation of extrinsic apoptotic signaling pathway, intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator, negative regulation of intrinsic apoptotic signaling pathway, etc. (Figure 3D). Whereas, in the low stemness score group, PI3K/AKT pathway was enriched in regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway, regulation of mitochondrial membrane permeability involved in apoptotic process, positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway, etc. (Figure 3E). MAPK/ERK pathway was enriched in regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway, regulation of mitochondrial membrane permeability involved in apoptotic process, regulation of oxidative stress induced intrinsic apoptotic signaling pathway, etc. (Figure 3F). As for the crosstalk enrichment of these two pathways, PI3K/AKT pathway combined with MAPK/ERK pathway in high stemness score group were enriched in regulation of stem cell differentiation, negative regulation of intrinsic apoptotic signaling pathway, negative regulation of extrinsic apoptotic signaling pathway, etc. (Figure 3G).

[15] A Preliminary Study to Investigate the Genetic Background of Longevity Based on Whole-Genome Sequence Data of Two Methuselah Dogs

• Authors: Dávid Jónás, Sára Sándor, K. Tátrai, B. Egyed, E. Kubinyi
• Year: 2020
• Venue: Frontiers in Genetics
• URL: https://www.semanticscholar.org/paper/3ac24db3f845e1915648e0d3a75f2c0ff22d5ae1
• DOI: 10.3389/fgene.2020.00315
• PMID: 32373156
• PMCID: 7176982
• Citations: 6
• Summary: A possible link between extreme longevity and the regulation of gene transcription/translation, which hypothesis should be further investigated in the future and could define an interesting direction for future research aiming to better understand longevity.
• Evidence snippets:
• Snippet 1 (score: 0.699)
  > Three example genes with missense mutations in protein domains as well as with some of the related GO terms are listed below:
  > 1. ENSCAFG00000003004: negative regulation of cell growth, negative regulation of apoptotic process; 2. ENSCAFG00000004892: regulation of apoptotic process, positive regulation of extrinsic apoptotic signaling pathway; 3. ENSCAFG00000019380: calcium ion transport, regulation of heart contraction, regulation of blood pressure, modulation of chemical synaptic transmission.

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