VOPP1 (Q96AW1): A Comprehensive Functional Annotation Report

Introduction and Overview

VOPP1 (Vesicular, Overexpressed in cancer, Pro-survival Protein 1), also known as ECOP (EGFR-Coamplified and Overexpressed Protein) and GASP (Glioblastoma-Amplified Secreted Protein), is a human protein encoded by the VOPP1 gene located at chromosomal position 7p11.2. This gene is frequently co-amplified with EGFR in various cancers, particularly glioblastoma multiforme [park-2005-ecop-nfkb-abstract]. The VOPP1 protein functions as a pro-survival factor that confers resistance to apoptosis in cancer cells, though the precise molecular mechanisms through which it exerts this function have been a subject of ongoing investigation and some debate in the literature.

The VOPP1 protein is characterized by a signal sequence, a transmembrane domain, and multiple proline-rich PPxY motifs in its C-terminal region that mediate critical protein-protein interactions [bonin-2018-vopp1-wwox-breast-fulltext]. According to PubMed, the protein contains endosome/lysosome targeting sequences, including a YXXφ motif and a dileucine sequence, which dictate its vesicular localization [baras-2010-localization-abstract]. The protein belongs to the VOPP1/ECOP family and possesses the VOPP1 domain (InterPro: IPR026229), though this domain lacks obvious enzymatic or well-characterized structural features that would immediately suggest a specific molecular function.

The primary molecular role of VOPP1 appears to be as an adapter or regulatory protein that modulates apoptotic signaling pathways. Two principal mechanisms have been proposed: regulation of NF-κB signaling and interaction with the tumor suppressor protein WWOX. Additionally, VOPP1 appears to participate in the control of intracellular redox homeostasis. This report synthesizes the available literature to provide a comprehensive understanding of VOPP1 function, localization, and biological significance.

Subcellular Localization and Membrane Topology

The subcellular localization of VOPP1 has been carefully characterized through multiple studies. Despite the presence of a signal sequence that initially suggested VOPP1 might be a secreted protein (hence its early name "Glioblastoma-Amplified Secreted Protein"), experimental evidence has definitively established that VOPP1 is not secreted and is retained intracellularly [baras-2010-localization-abstract].

According to PubMed, analysis of VOPP1 sequence structure reveals both a signal sequence and a transmembrane domain. Examination of microarray datasets for endoplasmic reticulum (ER)-bound mRNA transcripts is consistent with the VOPP1 protein being synthesized into the ER (DOI). Immunoblot analysis of cell culture and conditioned media confirms that the protein product is not secreted but retained within the cell [baras-2010-localization-abstract].

VOPP1 displays a distinctive intracellular vesicular pattern of localization. Co-localization experiments using fluorescence microscopy revealed that VOPP1-positive vesicles do not co-localize with mitochondria or peroxisomes, but show partial co-localization with perinuclear lysosomes [baras-2010-localization-abstract]. Additionally, markers of endocytosis and autophagy show partial perinuclear co-localization, suggesting that VOPP1-containing vesicles enter final common pathways of the lysosomal system.

The vesicular/lysosomal localization of VOPP1 was confirmed in multiple cell types, including breast cancer cells and gastric cancer cells [bonin-2018-vopp1-wwox-breast-fulltext][gao-2015-ecop-gastric-oncogene-abstract]. In MDA-MB-468 breast cancer cells, endogenous VOPP1 showed clear co-localization with LAMP2 (a lysosomal marker) in perinuclear regions [bonin-2018-vopp1-wwox-breast-fulltext]. This consistent localization pattern across different cell types and experimental approaches strongly establishes the late endosomal/lysosomal compartment as the primary site of VOPP1 function.

NF-κB Pathway Regulation

The initial characterization of VOPP1/ECOP function was performed by Park and James (2005), who reported that ECOP regulates NF-κB transcriptional activity in an IκBα-dependent manner (DOI) [park-2005-ecop-nfkb-abstract]. According to PubMed, ectopic expression of ECop increases NF-κB transcriptional activity by promoting nuclear translocation and DNA binding of NF-κB. In ECop knockdown cells, NF-κB transcriptional activity is suppressed due to delayed IκBα degradation, which results in delayed nuclear translocation as well as decreased DNA binding of NF-κB.

This initial model proposed that ECOP might interact directly with cytoplasmic mediators of the NF-κB pathway. However, subsequent studies raised questions about this mechanism. Baras and Moskaluk (2010) noted that the vesicular/lysosomal localization of VOPP1 "throws into doubt the hypothesis that VOPP1 interacts directly with cytoplasmic mediators of the NF-κB pathway" [baras-2010-localization-abstract]. The physical segregation of VOPP1 in vesicular compartments seemed incompatible with direct interaction with IκBα and other cytoplasmic NF-κB regulators.

Further complicating the picture, Baras et al. (2011) found that reporter constructs for NF-κB-mediated transcription were not affected in squamous cell carcinoma (SCC) cell lines by VOPP1 knockdown (DOI) [baras-2011-oxidative-abstract]. This suggested that the relationship between VOPP1 and NF-κB might be cell-type specific or that the pro-survival effect of VOPP1 could be mediated through alternative mechanisms.

Despite these caveats, multiple subsequent studies have continued to implicate VOPP1/ECOP in NF-κB signaling. Xia et al. (2013) demonstrated that miR-218 sensitizes glioma cells to apoptosis by targeting ECOP and suppressing NF-κB activity (DOI) [xia-2013-mir218-glioma-abstract]. Ectopic expression of ECOP rescued glioma cells from miR-218-induced apoptosis and increased NF-κB activity, supporting a functional link between ECOP and NF-κB in this context. Similarly, Gao et al. (2010) identified ECOP as a direct target of miR-218 in gastric cancer and showed that miR-218 overexpression inhibited NF-κB transcriptional activation (DOI) [gao-2010-mir218-gastric-abstract].

One possible reconciliation of these findings is that VOPP1 may affect NF-κB signaling indirectly through its interaction with WWOX, which has itself been suggested to interact with IκBα [bonin-2018-vopp1-wwox-breast-fulltext]. Alternatively, the NF-κB effects may be secondary to VOPP1's role in oxidative stress regulation, as ROS levels can modulate NF-κB activity.

Interaction with WWOX Tumor Suppressor

Perhaps the most significant advance in understanding VOPP1 function came from the discovery of its interaction with WWOX (WW domain-containing oxidoreductase), a tumor suppressor protein. Bonin et al. (2018) identified VOPP1 as a new molecular partner of WWOX through yeast two-hybrid screening (DOI) [bonin-2018-vopp1-wwox-breast-fulltext]. This interaction was validated by co-immunoprecipitation in both HEK-293T cells and MDA-MB-468 breast cancer cells, confirming that endogenous WWOX and VOPP1 are physically associated.

The molecular basis of the WWOX-VOPP1 interaction has been characterized in detail. WWOX contains two N-terminal WW domains (WW1 and WW2), with WW1 being the predominant functional interacting domain. WW1 belongs to Group I WW domains that specifically recognize proteins with PPxY consensus motifs [bonin-2018-vopp1-wwox-breast-fulltext]. VOPP1 contains three such PPxY motifs in its proline-rich C-terminal region: PPYY, PPAY, and PPPY. Mutagenesis studies demonstrated that the PPPY motif (specifically tyrosine 165) is required to sustain robust interaction with WWOX. Conversely, the Y33R mutation in the WW1 domain of WWOX abolished the WWOX-VOPP1 interaction [bonin-2018-vopp1-wwox-breast-fulltext].

The WWOX-VOPP1 interaction was independently confirmed by Hussain et al. (2018), who identified VOPP1 as a high-confidence WWOX interactor (interaction score 0.51) through tandem affinity purification-mass spectrometry (TAP-MS) (DOI) [hussain-2018-wwox-interactome-fulltext]. VOPP1 ranked among the top interacting proteins containing PPXY motifs.

The functional consequence of the WWOX-VOPP1 interaction is remarkable: VOPP1 sequesters WWOX in lysosomal vesicles. Normally, WWOX localizes to the Golgi apparatus. However, when co-expressed with VOPP1, WWOX completely loses its typical Golgi distribution and exhibits a punctate pattern consistent with lysosomal structures [bonin-2018-vopp1-wwox-breast-fulltext]. In MDA-MB-468 cells with endogenous VOPP1 expression, WWOX was found co-localized with VOPP1 and LAMP2 in perinuclear lysosomes rather than in the Golgi. Importantly, knockdown of VOPP1 in these cells induced re-localization of WWOX from lysosomal vesicles to the Golgi apparatus, demonstrating that VOPP1 is actively sequestering WWOX.

This sequestration has profound functional implications. WWOX is known to promote apoptosis through interaction with p73α, a pro-apoptotic transcription factor. The cytoplasmic WWOX-p73α complex induces apoptosis independently of p73 transcriptional activity [bonin-2018-vopp1-wwox-breast-fulltext]. VOPP1 disrupts this pro-apoptotic axis: ectopic expression of wild-type VOPP1 (but not the VOPP1-Y165A mutant that cannot bind WWOX) impaired the ability of WWOX to associate with p73α. Thus, VOPP1 inhibits WWOX-dependent apoptosis at least in part by preventing the WWOX-p73α interaction.

Role in Oxidative Stress and Redox Homeostasis

An alternative or complementary mechanism for VOPP1's pro-survival function emerged from studies by Baras et al. (2011), who investigated VOPP1 function in squamous cell carcinoma [baras-2011-oxidative-abstract]. According to PubMed, VOPP1 knockdown induces cell death at 72 hours post-transfection through induction of apoptosis via the intrinsic (mitochondrial) pathway.

Gene expression profiling of VOPP1 knockdown cells revealed enrichment in annotations of oxidative stress and mitochondrial dysfunction [baras-2011-oxidative-abstract]. Specifically, reactive oxygen species (ROS) levels became elevated and mitochondrial membrane potential was disrupted with VOPP1 knockdown at time points preceding the activation of effector caspases and cell death. This temporal sequence suggests that oxidative stress is a causative factor rather than a consequence of apoptosis.

Crucially, the antioxidant N-acetyl cysteine (NAC) was able to abrogate the induction of apoptosis observed with VOPP1 knockdown in a dose-responsive manner [baras-2011-oxidative-abstract]. This pharmacological rescue experiment provides strong evidence that VOPP1 participates in the control of the intracellular redox state, and that its loss leads to oxidative cellular injury culminating in cell death by the intrinsic apoptotic pathway.

This redox-regulatory function aligns with the lysosomal localization of VOPP1, as lysosomes are increasingly recognized as important regulators of cellular metabolism and redox balance. Interestingly, Kertai et al. (2016) found that VOPP1 was the most significantly upregulated gene in patients with postoperative atrial fibrillation after coronary artery bypass surgery, and gene set enrichment analysis highlighted VOPP1's role in pathways related to "myocardial homeostasis, and oxidative stress and redox modulation" (DOI) [kertai-2016-vopp1-atrial-fibrillation-abstract]. This unexpected finding in cardiac tissue suggests that VOPP1's role in redox regulation may have physiological relevance beyond cancer.

The relationship between VOPP1's role in oxidative stress and its interaction with WWOX may be interconnected. According to Bonin et al. (2018), increased ROS levels were observed in WWOX-overexpressing larvae in a Drosophila model, while WWOX mutants had consistently lower levels of ROS [bonin-2018-vopp1-wwox-breast-fulltext]. Thus, VOPP1's sequestration of WWOX might indirectly affect cellular ROS levels, providing a mechanistic link between the two pathways.

Regulation by MicroRNAs

VOPP1/ECOP expression is negatively regulated by several microRNAs, most notably miR-218. This regulatory relationship has been demonstrated in multiple cancer types and provides important insights into VOPP1's role in tumorigenesis.

In gastric cancer, Gao et al. (2010) showed that miR-218 expression was significantly reduced in gastric cancer tissues and in Helicobacter pylori-infected gastric mucosa (DOI) [gao-2010-mir218-gastric-abstract]. ECOP was identified as a direct target of miR-218 through luciferase reporter assays. Overexpression of miR-218 inhibited cell proliferation, increased apoptosis, and suppressed NF-κB transcriptional activation. The authors proposed that H. pylori infection leads to decreased miR-218 expression, which in turn increases ECOP levels and NF-κB activity, contributing to gastric carcinogenesis.

In glioma, Xia et al. (2013) demonstrated that miR-218 was downregulated in human glioma specimens, and overexpression of miR-218 induced glioma cell apoptosis and inhibited proliferation and tumorigenicity (DOI) [xia-2013-mir218-glioma-abstract]. ECOP was validated as a functional downstream target, and ectopic expression of ECOP rescued glioma cells from miR-218-induced apoptosis.

In lung adenocarcinoma, Li et al. (2017) showed that miR-218 suppresses epithelial-to-mesenchymal transition (EMT) by targeting both ECOP and Robo1 (DOI) [li-2017-mir218-lung-emt-abstract]. The suppression of ECOP by miR-218 reduced NF-κB activity and its downstream targets, inhibiting cell migration and invasion.

Beyond miR-218, VOPP1/ECOP has been identified as a target of the cellular microRNA Hs_154, which is induced by West Nile virus infection. Smith et al. (2012) found that ECOP/VOPP1 expression was reduced in WNV-infected cells due to Hs_154 upregulation, and expression of ECOP in infected cells reduced the number of cells undergoing apoptosis (DOI) [smith-2012-wnv-mirna-abstract]. This finding confirms VOPP1's role as an anti-apoptotic factor and demonstrates that modulation of its expression can influence cell survival in the context of viral infection.

Role in Cancer

VOPP1 is overexpressed in multiple human malignancies, consistent with its pro-survival function. The VOPP1 gene is located at 7p11.2, a region frequently amplified in cancers, often along with EGFR [park-2005-ecop-nfkb-abstract]. Expression profiling using the Oncomine database has revealed elevated VOPP1 transcript levels in glioblastoma multiforme, squamous cell carcinoma, breast carcinoma, pancreatic carcinoma, gastric carcinoma, and lymphoma [baras-2010-localization-abstract].

In breast cancer, Bonin et al. (2018) found that 25% of breast tumors (112/448) showed VOPP1 overexpression (≥2.5-fold increase compared to normal breast tissue) (DOI) [bonin-2018-vopp1-wwox-breast-fulltext]. Increased expression was observed across all molecular subtypes (luminal A, luminal B, ERBB2, and triple-negative), with ERBB2 tumors showing slightly higher amounts. Importantly, gene amplification at 7p11.2 was observed only in triple-negative tumors, indicating that other mechanisms (transcriptional regulation, epigenetic changes) drive VOPP1 overexpression in most breast cancers.

The clinical significance of VOPP1 overexpression was most evident when considered in relation to WWOX status. High VOPP1 expression was significantly associated with reduced metastasis-free survival in luminal B breast tumors (log-rank p=0.005) [bonin-2018-vopp1-wwox-breast-fulltext]. Moreover, there was a negative correlation between WWOX underexpression and VOPP1 overexpression. The VOPP1/WWOX ratio was a highly significant prognostic variable (p<0.00001) with a hazard ratio of 3.2 for metastasis. Strikingly, the authors estimated that 81.69% of breast tumors are affected by alterations in the WWOX pathway, either through WWOX underexpression or VOPP1 overexpression.

Functional studies support an oncogenic role for VOPP1. Stable expression of VOPP1 in NIH3T3 cells induced morphological transformation, anchorage-independent growth in soft agar, and tumor formation in vivo [bonin-2018-vopp1-wwox-breast-fulltext]. In gastric cancer, VOPP1 overexpression promoted cell proliferation and migration [gao-2015-ecop-gastric-oncogene-abstract].

Tissue Expression and Database Annotations

Analysis of tissue expression data from the Human Protein Atlas reveals that VOPP1 exhibits a distinctive tissue distribution pattern in normal human tissues. The highest expression is found in the retina (233.4 nTPM), with particularly striking cell type-enhanced expression in photoreceptor cells: cone photoreceptors show the highest expression (1,262.8 nCPM), followed by rod photoreceptors (841.0 nCPM) [human-protein-atlas]. This marked expression in photoreceptors is unexpected given the literature focus on cancer and suggests potential physiological functions in retinal biology that have not been explored.

VOPP1 also shows substantial expression in lymphoid tissues, including thymus (106.5 nTPM), lymph node (92.9 nTPM), tonsil (73.6 nTPM), and spleen (72.7 nTPM) [human-protein-atlas]. In the brain, notable expression is observed in the thalamus (121.7 nTPM). At the single-cell level, elevated expression is also observed in plasma cells, dendritic cells, and neutrophils, suggesting a role in immune cell function. This expression pattern led to the classification of VOPP1 in the "Retina & Lymphoid tissues - Signaling" expression cluster [human-protein-atlas].

The OMIM database entry for VOPP1 (OMIM: 611915) notes that in normal tissues, ECOP expression is strongest in thymus and ovary, with moderate levels in spleen, testes, colon, and small intestine, and weaker expression in placenta, prostate, and liver [omim-611915]. The database also notes that ECOP possesses "a signal peptide and is generally hydrophilic," with multiple transcript variants (3.6-kb and 4.2-kb forms) detected.

The Gene Ontology annotations for VOPP1 include molecular function terms related to enzyme binding activity, and cellular component terms placing the protein in cytoplasmic vesicle membrane, late endosome, and lysosome compartments [genecards]. These annotations are consistent with the experimental localization studies described above. The biological process annotations remain limited, reflecting the ongoing uncertainty about VOPP1's precise molecular function.

Role in Non-Cancer Conditions

Emerging evidence suggests that VOPP1 may play roles beyond cancer. Kertai et al. (2016) identified VOPP1 as the most significantly differentially expressed gene (1.83 fold change; P=3.47×10^-7) in patients with postoperative atrial fibrillation (AF) after coronary artery bypass grafting (DOI) [kertai-2016-vopp1-atrial-fibrillation-abstract]. Expression quantitative trait loci (eQTL) analysis revealed a trans-acting association between variants of the G protein-coupled receptor kinase 5 (GRK5) gene and high VOPP1 expression. These findings suggest that VOPP1 may play a role in cardiac homeostasis, potentially through its effects on oxidative stress.

Li et al. (2018) reported that miR-218 expression was reduced in peripheral blood mononuclear cells of sepsis patients, and this reduction correlated with disease severity (DOI) [li-2018-mir218-sepsis-abstract]. VOPP1 was identified as a miR-218 target in this context, and the miR-218/VOPP1 axis was linked to JAK/STAT pathway regulation and inflammatory cytokine production. This suggests that VOPP1 may participate in immune regulation and inflammatory responses.

Open Questions

Several important questions regarding VOPP1 function remain to be addressed:

1. Mechanism of NF-κB regulation: The precise mechanism by which VOPP1 affects NF-κB signaling remains unclear. Given VOPP1's vesicular localization, direct interaction with cytoplasmic NF-κB pathway components seems unlikely. Whether VOPP1 affects NF-κB indirectly through WWOX, through redox regulation, or through an unknown intermediate requires clarification.

2. Enzymatic or catalytic function: Despite the presence of identifiable domains, no enzymatic or catalytic activity has been attributed to VOPP1. Whether the protein functions purely as an adapter/scaffolding protein or possesses undiscovered enzymatic activity remains unknown.

3. Lysosomal function: The molecular function of VOPP1 within lysosomes is not understood. Does VOPP1 regulate lysosomal activity, autophagy, or protein degradation pathways? The presence of endosome/lysosome targeting sequences suggests active sorting to this compartment, but the purpose of this localization beyond WWOX sequestration is unclear.

4. Specificity of WWOX interaction: While the VOPP1-WWOX interaction is well characterized, it is not clear whether VOPP1 affects other WWOX functions beyond apoptosis, such as DNA damage response or metabolic regulation. WWOX has many interacting partners and pleiotropic functions.

5. Tissue-specific functions: The unexpected role of VOPP1 in atrial fibrillation suggests tissue-specific functions that may extend beyond its established role in cancer. Systematic characterization of VOPP1 expression and function in different tissues would be valuable.

6. Therapeutic potential: Given the oncogenic role of VOPP1 and its mechanism of action through WWOX sequestration, disrupting the VOPP1-WWOX interaction could potentially restore WWOX tumor suppressor function. Whether this interaction is amenable to pharmacological disruption and whether such intervention would have therapeutic benefit remains to be investigated.

7. Relationship between oxidative stress and WWOX: The connection between VOPP1's role in redox regulation and its interaction with WWOX needs further exploration. Do these represent independent mechanisms or are they functionally linked?

8. Function in photoreceptors: The Human Protein Atlas reveals striking expression of VOPP1 in cone and rod photoreceptors, with these cells showing the highest single-cell expression levels of any cell type examined. The function of VOPP1 in photoreceptors is entirely unexplored and represents a significant gap in understanding the normal physiological role of this protein.

References

• park-2005-ecop-nfkb: Park S, James CD. ECop (EGFR-coamplified and overexpressed protein), a novel protein, regulates NF-kappaB transcriptional activity and associated apoptotic response in an IkappaBalpha-dependent manner. Oncogene. 2005;24(15):2495-502. PMID: 15735698. DOI: 10.1038/sj.onc.1208496

• baras-2010-localization: Baras A, Moskaluk CA. Intracellular localization of GASP/ECOP/VOPP1. J Mol Histol. 2010;41(2-3):153-64. PMID: 20571887. DOI: 10.1007/s10735-010-9272-8

• baras-2011-oxidative: Baras AS, Solomon A, Davidson R, Moskaluk CA. Loss of VOPP1 overexpression in squamous carcinoma cells induces apoptosis through oxidative cellular injury. Lab Invest. 2011;91(8):1170-80. PMID: 21519330. DOI: 10.1038/labinvest.2011.70

• bonin-2018-vopp1-wwox-breast: Bonin F, Taouis K, Azorin P, et al. VOPP1 promotes breast tumorigenesis by interacting with the tumor suppressor WWOX. BMC Biol. 2018;16(1):109. PMID: 30285739. PMC: PMC6169085. DOI: 10.1186/s12915-018-0576-6

• hussain-2018-wwox-interactome: Hussain T, Lee J, Abba MC, Chen J, Aldaz CM. Delineating WWOX Protein Interactome by Tandem Affinity Purification-Mass Spectrometry: Identification of Top Interactors and Key Metabolic Pathways Involved. Front Oncol. 2018;8:591. PMID: 30619736. PMC: PMC6300487. DOI: 10.3389/fonc.2018.00591

• xia-2013-mir218-glioma: Xia H, Yan Y, Hu M, et al. MiR-218 sensitizes glioma cells to apoptosis and inhibits tumorigenicity by regulating ECOP-mediated suppression of NF-κB activity. Neuro Oncol. 2013;15(4):413-22. PMID: 23243056. PMC: PMC3607258. DOI: 10.1093/neuonc/nos296

• gao-2010-mir218-gastric: Gao C, Zhang Z, Liu W, Xiao S, Gu W, Lu H. Reduced microRNA-218 expression is associated with high nuclear factor kappa B activation in gastric cancer. Cancer. 2010;116(1):41-9. PMID: 19890957. DOI: 10.1002/cncr.24743

• gao-2015-ecop-gastric-oncogene: Gao C, Pang M, Zhou Z, et al. Epidermal growth factor receptor-coamplified and overexpressed protein (VOPP1) is a putative oncogene in gastric cancer. Clin Exp Med. 2015;15(4):469-75. PMID: 25398664. DOI: 10.1007/s10238-014-0320-7

• smith-2012-wnv-mirna: Smith JL, Grey FE, Uhrlaub JL, Nikolich-Zugich J, Hirsch AJ. Induction of the cellular microRNA, Hs_154, by West Nile virus contributes to virus-mediated apoptosis through repression of antiapoptotic factors. J Virol. 2012;86(9):5278-87. PMID: 22345437. PMC: PMC3347395. DOI: 10.1128/JVI.06883-11

• kertai-2016-vopp1-atrial-fibrillation: Kertai MD, Qi W, Li YJ, et al. Gene signatures of postoperative atrial fibrillation in atrial tissue after coronary artery bypass grafting surgery in patients receiving β-blockers. J Mol Cell Cardiol. 2016;92:109-15. PMID: 26860460. PMC: PMC4967350. DOI: 10.1016/j.yjmcc.2016.02.006

• li-2017-mir218-lung-emt: Li YJ, Zhang W, Xia H, et al. miR-218 suppresses epithelial-to-mesenchymal transition by targeting Robo1 and Ecop in lung adenocarcinoma cells. Future Oncol. 2017;13(28):2571-2582. PMID: 28936884. DOI: 10.2217/fon-2017-0398

• li-2018-mir218-sepsis: Li JM, Zhang H, Zuo YJ. MicroRNA-218 alleviates sepsis inflammation by negatively regulating VOPP1 via JAK/STAT pathway. Eur Rev Med Pharmacol Sci. 2018;22(17):5620-5626. PMID: 30229837. DOI: 10.26355/eurrev_201809_15827

• human-protein-atlas: VOPP1 protein expression summary. The Human Protein Atlas. URL: https://www.proteinatlas.org/ENSG00000154978-VOPP1

• omim-611915: VESICULAR, OVEREXPRESSED IN CANCER, PROSURVIVAL PROTEIN 1; VOPP1. Online Mendelian Inheritance in Man (OMIM). Entry #611915. URL: https://omim.org/entry/611915

• genecards: VOPP1 Gene. GeneCards Human Gene Database. URL: https://www.genecards.org/cgi-bin/carddisp.pl?gene=VOPP1

Citations

1. baras-2010-localization-abstract.md
2. baras-2011-oxidative-abstract.md
3. bonin-2018-vopp1-wwox-breast-fulltext.txt
4. bonin-2018-vopp1-wwox-breast-summary.md
5. gao-2010-mir218-gastric-abstract.md
6. gao-2015-ecop-gastric-oncogene-abstract.md
7. human-protein-atlas-vopp1.md
8. hussain-2018-wwox-interactome-fulltext.txt
9. kertai-2016-vopp1-atrial-fibrillation-abstract.md
10. li-2017-mir218-lung-emt-abstract.md
11. li-2018-mir218-sepsis-abstract.md
12. omim-611915.md
13. park-2005-ecop-nfkb-abstract.md
14. smith-2012-wnv-mirna-abstract.md
15. xia-2013-mir218-glioma-abstract.md

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Plan and approach
We verified identity and nomenclature (VOPP1/ECOP/GASP; UniProt Q96AW1; human) and searched for recent primary/review literature (2023–2024). Because dedicated, recent mechanistic work on VOPP1 is sparse, we anchored the report on foundational peer‑reviewed studies and interaction datasets, and we note the recency limitation explicitly (see Expert perspectives). We then synthesized functional roles, localization, pathways, and disease relevance with quantitative data where available.

Table: Compact summary table of VOPP1 identity, interactions, localization, functions, pathway links, disease associations, and key quantitative experimental results with primary citations from the available evidence; useful as a quick reference for mechanistic and translational follow-up.

1) Key concepts and definitions with current understanding
- Gene/protein identity: VOPP1 (HGNC:34518), also known as ECOP (EGFR‑coamplified and overexpressed protein) and GASP (glioblastoma‑amplified secreted protein), encodes a small vesicle‑associated protein implicated in pro‑survival signaling in cancer. The aliases and human specificity match UniProt Q96AW1 and are used consistently in mechanistic literature (e.g., glioma studies) (xia2013mir218sensitizesglioma pages 1-2, dai2019vopp1promoteshepatocellular pages 1-4).
- Subcellular localization and molecular nature: Proteomic interactome mapping places VOPP1 within a network of proteins from ER/Golgi/late endosome/lysosome systems and perinuclear compartments, consistent with a vesicle‑associated or vesicle‑trafficking role rather than an enzyme or transporter. VOPP1 binds the WW domain of the tumor suppressor WWOX via a PPPY motif, supporting a role as a WW‑binding adapter localized to membrane/vesicular pathways (hussain2018delineatingwwoxprotein pages 6-8).
- Core signaling function: Foundational work in glioma identifies ECOP/VOPP1 as a modulator of NF‑κB transcriptional activity that promotes cell survival; miR‑218 directly targets ECOP to suppress NF‑κB activity and sensitize cells to apoptosis (luciferase reporters, rescue experiments) (xia2013mir218sensitizesglioma pages 1-2).

2) Recent developments and latest research (2023–2024 prioritized)
- Direct, VOPP1‑focused mechanistic papers from 2023–2024 are limited in the retrieved evidence. Contemporary reviews continue to cite ECOP/VOPP1 within NF‑κB/EGFR‑linked stress and vesicular signaling contexts, but primary mechanistic advances remain anchored in earlier studies. The newest quantitative work in our evidence set remains a 2019 preprint describing VOPP1‑dependent proliferation pathways in HCC that implicate MAPK14 and RPS6KB1 (mTOR/S6K) (dai2019vopp1promoteshepatocellular pages 1-4, dai2019vopp1promoteshepatocellular pages 11-18, dai2019vopp1promoteshepatocellular pages 7-11, dai2019vopp1promoteshepatocellular pages 4-7).

3) Current applications and real‑world implementations
- Oncology biomarker and target potential: Multiple tumor contexts report VOPP1 overexpression or amplification within the EGFR amplicon, suggesting utility as a tumor biomarker and a candidate therapeutic vulnerability, particularly where NF‑κB signaling contributes to survival. Functional knockdown in HCC reduces proliferation in vitro and suppresses xenograft growth, supporting target plausibility in preclinical models (xia2013mir218sensitizesglioma pages 1-2, dai2019vopp1promoteshepatocellular pages 4-7, dai2019vopp1promoteshepatocellular pages 11-18).

4) Expert opinions and analysis from authoritative sources
- Mechanistic axis: The Neuro‑Oncology study demonstrates that ECOP/VOPP1 is both necessary and sufficient to modulate NF‑κB–dependent survival outputs downstream of miR‑218, providing causal evidence for its role in pro‑survival signaling in glioma cells (xia2013mir218sensitizesglioma pages 1-2). The WWOX interactome work independently positions VOPP1 as a WW domain‑binding partner associated with secretory and endo‑lysosomal trafficking, consistent with a scaffolding/adapter role that can integrate signaling with vesicular compartments (hussain2018delineatingwwoxprotein pages 6-8). Together, these sources support a model in which VOPP1 functions as a vesicle‑associated adaptor that tunes NF‑κB and growth‑factor–adjacent pathways across tumor contexts (xia2013mir218sensitizesglioma pages 1-2, hussain2018delineatingwwoxprotein pages 6-8).
- Pathway linkage in liver cancer: The HCC preclinical study links VOPP1 to MAPK14 (p38) and RPS6KB1 (S6K) abundance and pathway activity after VOPP1 knockdown, aligning VOPP1 with stress‑response and anabolic growth signaling frequently co‑opted in tumors (dai2019vopp1promoteshepatocellular pages 1-4, dai2019vopp1promoteshepatocellular pages 7-11).

5) Relevant statistics and data from recent studies
- HCC knockdown phenotypes (quantitative): VOPP1 knockdown markedly reduced colony formation (e.g., SMMC‑7721 colonies 111 ± 2 vs 18 ± 3; BEL‑7404 168 ± 11 vs 22 ± 4; P<0.01), increased apoptosis (SMMC‑7721 4.48% → 12.47%; BEL‑7404 2.24% → 23.66%; P<0.001), and reduced in vivo xenograft tumor volume/weight (P<0.001), with microarray implicating TNF‑mediated signaling; MAPK14 and RPS6KB1 protein levels decreased upon VOPP1 silencing (dai2019vopp1promoteshepatocellular pages 4-7, dai2019vopp1promoteshepatocellular pages 11-18, dai2019vopp1promoteshepatocellular pages 7-11).

Functional roles and pathways
- NF‑κB modulation: ECOP/VOPP1 enhances NF‑κB activity; loss of ECOP via miR‑218 suppresses NF‑κB target transcription and increases apoptosis. ECOP overexpression rescues NF‑κB activity and cell survival, indicating that ECOP/VOPP1 is a proximal modulator of NF‑κB–dependent transcriptional programs in glioma (xia2013mir218sensitizesglioma pages 1-2).
- EGFR amplicon context and growth signaling: VOPP1 has been described in the EGFR co‑amplified region in glioblastoma, and HCC data connect VOPP1 to MAPK14 (stress kinase) and mTOR/S6K growth pathways, suggesting that VOPP1 integrates vesicle‑associated signaling with proliferative and survival networks (dai2019vopp1promoteshepatocellular pages 1-4, dai2019vopp1promoteshepatocellular pages 7-11).
- Protein–protein interactions: The WWOX–VOPP1 interaction via a WW1–PPPY interface supports a model in which VOPP1 may participate in scaffolding complexes at perinuclear/vesicular compartments linking trafficking to signal transduction (hussain2018delineatingwwoxprotein pages 6-8).

Cellular and subcellular localization
- Evidence for perinuclear ER/Golgi/late endosome/lysosome association comes from WWOX interactome localization and partner enrichment analyses; this aligns with the “vesicular, overexpressed in cancer” nomenclature and supports a role at vesicle membranes where signaling platforms assemble (hussain2018delineatingwwoxprotein pages 6-8).

Disease relevance across indications
- Glioma/glioblastoma: ECOP/VOPP1 is upregulated in glioma and modulates NF‑κB–dependent survival; the miR‑218–ECOP axis reduces tumorigenicity when ECOP is suppressed (xia2013mir218sensitizesglioma pages 1-2).
- Hepatocellular carcinoma: VOPP1 is overexpressed in HCC; knockdown impairs proliferation, increases apoptosis, and reduces xenograft growth, associated with downregulation of MAPK14 and RPS6KB1 (dai2019vopp1promoteshepatocellular pages 1-4, dai2019vopp1promoteshepatocellular pages 11-18, dai2019vopp1promoteshepatocellular pages 4-7).
- Other tumors: Historical reports (referenced within the HCC study) include gastric and squamous cell carcinomas; while not directly quantified here, they support the general pattern of VOPP1 involvement in EGFR‑linked epithelial tumors (dai2019vopp1promoteshepatocellular pages 7-11).

Limitations and open questions (2023–2024 landscape)
- Despite broad citation of ECOP/VOPP1 in reviews, there is limited new primary mechanistic work in 2023–2024 directly dissecting VOPP1 biochemistry, structure, and pathway wiring. Structural definition (domains beyond a PPPY motif), high‑resolution localization, and unbiased dependency screens in modern multi‑omic cohorts remain areas for future research (hussain2018delineatingwwoxprotein pages 6-8, xia2013mir218sensitizesglioma pages 1-2, dai2019vopp1promoteshepatocellular pages 1-4).

Practical implications
- Biomarker potential: Given overexpression in multiple cancers and functional linkage to survival pathways, VOPP1 may serve as an adjunct biomarker within EGFR‑amplicon tumors and HCC; however, standardized assays and prospective validation are needed (xia2013mir218sensitizesglioma pages 1-2, dai2019vopp1promoteshepatocellular pages 1-4).
- Therapeutic strategies: Targeting the VOPP1–NF‑κB axis (e.g., restoring miR‑218 or disrupting VOPP1 scaffolding functions) and exploiting the VOPP1–MAPK14/mTOR connection in HCC are plausible strategies suggested by preclinical data and warrant medicinal chemistry and delivery exploration (xia2013mir218sensitizesglioma pages 1-2, dai2019vopp1promoteshepatocellular pages 7-11, dai2019vopp1promoteshepatocellular pages 11-18).

Source list with URLs and publication dates
- Xia et al., Neuro‑Oncology, April 2013. “MiR‑218 sensitizes glioma cells to apoptosis and inhibits tumorigenicity by regulating ECOP‑mediated suppression of NF‑κB activity.” https://doi.org/10.1093/neuonc/nos296 (xia2013mir218sensitizesglioma pages 1-2).
- Hussain et al., Frontiers in Oncology, December 2018. “Delineating WWOX Protein Interactome by Tandem Affinity Purification‑Mass Spectrometry: Identification of Top Interactors and Key Metabolic Pathways Involved.” https://doi.org/10.3389/fonc.2018.00591 (hussain2018delineatingwwoxprotein pages 6-8).
- Dai et al., Research Square/ArXiv preprint, July 2019. “VOPP1 promotes hepatocellular carcinoma proliferation through MAPK14 and RPS6KB1.” https://doi.org/10.21203/rs.2.11083/v1 (dai2019vopp1promoteshepatocellular pages 1-4, dai2019vopp1promoteshepatocellular pages 11-18, dai2019vopp1promoteshepatocellular pages 7-11, dai2019vopp1promoteshepatocellular pages 4-7).

Conclusion
VOPP1 (ECOP/GASP; Q96AW1) is a vesicle‑associated adaptor that binds WW domains (e.g., WWOX) and modulates NF‑κB–driven survival programs, with additional links to MAPK14 and mTOR/S6K signaling in HCC. It localizes to perinuclear secretory/endo‑lysosomal compartments and is embedded in the EGFR co‑amplified region in glioblastoma. Functional knockdowns in HCC yield strong anti‑tumor phenotypes, positioning VOPP1 as a biomarker/target candidate in select cancers. Recent primary literature (2023–2024) appears limited, underscoring the need for renewed mechanistic and translational studies (xia2013mir218sensitizesglioma pages 1-2, hussain2018delineatingwwoxprotein pages 6-8, dai2019vopp1promoteshepatocellular pages 1-4).

References

1. (xia2013mir218sensitizesglioma pages 1-2): Hongping Xia, Yukui Yan, Minghua Hu, Yaxian Wang, Yongsheng Wang, Yi Dai, Jianming Chen, Guangfu Di, Xiaobing Chen, and Xiaochun Jiang. Mir-218 sensitizes glioma cells to apoptosis and inhibits tumorigenicity by regulating ecop-mediated suppression of nf-κb activity. Neuro-oncology, 15 4:413-22, Apr 2013. URL: https://doi.org/10.1093/neuonc/nos296, doi:10.1093/neuonc/nos296. This article has 102 citations and is from a domain leading peer-reviewed journal.

2. (dai2019vopp1promoteshepatocellular pages 1-4): Haojiang Dai, Peng Hu, Binfeng Wang, Qiuyue Han, Yongfu Xu, Shangdong Lv, Yu Zhu, Meifu Gan, Weijie Zhou, Zheping Fang, and Wenlong Zhang. Vopp1 promotes hepatocellular carcinoma proliferation through mapk14 and rps6kb1. ArXiv, Jul 2019. URL: https://doi.org/10.21203/rs.2.11083/v1, doi:10.21203/rs.2.11083/v1. This article has 0 citations.

3. (hussain2018delineatingwwoxprotein pages 6-8): Tabish Hussain, Jaeho Lee, Martin C. Abba, Junjie Chen, and C. Marcelo Aldaz. Delineating wwox protein interactome by tandem affinity purification-mass spectrometry: identification of top interactors and key metabolic pathways involved. Frontiers in Oncology, Dec 2018. URL: https://doi.org/10.3389/fonc.2018.00591, doi:10.3389/fonc.2018.00591. This article has 30 citations and is from a poor quality or predatory journal.

4. (dai2019vopp1promoteshepatocellular pages 4-7): Haojiang Dai, Peng Hu, Binfeng Wang, Qiuyue Han, Yongfu Xu, Shangdong Lv, Yu Zhu, Meifu Gan, Weijie Zhou, Zheping Fang, and Wenlong Zhang. Vopp1 promotes hepatocellular carcinoma proliferation through mapk14 and rps6kb1. ArXiv, Jul 2019. URL: https://doi.org/10.21203/rs.2.11083/v1, doi:10.21203/rs.2.11083/v1. This article has 0 citations.

5. (dai2019vopp1promoteshepatocellular pages 11-18): Haojiang Dai, Peng Hu, Binfeng Wang, Qiuyue Han, Yongfu Xu, Shangdong Lv, Yu Zhu, Meifu Gan, Weijie Zhou, Zheping Fang, and Wenlong Zhang. Vopp1 promotes hepatocellular carcinoma proliferation through mapk14 and rps6kb1. ArXiv, Jul 2019. URL: https://doi.org/10.21203/rs.2.11083/v1, doi:10.21203/rs.2.11083/v1. This article has 0 citations.

6. (dai2019vopp1promoteshepatocellular pages 7-11): Haojiang Dai, Peng Hu, Binfeng Wang, Qiuyue Han, Yongfu Xu, Shangdong Lv, Yu Zhu, Meifu Gan, Weijie Zhou, Zheping Fang, and Wenlong Zhang. Vopp1 promotes hepatocellular carcinoma proliferation through mapk14 and rps6kb1. ArXiv, Jul 2019. URL: https://doi.org/10.21203/rs.2.11083/v1, doi:10.21203/rs.2.11083/v1. This article has 0 citations.

Citations

1. hussain2018delineatingwwoxprotein pages 6-8
2. https://doi.org/10.1093/neuonc/nos296,
3. https://doi.org/10.21203/rs.2.11083/v1
4. https://doi.org/10.3389/fonc.2018.00591
5. https://doi.org/10.1093/neuonc/nos296
6. https://doi.org/10.21203/rs.2.11083/v1,
7. https://doi.org/10.3389/fonc.2018.00591,

Introduction & Gene Overview

VOPP1 (Vesicular, Overexpressed in Cancer, Prosurvival Protein 1) is a human gene encoding a small protein (172 amino acids) known for its role in cell survival and cancer biology (www.ncbi.nlm.nih.gov) (www.nature.com). It was initially identified in chromosome 7p11.2 within the EGFR amplification region frequently seen in glioblastoma, hence early names GASP (“glioblastoma-amplified secreted protein”) and ECOP (“EGFR-coamplified and overexpressed protein”) (www.nature.com). The official gene symbol VOPP1 reflects its characterization as a “WW domain-binding protein,” indicating it binds to proteins containing WW domains. Indeed, VOPP1 contains conserved proline-rich PPPY motifs that mediate binding to WW-domain proteins (pubmed.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). The protein is synthesized as a precursor with a signal peptide (“Flags: Precursor” in UniProt), targeting it to the secretory/endosomal pathway. Consistent with this, confocal microscopy has localized VOPP1 to intracellular vesicles (late endosomes/lysosomes) clustered near the nucleus (pubmed.ncbi.nlm.nih.gov). Bioinformatic and antibody-based profiling predict VOPP1 to be an intracellular membrane-associated protein, likely residing on vesicular/lysosomal membranes (www.proteinatlas.org) (pubmed.ncbi.nlm.nih.gov). VOPP1 is ubiquitously expressed at baseline in human tissues, with especially high mRNA levels in the retina and certain tumors (www.proteinatlas.org) (www.proteinatlas.org). Importantly, its expression is frequently elevated in cancers such as glioblastoma, squamous cell carcinomas, breast and gastric tumors (www.nature.com) (pubmed.ncbi.nlm.nih.gov), suggesting an oncogenic function. Below, we discuss the current understanding of VOPP1’s function, recent research (2023–2024), its roles in disease and potential clinical applications, expert insights, and key data from recent studies, with emphasis on authoritative sources.

Function and Mechanisms: NF-κB Activation and Survival

One of the key functions of VOPP1 is regulating the NF-κB signaling pathway to promote cell survival. NF-κB is a transcription factor controlling genes for inflammation and anti-apoptotic proteins. VOPP1 enhances canonical NF-κB activity: experimental overexpression of VOPP1 (ECOP) drives NF-κB p50/p65 to translocate into the nucleus and bind DNA, boosting NF-κB-dependent transcription (www.nature.com). This heightened NF-κB activity, in turn, confers resistance to apoptosis (programmed cell death) under stress conditions (www.nature.com). Conversely, silencing VOPP1 dampens NF-κB signaling – when VOPP1 is knocked down, cells show delayed degradation of IκBα (the inhibitor of NF-κB), leading to slower NF-κB nuclear entry and reduced target gene expression (www.nature.com). As a result, VOPP1-depleted cells become more susceptible to apoptotic triggers (www.nature.com). These findings (first reported in 2011) established VOPP1 as a positive regulator of NF-κB. Researchers described VOPP1 as a “key regulator” of NF-κB signaling whose overexpression (for example, via gene amplification with EGFR) could promote cell survival and therapy resistance by keeping NF-κB active (www.nature.com). Notably, this NF-κB enhancement by VOPP1 seems to operate via controlling IκBα turnover – suggesting VOPP1 might influence the ubiquitin-proteasome machinery or signaling upstream of IκB degradation, although the precise biochemical mechanism is still being clarified.

Beyond NF-κB, VOPP1 has been implicated in maintaining cellular redox balance and mitochondrial integrity, further supporting its pro-survival role. In cancer cells that naturally overexpress VOPP1, acute knockdown of VOPP1 triggers intrinsic apoptosis accompanied by oxidative stress (www.nature.com) (www.nature.com). For example, in squamous carcinoma cell lines (SCC) and HeLa cells, VOPP1 silencing caused cell death within ~72 hours via the intrinsic (mitochondrial) apoptotic pathway (www.nature.com). Gene expression profiling of these VOPP1-depleted cells showed enrichment of oxidative stress and mitochondrial dysfunction signatures (www.nature.com). Indeed, investigators observed a rise in reactive oxygen species (ROS) and loss of mitochondrial membrane potential following VOPP1 knockdown (www.nature.com). Strikingly, treating the cells with the antioxidant N-acetylcysteine could rescue them from apoptosis, indicating that excess ROS is a major driver of cell death when VOPP1 is lost (www.nature.com). This suggests VOPP1 normally helps limit oxidative damage, either by regulating antioxidant gene expression (potentially via NF-κB target genes) or by influencing organelle function. Interestingly, in those SCC cells, NF-κB reporter activity was not significantly changed by VOPP1 knockdown (www.nature.com), implying VOPP1’s redox protective function might be partially independent of NF-κB or context-dependent. Nonetheless, taken together, these findings indicate that VOPP1 is a multi-faceted prosurvival protein: it augments pro-survival signaling (NF-κB) and guards against oxidative stress-induced damage, thereby supporting the survival and proliferation of cells.

Localization and Interactions: Lysosomal Sequestration and WW Domain Binding

At the subcellular level, VOPP1 is a vesicle-associated protein. Immunofluorescence studies have shown that VOPP1 localizes predominantly to perinuclear endo/lysosomal compartments (pubmed.ncbi.nlm.nih.gov). In gastric cancer cells, for example, GFP-tagged VOPP1 was found concentrated on lysosomal membranes near the nucleus (pubmed.ncbi.nlm.nih.gov), consistent with earlier reports in other cell types. This localization aligns with VOPP1’s having a signal peptide and a predicted membrane association. Notably, VOPP1 lacks any well-known catalytic domains – instead, it functions through protein–protein interactions. As its name suggests, VOPP1 can bind “WW” domains (protein interaction modules that recognize proline-rich PPxY motifs). VOPP1 contains PPXY sequence motifs in its C-terminal region (pubmed.ncbi.nlm.nih.gov), and these motifs mediate binding to WW-domain proteins. A prime example is the tumor suppressor WWOX (WW domain-containing oxidoreductase). WWOX carries two N-terminal WW domains and is frequently lost or inactivated in cancers. Proteomic analyses (TAP–mass spectrometry) identified VOPP1 as a top WWOX-binding partner, interacting specifically via the PPPY motif of VOPP1 and the first WW domain of WWOX (pmc.ncbi.nlm.nih.gov). Co-immunoprecipitation confirmed a direct VOPP1–WWOX interaction in cells (pubmed.ncbi.nlm.nih.gov). Significantly, VOPP1–WWOX binding has functional consequences: VOPP1 can literally sequester WWOX inside lysosomal vesicles, away from its usual sites of action (bmcbiol.biomedcentral.com).

This WWOX sequestration mechanism was elucidated in a 2018 study focusing on breast cancer. Researchers discovered that VOPP1 acts as a negative regulator of WWOX’s tumor suppressor function (bmcbiol.biomedcentral.com). Under normal conditions, WWOX promotes apoptosis (for instance by binding pro-apoptotic transcription factor p73α). But in breast cancer cells that express high VOPP1, VOPP1 binds to WWOX and traps it in the lysosomal compartment, preventing WWOX from interacting with p73α and other partners (bmcbiol.biomedcentral.com). This interaction functionally “silences” WWOX, impairing WWOX-mediated apoptosis and tumor suppression (bmcbiol.biomedcentral.com). The outcome is that cancer cells can survive and proliferate despite having an intact WWOX gene. In line with this, VOPP1 overexpression was shown to enhance oncogenic phenotypes: experimentally increasing VOPP1 levels in breast epithelial cells led to increased cellular transformation in vitro and faster tumor growth in vivo (mouse xenografts) (bmcbiol.biomedcentral.com). Clinically, the study found that VOPP1 is overexpressed in many breast tumors, especially those that still retain wild-type WWOX (bmcbiol.biomedcentral.com). Moreover, high VOPP1 expression correlates with significantly worse patient survival in breast cancers that are WWOX-positive (but not in WWOX-negative cases that lack the target) (bmcbiol.biomedcentral.com). These data indicate that VOPP1 is an oncogenic factor at least in part by disabling WWOX – effectively mimicking a WWOX loss-of-function even when WWOX is present (bmcbiol.biomedcentral.com). This concept has been echoed by experts: a 2023 review highlighted VOPP1 as a “significant regulator of WWOX”, noting that overexpression of VOPP1 (through its PPPY motif binding WWOX’s WW domain) diminishes WWOX’s tumor-suppressive functions (pmc.ncbi.nlm.nih.gov). In summary, VOPP1’s ability to interact with specific WW-domain proteins (like WWOX) in vesicular compartments is central to its role in modulating signaling pathways and cell fate. By tethering crucial factors in endo-lysosomal sites, VOPP1 can alter the balance of pro- and anti-apoptotic signals inside the cell.

Roles in Cancer: Oncogenic Impact and Clinical Relevance

Given its pro-survival functions, it is not surprising that VOPP1 has emerged as a context-dependent oncogene. The gene is frequently overexpressed or amplified in various cancers, and experimental studies support its tumor-promoting activity. In glioblastoma multiforme (GBM), VOPP1 resides in the same 7p11.2 amplicon as EGFR – a region amplified in ~40% of GBMs. Co-amplification leads to VOPP1 overexpression alongside EGFR (www.nature.com). It has been proposed that high VOPP1 in EGFR-amplified tumors contributes to the aggressive behavior of these cancers by enhancing NF-κB–driven survival signals (www.nature.com). Indeed, The Cancer Genome Atlas data indicate VOPP1 mRNA is particularly elevated in GBM tumors compared to most other cancer types (www.proteinatlas.org). Beyond brain tumors, VOPP1 upregulation is observed in many epithelial cancers. For example, gastric adenocarcinoma tissues show elevated VOPP1 protein expression relative to adjacent normal stomach tissue (pubmed.ncbi.nlm.nih.gov) (pubmed.ncbi.nlm.nih.gov). In one study, immunohistochemistry and Western blots confirmed overexpression of VOPP1 in gastric tumors (pubmed.ncbi.nlm.nih.gov). Functionally, manipulating VOPP1 levels in a gastric cancer cell line (AGS) impacted its malignancy: ectopic VOPP1 overexpression promoted cell proliferation and migration, while RNAi silencing of VOPP1 suppressed these traits (pubmed.ncbi.nlm.nih.gov). The same study visualized VOPP1’s subcellular localization in cancer cells, finding VOPP1 concentrated on lysosomal membranes in the perinuclear area, consistent with its proposed mode of action (pubmed.ncbi.nlm.nih.gov). Likewise, in squamous cell carcinomas, VOPP1 is often overexpressed; as discussed, acute loss of VOPP1 triggers apoptosis in SCC cells (www.nature.com), highlighting that these cancer cells become “addicted” to VOPP1 for survival. In breast cancer, as detailed above, VOPP1 overexpression correlates with poorer outcomes in patients with functional WWOX (bmcbiol.biomedcentral.com) and directly drives tumorigenic processes by neutralizing WWOX (bmcbiol.biomedcentral.com). There is also evidence that VOPP1 may be involved in hepatocellular carcinoma and other malignancies. The Human Protein Atlas identifies VOPP1 as an unfavorable prognostic marker in liver cancer: high VOPP1 expression in hepatocellular carcinoma is associated with significantly shorter patient survival (p < 0.001) (www.proteinatlas.org). This suggests VOPP1 could serve as a biomarker for aggressive disease in certain contexts. More broadly, numerous studies have found oncogenic non-coding RNAs targeting the VOPP1 pathway – for instance, loss of certain microRNAs (e.g. miR-218 or others) or gain of specific lncRNAs can lead to VOPP1 upregulation, driving cancer progression (pubmed.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Such findings underscore VOPP1’s position in a network of oncogenic signals.

Importantly, VOPP1’s contribution to cancer appears to involve multiple pathways. Its original link to NF-κB activation suggests that VOPP1-overexpressing tumors may exhibit chronic NF-κB activity, supporting inflammation, cell survival, and therapy resistance. In fact, sustained NF-κB signaling is one mechanism by which VOPP1-overexpressing cancer cells evade apoptosis (www.nature.com). For example, a study in cervical cancer reported that knocking down a long noncoding RNA suppressed tumor growth by upregulating a microRNA that in turn downregulated VOPP1, thereby reducing NF-κB activity and cancer cell invasiveness (pmc.ncbi.nlm.nih.gov). Separately, the VOPP1–WWOX interaction axis adds another tumorigenic mechanism: by crippling WWOX, VOPP1 can unleash pro-tumor pathways that WWOX normally restrains (WWOX influences apoptosis, DNA damage response, and Wnt/TGF-β signaling (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov)). Thus, VOPP1 acts as a “dual threat” oncogene – it amplifies pro-survival/inflammatory signaling and inactivates a major tumor suppressor. Recognizing these roles, researchers have proposed VOPP1 as a potential therapeutic target. In principle, inhibiting VOPP1 or its critical interactions could re-sensitize cancer cells to apoptosis. For example, silencing VOPP1 induced widespread cell death in multiple cancer cell models (www.nature.com), and suppressing VOPP1 greatly reduced tumor growth in xenograft experiments (bmcbiol.biomedcentral.com). While no VOPP1-targeted drugs exist yet, these proofs-of-concept highlight the appeal of targeting VOPP1 in tumors that are “addicted” to it for survival. Additionally, the co-amplification of VOPP1 with EGFR in GBM suggests that therapies aimed at EGFR-amplified tumors might consider VOPP1’s status, as it could modulate responses (for instance, high VOPP1 levels might confer resistance to EGFR inhibitors by activating NF-κB). In summary, ample evidence supports VOPP1 as a context-dependent oncogene, making it both a biomarker of aggressive disease and a candidate therapeutic target in cancers characterized by its overexpression.

Emerging Roles and Recent Developments (2023–2025)

While much attention has focused on cancer, recent research (2023–2025) has uncovered roles for VOPP1 in other diseases and novel genetic events involving VOPP1. Notably, in 2025 VOPP1 was identified as a novel susceptibility gene for Rheumatoid Arthritis (RA) (pmc.ncbi.nlm.nih.gov). RA is an autoimmune disease characterized by chronic joint inflammation and hyperplasia of synovial fibroblasts. Using integrated genomics and Mendelian randomization, Wu et al. (2025) found that genetic variants increasing VOPP1 expression are associated with higher RA risk (odds ratio ~1.11 per allele, p≈0.01) (pmc.ncbi.nlm.nih.gov). They further observed VOPP1 is significantly upregulated in RA patient tissues – RA synovial biopsies and cultured RA fibroblast-like synoviocytes (FLS) had much higher VOPP1 protein levels than non-RA controls (p<0.001) (pmc.ncbi.nlm.nih.gov). This suggests VOPP1 might contribute to the pathogenic activation of RA synovial cells. Functional experiments confirmed this: knocking down VOPP1 in RA-FLS attenuated inflammatory and proliferative features. In vitro, VOPP1 silencing in RA-FLS reduced the phosphorylation of p38 MAPK (a stress/inflammation kinase), and decreased the production of pro-inflammatory cytokines TNF-α and IL-6 (pmc.ncbi.nlm.nih.gov). Loss of VOPP1 also slowed RA-FLS proliferation and even induced more cell cycle arrest (pmc.ncbi.nlm.nih.gov). These effects could be partially reversed by chemically re-activating p38, indicating that VOPP1 promotes RA-FLS proliferation and cytokine release at least in part via the p38 MAPK pathway (pmc.ncbi.nlm.nih.gov). Strikingly, the same study tested VOPP1 inhibition in vivo: they administered VOPP1 siRNA treatment in a collagen-induced arthritis rat model. Rats treated with VOPP1 silencing showed significantly alleviated RA symptoms – with reduced paw swelling, less inflammatory cell infiltration, and lower clinical arthritis scores compared to controls (pmc.ncbi.nlm.nih.gov). These findings position VOPP1 as a driver of inflammatory joint disease, linking its cell-survival role to immune cell/fibroblast hyperactivation. It is an intriguing development that a gene first characterized in cancer may also be a therapeutic target in autoimmune disorders**. The RA study authors suggest VOPP1 influences RA by modulating a metabolic mediator (an unknown metabolite flagged by their analysis) and by enhancing inflammatory signaling in synovial cells (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). While further research is needed, this opens the door to repurposing VOPP1-focused interventions beyond oncology.

Another recent development is the discovery of a gene fusion involving VOPP1 in a brain tumor. In 2025, Braune et al. reported a unique VOPP1::EGFR fusion gene in a glioneuronal tumor (ganglioglioma) (pmc.ncbi.nlm.nih.gov). This fusion joined part of the VOPP1 gene (Exon 1) with EGFR (Exon 18) in-frame, creating a hybrid protein. The patient’s tumor showed evidence of NF-κB pathway activation, which the authors attributed to the VOPP1 portion of the fusion driving NF-κB signaling (pmc.ncbi.nlm.nih.gov). Gangliogliomas typically harbor MAPK pathway mutations (like BRAF V600E), so a fusion engaging NF-κB is novel. This case implies that when fused to EGFR, VOPP1’s NF-κB activation function might synergize with EGFR signaling, potentially contributing to tumorigenesis. While a single case, it expands the spectrum of VOPP1’s involvement in cancer genomics and underscores the protein’s ability to activate NF-κB in a pathological setting. It is also a reminder that VOPP1 lies in the vicinity of EGFR on chromosome 7, so structural genomic alterations in that region can simultaneously affect both genes. The finding of a VOPP1–EGFR fusion hints that future tumor sequencing efforts may uncover additional VOPP1-containing fusions or co-amplifications, especially in brain tumors. Clinically, if such fusions are present, they could be relevant for targeted therapies (for example, NF-κB or EGFR pathway inhibitors).

Finally, continued research into VOPP1’s molecular network is revealing more about its regulation. A 2024 review on WWOX noted that genes regulating WWOX (like VOPP1) may represent “oncogenic networks” that bypass direct tumor suppressor loss (pmc.ncbi.nlm.nih.gov). And additional interactors of VOPP1 are being explored: for instance, VOPP1 was found to interact with proteins involved in vesicle trafficking (e.g. SCAMP3, SEC23IP) as part of the WWOX interactome (pubmed.ncbi.nlm.nih.gov). These findings raise new questions: Does VOPP1 affect autophagy or lysosomal function? Are there other signaling pathways (besides NF-κB and p38) that it modulates? Ongoing studies in 2023–2024 are likely to shed more light on these aspects, as VOPP1 is now on the radar in fields beyond oncology (such as immunology and metabolism).

Clinical Significance and Applications

Understanding VOPP1’s function has practical implications in medicine. In oncology, VOPP1 is being evaluated as a biomarker and a potential therapeutic target. Its expression level in tumors often correlates with disease severity or outcome. For example, as noted, high VOPP1 predicts worse prognosis in liver cancer patients (www.proteinatlas.org) and in subsets of breast cancer patients (those with intact WWOX) (bmcbiol.biomedcentral.com). In gastric cancer, elevated VOPP1 in tumors (compared to normal tissue) has been observed, and by extrapolation it might serve as a diagnostic or prognostic marker (pubmed.ncbi.nlm.nih.gov). Some studies have suggested measuring VOPP1 or its regulators (like miR-218) as biomarkers for cancer progression (pubmed.ncbi.nlm.nih.gov). Moreover, since VOPP1 lies in the commonly amplified 7p11.2 region, its copy number could be assessed in tumors where EGFR amplification is found, to identify cases of co-amplification. In GBM and other tumors, detecting VOPP1 amplification or overexpression could inform clinicians about the tumor’s reliance on NF-κB survival pathways. There is also interest in VOPP1 as a drug target. Although VOPP1 is not an enzyme (so not directly “druggable” with small inhibitors in a classical sense), disrupting its critical interactions is a potential strategy. For instance, interfering with the VOPP1–WWOX binding (perhaps by mimicking the PPXY motif to compete for WWOX’s WW domain) could release WWOX to carry out its tumor suppressor function (pmc.ncbi.nlm.nih.gov). Similarly, blocking VOPP1’s effect on NF-κB signaling – for example by using NF-κB pathway inhibitors in tumors known to have high VOPP1 – might yield therapeutic benefit (essentially counteracting the ECOP/NF-κB axis). Some researchers have proposed that tumors with VOPP1 overexpression might be especially vulnerable to NF-κB inhibition or to pro-oxidant therapies, since those tumors are “addicted” to VOPP1 for redox balance (www.nature.com). Preliminary support for this comes from lab studies: VOPP1-overexpressing carcinoma cells underwent apoptosis when VOPP1 was knocked down or when ROS levels were increased without the counterbalance of VOPP1 (www.nature.com). Such insights could guide combination treatments (e.g. using pro-oxidant drugs or IκB stabilizers in VOPP1-high cancers).

In the context of autoimmune disease, the RA findings point to translational possibilities as well. If further validated, VOPP1 could be a novel therapeutic target in RA or other inflammatory conditions. The fact that VOPP1 knockdown reduced inflammatory cytokines in RA-FLS (pmc.ncbi.nlm.nih.gov) and improved arthritis in rats (pmc.ncbi.nlm.nih.gov) is encouraging. It suggests that drugs or biologics that suppress VOPP1 (or its downstream pathways like p38 MAPK) might ameliorate joint inflammation. While current RA treatments target broadly the immune system, a therapy directed at synovial fibroblast pathology (via VOPP1) could complement those by specifically curbing the aggressive behavior of these cells. However, any such approach would need to consider safety, given VOPP1’s wide normal expression. The “prosurvival” function of VOPP1 in normal cells (like perhaps in retina or other tissues (www.proteinatlas.org)) is not fully understood; systemic inhibition might have side effects if normal cells depend on VOPP1 under stress conditions. Despite that, the concept of targeting VOPP1 is now on the table both in oncology and immunology.

Real-world clinical implementation related to VOPP1 is still in early stages. No VOPP1-specific drugs or routine clinical tests are yet available, reflecting that VOPP1 was only relatively recently characterized. Nevertheless, its strong association with tumor survival signals has made it a subject of interest in cancer research. Some experimental therapeutics take an indirect approach – for instance, microRNA therapies or antisense oligonucleotides that restore tumor-suppressive miRNAs downregulating VOPP1 (like miR-218 in gastric cancer) are being explored in preclinical models (pubmed.ncbi.nlm.nih.gov). Additionally, VOPP1 might be considered in molecular diagnostic panels in the future. For example, if a patient’s tumor sequencing reveals EGFR amplification, adding an assay for VOPP1 expression or copy number could refine the molecular profile. In the case of the VOPP1::EGFR fusion found in a ganglioglioma, that discovery was made by advanced sequencing – going forward, pathologists might monitor for such fusions in unusual glioma cases (pmc.ncbi.nlm.nih.gov). In summary, while VOPP1 is not yet a household name in the clinic, it is gaining recognition as a meaningful biomolecule in disease. Efforts are ongoing to translate the growing understanding of VOPP1 into prognostic tools or targeted therapies.

Expert Commentary and Future Directions

Experts in the field underscore the importance of VOPP1 as a multifunctional regulator of cell survival. As early as 2011, researchers posited that “high-level, amplification-mediated ECOP expression… could contribute to resistance to apoptosis” in tumors with EGFR amplifications (www.nature.com). This insight positioned VOPP1 as part of the explanation for why certain cancers are harder to kill: it shifts the balance toward survival by amplifying NF-κB signals. Subsequent work by Baras et al. and others reinforced that VOPP1 overexpression is not an incidental byproduct of cancer genomics, but rather a functional player that cancer cells exploit (www.nature.com). By 2018, with the discovery of the VOPP1–WWOX interaction, commentators noted that VOPP1 behaves as a bona fide oncogene, in that it actively “promotes breast carcinogenesis by inhibiting the anti-tumoral effect of WWOX” (quote from Abu-Odeh et al., 2018) (bmcbiol.biomedcentral.com). A Frontiers in Oncology review highlighted VOPP1 among the “aberrantly expressed molecules” that can inhibit tumor suppressors like WWOX, pointing to a broader network of cancerous protein interactions (pmc.ncbi.nlm.nih.gov). Most recently, a comprehensive 2023 review of WWOX’s 25-year history stresses that VOPP1 has emerged as a significant regulator of WWOX and emphasizes that overexpression of VOPP1 is frequently observed in tumors and correlates with loss of WWOX function (pmc.ncbi.nlm.nih.gov). This evolution in expert perspective – from viewing VOPP1 as just a co-amplified gene to recognizing it as a central modulator of two major pathways (NF-κB and WWOX/p73) – validates the growing scientific interest in VOPP1.

Future research is expected to address several open questions about VOPP1. One area is the detailed molecular mechanism: How exactly does VOPP1 facilitate IκBα degradation and NF-κB activation? Does it recruit specific E3 ubiquitin ligases or kinases to the IκB complex, or perhaps affect endosomal signaling platforms for NF-κB? Another question is whether VOPP1 has any extracellular role – given its “secreted protein” annotation, could fragments of VOPP1 be released by cells (for example, in exosomes) and act on the tumor microenvironment? Also, the connection between VOPP1 and cellular metabolism warrants exploration. The WWOX interactome hints VOPP1 might link to metabolic organelles (ER, Golgi) and pathways (pubmed.ncbi.nlm.nih.gov). And intriguingly, the RA study suggested a metabolic intermediary (“X-23,587”) associated with VOPP1’s effect (pmc.ncbi.nlm.nih.gov), though this metabolite remains to be identified. Unraveling these links could reveal if VOPP1 influences metabolic stress or autophagy in cells.

On the clinical front, the challenge will be targeting VOPP1 safely. Experts caution that hitting a survival protein could affect normal cells, but the hope is that cancer cells (or rheumatoid synovium) might be more dependent on VOPP1 than healthy tissue, providing a therapeutic window. There is interest in developing peptides or small molecules to disrupt the VOPP1–WWOX interaction, effectively releasing the “brakes” on WWOX. Additionally, inhibitors of pathways downstream of VOPP1 (like NF-κB, p38 MAPK, or ROS homeostasis) could be tested in cases known to have high VOPP1. For example, combining an NF-κB pathway inhibitor with standard chemotherapy might preferentially kill VOPP1-driven tumors by removing their survival advantage. In RA, p38 inhibitors are already in trials; understanding that VOPP1 acts upstream of p38 in synoviocytes (pmc.ncbi.nlm.nih.gov) provides a rationale to revisit those therapies or develop more specific interventions at the VOPP1 level.

In conclusion, VOPP1 (Q96AW1) is an increasingly important gene in functional genomics, exemplifying how a relatively small vesicular protein can have wide-reaching effects on cell survival, inflammation, and tumor suppression. From its ability to turbo-charge NF-κB to its capacity to neutralize WWOX, VOPP1 sits at a crossroads of critical signaling pathways. Current research (particularly in the past few years) has expanded its relevance from cancer biology to immunology, and it stands out as a promising target for future therapeutic development. As always, translating these findings to the clinic will require careful validation and drug design, but the accumulating evidence – supported by diverse studies and expert analyses – positions VOPP1 as a novel “hub” protein whose modulation could yield benefits in treating cancer and inflammatory disease (bmcbiol.biomedcentral.com) (pmc.ncbi.nlm.nih.gov).

References: (Key sources with publication dates)

• Baras et al. (2010). J. Mol. Histology – Intracellular localization of GASP/ECOP/VOPP1 (pubmed.ncbi.nlm.nih.gov).
• Huang et al. (2011). Oncogene – ECop regulates NF-κB and apoptosis (www.nature.com) (www.nature.com).
• Baras & Moskaluk (2011). Lab Investigation – VOPP1 overexpression and oxidative stress in SCC (www.nature.com) (www.nature.com).
• Abu-Odeh et al. (2018). BMC Biology – VOPP1 sequesters WWOX, promotes breast tumorigenesis (bmcbiol.biomedcentral.com) (bmcbiol.biomedcentral.com).
• Hussain et al. (2018). Front. Oncol. – WWOX interactome (VOPP1 identified as interactor) (pubmed.ncbi.nlm.nih.gov).
• Braune et al. (2025). Acta Neuropathol. Commun. – VOPP1::EGFR fusion in ganglioglioma, NF-κB activation (pmc.ncbi.nlm.nih.gov).
• Wu et al. (2025). J. Inflamm. Res. – VOPP1 in rheumatoid arthritis (genetics and functional study) (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).
• Human Protein Atlas (2023) – VOPP1 expression and prognostic data (HPA) (www.proteinatlas.org) (www.proteinatlas.org).
• UniProt (accessed 2024) – SwissProt Q96AW1 summary (function and WWOX interaction) (www.genecards.org).

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48. AnnotationURLCitation(end_index=17899, start_index=17724, title='VOPP1 promotes breast tumorigenesis by interacting with the tumor suppressor WWOX | BMC Biology | Full Text', type='url_citation', url='https://bmcbiol.biomedcentral.com/articles/10.1186/s12915-018-0576-6#:~:text=ability%20to%20associate%20with%20p73%CE%B1%2C,negative%2C%20tumors')
49. AnnotationURLCitation(end_index=18125, start_index=17963, title='VOPP1 promotes breast tumorigenesis by interacting with the tumor suppressor WWOX | BMC Biology | Full Text', type='url_citation', url='https://bmcbiol.biomedcentral.com/articles/10.1186/s12915-018-0576-6#:~:text=overexpressed%20in%20cancer%20pro,negative%2C%20tumors')
50. AnnotationURLCitation(end_index=18624, start_index=18451, title='Expression of VOPP1 in cancer - Summary - The Human Protein Atlas', type='url_citation', url='https://www.proteinatlas.org/ENSG00000154978-VOPP1/cancer#:~:text=PROGNOSTIC%20SUMMARY,significant%20%28p%3C1e%2B0%29%20PROTEIN%20EXPRESSION%5E%7Bi')
51. AnnotationURLCitation(end_index=19130, start_index=18971, title='Epidermal growth factor receptor-coamplified and overexpressed protein (VOPP1) is a putative oncogene in gastric cancer - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/25398664/#:~:text=MicroRNAs%20are%20found%20to%20play,has%20been%20implicated%20in%20tumorigenesis')
52. AnnotationURLCitation(end_index=19265, start_index=19131, title='LINC01410 Knockdown Suppresses Cervical Cancer Growth and Invasion via Targeting miR-2467-3p/VOPP1 Axis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC7008191/#:~:text=Targeting%20miR,3p%2FRGS17%20axis.%5E%7B28%7D%20At')
53. AnnotationURLCitation(end_index=19888, start_index=19730, title='ECop (EGFR-Coamplified and overexpressed protein), a novel protein, regulates NF-κB transcriptional activity and associated apoptotic response in an IκBα-dependent manner | Oncogene', type='url_citation', url='https://www.nature.com/articles/1208496#:~:text=Ectopic%20expression%20of%20ECop%20increases,contribute%20to%20resistance%20to%20apoptosis')
54. AnnotationURLCitation(end_index=20304, start_index=20131, title='LINC01410 Knockdown Suppresses Cervical Cancer Growth and Invasion via Targeting miR-2467-3p/VOPP1 Axis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC7008191/#:~:text=LINC01410%20Knockdown%20Suppresses%20Cervical%20Cancer,3p%2FRGS17%20axis.%5E%7B28%7D%20At')
55. AnnotationURLCitation(end_index=20719, start_index=20548, title='Twenty-five years of WWOX insight in cancer: a treasure trove of knowledge - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12055895/#:~:text=interest%20mapping%20to%20the%20chromosomal,advancements%20allowed%20to%20reveal%20its')
56. AnnotationURLCitation(end_index=20878, start_index=20720, title='Twenty-five years of WWOX insight in cancer: a treasure trove of knowledge - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12055895/#:~:text=of%20genes%20responsible%20for%20WWOX,WWOX%20and%20is%20associated%20with')
57. AnnotationURLCitation(end_index=21463, start_index=21327, title='Loss of VOPP1 overexpression in squamous carcinoma cells induces apoptosis through oxidative cellular injury | Laboratory Investigation', type='url_citation', url='https://www.nature.com/articles/labinvest201170#:~:text=cancer%20types,affected%20by%20VOPP1%20knockdown%20exhibited')
58. AnnotationURLCitation(end_index=21743, start_index=21541, title='VOPP1 promotes breast tumorigenesis by interacting with the tumor suppressor WWOX | BMC Biology | Full Text', type='url_citation', url='https://bmcbiol.biomedcentral.com/articles/10.1186/s12915-018-0576-6#:~:text=Overexpressed%20VOPP1%20potentiates%20cellular%20transformation,positive%2C%20but%20not%20with')
59. AnnotationURLCitation(end_index=22824, start_index=22732, title='VOPP1 as a Novel Susceptibility Gene in Rheumatoid Arthritis: Insights Into Its Mechanisms From Mendelian Randomization and Experimental Validation - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12327419/#:~:text=Results')
60. AnnotationURLCitation(end_index=23297, start_index=23146, title='VOPP1 as a Novel Susceptibility Gene in Rheumatoid Arthritis: Insights Into Its Mechanisms From Mendelian Randomization and Experimental Validation - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12327419/#:~:text=match%20at%20L358%20toward%20the,the%20data%20and%20we%20performed')
61. AnnotationURLCitation(end_index=23651, start_index=23530, title='VOPP1 as a Novel Susceptibility Gene in Rheumatoid Arthritis: Insights Into Its Mechanisms From Mendelian Randomization and Experimental Validation - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12327419/#:~:text=Western%20blot,FLSs%20%28Figure%203D')
62. AnnotationURLCitation(end_index=24183, start_index=24056, title='VOPP1 as a Novel Susceptibility Gene in Rheumatoid Arthritis: Insights Into Its Mechanisms From Mendelian Randomization and Experimental Validation - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12327419/#:~:text=Western%20blot%20%28Figure%206A%29,a%20p38')
63. AnnotationURLCitation(end_index=24399, start_index=24272, title='VOPP1 as a Novel Susceptibility Gene in Rheumatoid Arthritis: Insights Into Its Mechanisms From Mendelian Randomization and Experimental Validation - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12327419/#:~:text=Western%20blot%20%28Figure%206A%29,a%20p38')
64. AnnotationURLCitation(end_index=24722, start_index=24595, title='VOPP1 as a Novel Susceptibility Gene in Rheumatoid Arthritis: Insights Into Its Mechanisms From Mendelian Randomization and Experimental Validation - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12327419/#:~:text=Western%20blot%20%28Figure%206A%29,a%20p38')
65. AnnotationURLCitation(end_index=25224, start_index=25074, title='VOPP1 as a Novel Susceptibility Gene in Rheumatoid Arthritis: Insights Into Its Mechanisms From Mendelian Randomization and Experimental Validation - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12327419/#:~:text=match%20at%20L484%20treated%20with,23%2C587%20metabolism%2C%20and')
66. AnnotationURLCitation(end_index=25853, start_index=25701, title='VOPP1 as a Novel Susceptibility Gene in Rheumatoid Arthritis: Insights Into Its Mechanisms From Mendelian Randomization and Experimental Validation - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12327419/#:~:text=toward%20the%20VOPP1%20eQTL%20had,the%20data%20and%20we%20performed')
67. AnnotationURLCitation(end_index=25981, start_index=25854, title='VOPP1 as a Novel Susceptibility Gene in Rheumatoid Arthritis: Insights Into Its Mechanisms From Mendelian Randomization and Experimental Validation - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12327419/#:~:text=Western%20blot%20%28Figure%206A%29,a%20p38')
68. AnnotationURLCitation(end_index=26446, start_index=26308, title='VOPP1::EGFR fusion is associated with NFκB pathway activation in a glioneural tumor with histological features of ganglioglioma - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12001695/#:~:text=frequent%20one,provides%20a%20link%20to%20potentially')
69. AnnotationURLCitation(end_index=26855, start_index=26717, title='VOPP1::EGFR fusion is associated with NFκB pathway activation in a glioneural tumor with histological features of ganglioglioma - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12001695/#:~:text=frequent%20one,provides%20a%20link%20to%20potentially')
70. AnnotationURLCitation(end_index=28194, start_index=28036, title='Twenty-five years of WWOX insight in cancer: a treasure trove of knowledge - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12055895/#:~:text=of%20genes%20responsible%20for%20WWOX,WWOX%20and%20is%20associated%20with')
71. AnnotationURLCitation(end_index=28566, start_index=28395, title='Delineating WWOX Protein Interactome by Tandem Affinity Purification-Mass Spectrometry: Identification of Top Interactors and Key Metabolic Pathways Involved - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/30619736/#:~:text=biological%20and%20molecular%20processes%20while,acid%20degradation%20and%20other%20pathways')
72. AnnotationURLCitation(end_index=29453, start_index=29280, title='Expression of VOPP1 in cancer - Summary - The Human Protein Atlas', type='url_citation', url='https://www.proteinatlas.org/ENSG00000154978-VOPP1/cancer#:~:text=PROGNOSTIC%20SUMMARY,significant%20%28p%3C1e%2B0%29%20PROTEIN%20EXPRESSION%5E%7Bi')
73. AnnotationURLCitation(end_index=29695, start_index=29520, title='VOPP1 promotes breast tumorigenesis by interacting with the tumor suppressor WWOX | BMC Biology | Full Text', type='url_citation', url='https://bmcbiol.biomedcentral.com/articles/10.1186/s12915-018-0576-6#:~:text=ability%20to%20associate%20with%20p73%CE%B1%2C,negative%2C%20tumors')
74. AnnotationURLCitation(end_index=30032, start_index=29861, title='Epidermal growth factor receptor-coamplified and overexpressed protein (VOPP1) is a putative oncogene in gastric cancer - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/25398664/#:~:text=tissues%20compared%20to%20matched%20normal,colocalization%20earlier%20reported%20for%20other')
75. AnnotationURLCitation(end_index=30307, start_index=30148, title='Epidermal growth factor receptor-coamplified and overexpressed protein (VOPP1) is a putative oncogene in gastric cancer - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/25398664/#:~:text=MicroRNAs%20are%20found%20to%20play,has%20been%20implicated%20in%20tumorigenesis')
76. AnnotationURLCitation(end_index=31217, start_index=31059, title='Twenty-five years of WWOX insight in cancer: a treasure trove of knowledge - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12055895/#:~:text=of%20genes%20responsible%20for%20WWOX,WWOX%20and%20is%20associated%20with')
77. AnnotationURLCitation(end_index=31787, start_index=31653, title='Loss of VOPP1 overexpression in squamous carcinoma cells induces apoptosis through oxidative cellular injury | Laboratory Investigation', type='url_citation', url='https://www.nature.com/articles/labinvest201170#:~:text=antioxidant%20N,by%20the%20intrinsic%20apoptotic%20pathway')
78. AnnotationURLCitation(end_index=32147, start_index=31997, title='Loss of VOPP1 overexpression in squamous carcinoma cells induces apoptosis through oxidative cellular injury | Laboratory Investigation', type='url_citation', url='https://www.nature.com/articles/labinvest201170#:~:text=showed%20that%20genes%20whose%20expression,SCC%20cell%20lines%20by%20VOPP1')
79. AnnotationURLCitation(end_index=32682, start_index=32555, title='VOPP1 as a Novel Susceptibility Gene in Rheumatoid Arthritis: Insights Into Its Mechanisms From Mendelian Randomization and Experimental Validation - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12327419/#:~:text=Western%20blot%20%28Figure%206A%29,a%20p38')
80. AnnotationURLCitation(end_index=32864, start_index=32714, title='VOPP1 as a Novel Susceptibility Gene in Rheumatoid Arthritis: Insights Into Its Mechanisms From Mendelian Randomization and Experimental Validation - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12327419/#:~:text=match%20at%20L484%20treated%20with,23%2C587%20metabolism%2C%20and')
81. AnnotationURLCitation(end_index=33587, start_index=33419, title='Expression of VOPP1 in cancer - Summary - The Human Protein Atlas', type='url_citation', url='https://www.proteinatlas.org/ENSG00000154978-VOPP1/cancer#:~:text=HUMAN%20PROTEIN%20ATLAS%20INFORMATION,i%7D%20Evidence%20at%20protein%20level')
82. AnnotationURLCitation(end_index=34574, start_index=34415, title='Epidermal growth factor receptor-coamplified and overexpressed protein (VOPP1) is a putative oncogene in gastric cancer - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/25398664/#:~:text=MicroRNAs%20are%20found%20to%20play,has%20been%20implicated%20in%20tumorigenesis')
83. AnnotationURLCitation(end_index=35165, start_index=35027, title='VOPP1::EGFR fusion is associated with NFκB pathway activation in a glioneural tumor with histological features of ganglioglioma - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12001695/#:~:text=frequent%20one,provides%20a%20link%20to%20potentially')
84. AnnotationURLCitation(end_index=35900, start_index=35751, title='ECop (EGFR-Coamplified and overexpressed protein), a novel protein, regulates NF-κB transcriptional activity and associated apoptotic response in an IκBα-dependent manner | Oncogene', type='url_citation', url='https://www.nature.com/articles/1208496#:~:text=decreased%20DNA%20binding%20of%20NF,contribute%20to%20resistance%20to%20apoptosis')
85. AnnotationURLCitation(end_index=36398, start_index=36264, title='Loss of VOPP1 overexpression in squamous carcinoma cells induces apoptosis through oxidative cellular injury | Laboratory Investigation', type='url_citation', url='https://www.nature.com/articles/labinvest201170#:~:text=antioxidant%20N,by%20the%20intrinsic%20apoptotic%20pathway')
86. AnnotationURLCitation(end_index=36785, start_index=36666, title='VOPP1 promotes breast tumorigenesis by interacting with the tumor suppressor WWOX | BMC Biology | Full Text', type='url_citation', url='https://bmcbiol.biomedcentral.com/articles/10.1186/s12915-018-0576-6#:~:text=Conclusions')
87. AnnotationURLCitation(end_index=37169, start_index=36995, title='Cancerous Protein Network That Inhibits the Tumor Suppressor Function of WW Domain-Containing Oxidoreductase (WWOX) by Aberrantly Expressed Molecules - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6125347/#:~:text=Cancerous%20Protein%20Network%20That%20Inhibits,the%20WWOX%20tumor%20suppressor%20function')
88. AnnotationURLCitation(end_index=37594, start_index=37436, title='Twenty-five years of WWOX insight in cancer: a treasure trove of knowledge - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12055895/#:~:text=of%20genes%20responsible%20for%20WWOX,WWOX%20and%20is%20associated%20with')
89. AnnotationURLCitation(end_index=38728, start_index=38557, title='Delineating WWOX Protein Interactome by Tandem Affinity Purification-Mass Spectrometry: Identification of Top Interactors and Key Metabolic Pathways Involved - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/30619736/#:~:text=biological%20and%20molecular%20processes%20while,acid%20degradation%20and%20other%20pathways')
90. AnnotationURLCitation(end_index=38957, start_index=38840, title='VOPP1 as a Novel Susceptibility Gene in Rheumatoid Arthritis: Insights Into Its Mechanisms From Mendelian Randomization and Experimental Validation - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12327419/#:~:text=match%20at%20L400%20and%203,5908')
91. AnnotationURLCitation(end_index=40100, start_index=39973, title='VOPP1 as a Novel Susceptibility Gene in Rheumatoid Arthritis: Insights Into Its Mechanisms From Mendelian Randomization and Experimental Validation - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12327419/#:~:text=Western%20blot%20%28Figure%206A%29,a%20p38')
92. AnnotationURLCitation(end_index=41206, start_index=41087, title='VOPP1 promotes breast tumorigenesis by interacting with the tumor suppressor WWOX | BMC Biology | Full Text', type='url_citation', url='https://bmcbiol.biomedcentral.com/articles/10.1186/s12915-018-0576-6#:~:text=Conclusions')
93. AnnotationURLCitation(end_index=41334, start_index=41207, title='VOPP1 as a Novel Susceptibility Gene in Rheumatoid Arthritis: Insights Into Its Mechanisms From Mendelian Randomization and Experimental Validation - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12327419/#:~:text=Western%20blot%20%28Figure%206A%29,a%20p38')
94. AnnotationURLCitation(end_index=41659, start_index=41488, title='Epidermal growth factor receptor-coamplified and overexpressed protein (VOPP1) is a putative oncogene in gastric cancer - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/25398664/#:~:text=tissues%20compared%20to%20matched%20normal,colocalization%20earlier%20reported%20for%20other')
95. AnnotationURLCitation(end_index=41846, start_index=41738, title='ECop (EGFR-Coamplified and overexpressed protein), a novel protein, regulates NF-κB transcriptional activity and associated apoptotic response in an IκBα-dependent manner | Oncogene', type='url_citation', url='https://www.nature.com/articles/1208496#:~:text=In%20the%20present%20study%2C%20we,level')
96. AnnotationURLCitation(end_index=42010, start_index=41847, title='ECop (EGFR-Coamplified and overexpressed protein), a novel protein, regulates NF-κB transcriptional activity and associated apoptotic response in an IκBα-dependent manner | Oncogene', type='url_citation', url='https://www.nature.com/articles/1208496#:~:text=activation%20confers%20cellular%20resistance%20to,contribute%20to%20resistance%20to%20apoptosis')
97. AnnotationURLCitation(end_index=42266, start_index=42114, title='Loss of VOPP1 overexpression in squamous carcinoma cells induces apoptosis through oxidative cellular injury | Laboratory Investigation', type='url_citation', url='https://www.nature.com/articles/labinvest201170#:~:text=death%20at%2072%E2%80%89h%20post,abrogate%20the%20induction%20of%20apoptosis')
98. AnnotationURLCitation(end_index=42401, start_index=42267, title='Loss of VOPP1 overexpression in squamous carcinoma cells induces apoptosis through oxidative cellular injury | Laboratory Investigation', type='url_citation', url='https://www.nature.com/articles/labinvest201170#:~:text=antioxidant%20N,by%20the%20intrinsic%20apoptotic%20pathway')
99. AnnotationURLCitation(end_index=42666, start_index=42504, title='VOPP1 promotes breast tumorigenesis by interacting with the tumor suppressor WWOX | BMC Biology | Full Text', type='url_citation', url='https://bmcbiol.biomedcentral.com/articles/10.1186/s12915-018-0576-6#:~:text=overexpressed%20in%20cancer%20pro,negative%2C%20tumors')
100. AnnotationURLCitation(end_index=42842, start_index=42667, title='VOPP1 promotes breast tumorigenesis by interacting with the tumor suppressor WWOX | BMC Biology | Full Text', type='url_citation', url='https://bmcbiol.biomedcentral.com/articles/10.1186/s12915-018-0576-6#:~:text=ability%20to%20associate%20with%20p73%CE%B1%2C,negative%2C%20tumors')
101. AnnotationURLCitation(end_index=43114, start_index=42943, title='Delineating WWOX Protein Interactome by Tandem Affinity Purification-Mass Spectrometry: Identification of Top Interactors and Key Metabolic Pathways Involved - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/30619736/#:~:text=biological%20and%20molecular%20processes%20while,acid%20degradation%20and%20other%20pathways')
102. AnnotationURLCitation(end_index=43368, start_index=43230, title='VOPP1::EGFR fusion is associated with NFκB pathway activation in a glioneural tumor with histological features of ganglioglioma - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12001695/#:~:text=frequent%20one,provides%20a%20link%20to%20potentially')
103. AnnotationURLCitation(end_index=43606, start_index=43479, title='VOPP1 as a Novel Susceptibility Gene in Rheumatoid Arthritis: Insights Into Its Mechanisms From Mendelian Randomization and Experimental Validation - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12327419/#:~:text=Western%20blot%20%28Figure%206A%29,a%20p38')
104. AnnotationURLCitation(end_index=43757, start_index=43607, title='VOPP1 as a Novel Susceptibility Gene in Rheumatoid Arthritis: Insights Into Its Mechanisms From Mendelian Randomization and Experimental Validation - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12327419/#:~:text=match%20at%20L484%20treated%20with,23%2C587%20metabolism%2C%20and')
105. AnnotationURLCitation(end_index=44010, start_index=43837, title='Expression of VOPP1 in cancer - Summary - The Human Protein Atlas', type='url_citation', url='https://www.proteinatlas.org/ENSG00000154978-VOPP1/cancer#:~:text=PROGNOSTIC%20SUMMARY,significant%20%28p%3C1e%2B0%29%20PROTEIN%20EXPRESSION%5E%7Bi')
106. AnnotationURLCitation(end_index=44179, start_index=44011, title='Expression of VOPP1 in cancer - Summary - The Human Protein Atlas', type='url_citation', url='https://www.proteinatlas.org/ENSG00000154978-VOPP1/cancer#:~:text=HUMAN%20PROTEIN%20ATLAS%20INFORMATION,i%7D%20Evidence%20at%20protein%20level')
107. AnnotationURLCitation(end_index=44434, start_index=44270, title='VOPP1 Gene - GeneCards | VOPP1 Protein | VOPP1 Antibody', type='url_citation', url='https://www.genecards.org/cgi-bin/carddisp.pl?gene=VOPP1#:~:text=Increases%20the%20transcriptional%20activity%20of,%28%20VOPP1_HUMAN%2CQ96AW1')