ETV4 collaborates with Wnt/β-catenin signaling to alter cell cycle activity and promote tumor aggressiveness in gastrointestinal stromal tumor Journal Article

Authors: Zeng, S.; Seifert, A. M.; Zhang, J. Q.; Kim, T. S.; Bowler, T. G.; Cavnar, M. J.; Medina, B. D.; Vitiello, G. A.; Rossi, F.; Loo, J. K.; Param, N. J.; DeMatteo, R. P.
Article Title: ETV4 collaborates with Wnt/β-catenin signaling to alter cell cycle activity and promote tumor aggressiveness in gastrointestinal stromal tumor
Abstract: Gastrointestinal stromal tumor (GIST) is the most common sarcoma, often resulting from a KIT or platelet-derived growth factor receptor alpha (PDGFRA) mutation. The lineage transcription factor ETV1 is expressed similarly in GISTs regardless of malignant potential. Although the related transcription factor ETV4 has been associated with metastasis and tumor progression in other cancers, its role in GIST is unknown. In this study, we found that ETV4 levels were high in a subset of human GISTs and correlated with high mitotic rate. Through Gene Set Enrichment Analysis in selected human GISTs, we identified a relationship between ETV4 levels and β-catenin signaling, especially in advanced GISTs. GIST specimens with high ETV4 levels overexpressed cell cycle regulating genes and had aberrant activation of the canonical Wnt pathway. In human GIST cell lines, ETV4 RNA interference suppressed cell cycle genes and Wnt/β-catenin signaling. ETV4 knockdown also reduced tumor cell proliferation, invasion, and tumor growth in vivo. Conversely, ETV4 overexpression increased cyclin D1 expression and Wnt/β-catenin signaling. Moreover, we determined that ETV4 knockdown destabilized nuclear β-catenin and increased its degradation via COP1, an E3 ligase involved in both ETV4 and β-catenin turnover. Aberrant accumulation of ETV4 and nuclear β-catenin was found in patient derived xenografts created from metastatic GISTs that became resistant to tyrosine kinase inhibitors. Collectively, our findings highlight the significance of ETV4 expression in GIST and identify ETV4 as a biomarker in human GISTs. © Zeng et al.
Keywords: controlled study; human tissue; protein expression; unclassified drug; human cell; histopathology; nonhuman; pathophysiology; protein function; protein localization; cell proliferation; mitosis; animal cell; mouse; gastrointestinal stromal tumor; protein degradation; protein protein interaction; animal experiment; animal model; protein stability; transcription factor; rna interference; in vivo study; tumor xenograft; protein tyrosine kinase inhibitor; cancer inhibition; disease severity; transcription regulation; tumor cell; gene control; metastasis potential; cell nucleus; tumor growth; cyclin d1; ubiquitin protein ligase e3; cell cycle regulation; beta catenin; wnt protein; cell invasion; bioaccumulation; tumor resistance; wnt/β-catenin signaling; wnt signaling; disease activity; regulator gene; transcription factor etv4; human; article; etv4; ubiquitin protein ligase cop1; gastrointestinal stromal tumor cell line
Journal Title: Oncotarget
Volume: 8
Issue: 69
ISSN: 1949-2553
Publisher: Impact Journals  
Date Published: 2017-12-26
Start Page: 114195
End Page: 114209
Language: English
DOI: 10.18632/oncotarget.23173
PROVIDER: scopus
PMCID: PMC5768396
PUBMED: 29371979
Notes: Article -- Export Date: 1 February 2018 -- Source: Scopus
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MSK Authors
  1. Ronald P DeMatteo
    597 DeMatteo
  2. Michael Joseph Cavnar
    26 Cavnar
  3. Ferdinando Rossi
    19 Rossi
  4. Shan Zeng
    22 Zeng
  5. Teresa Sora Kim
    23 Kim
  6. Adrian Marcel Seifert
    13 Seifert
  7. Jennifer Qi Zhang
    13 Zhang
  8. Benjamin Medina
    7 Medina
  9. Jennifer Loo
    9 Loo
  10. Timothy Geoffrey Bowler
    2 Bowler
  11. Nesteene Joy Param
    3 Param