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

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Shan Zeng - , Memorial Sloan-Kettering Cancer Center (Author)
  • Adrian M Seifert - , Department of Visceral, Thoracic and Vascular Surgery, National Center for Tumor Diseases (Partners: UKD, MFD, HZDR, DKFZ), Memorial Sloan-Kettering Cancer Center (Author)
  • Jennifer Q Zhang - , Memorial Sloan-Kettering Cancer Center (Author)
  • Teresa S Kim - , Memorial Sloan-Kettering Cancer Center (Author)
  • Timothy G Bowler - , Memorial Sloan-Kettering Cancer Center (Author)
  • Michael J Cavnar - , Memorial Sloan-Kettering Cancer Center (Author)
  • Benjamin D Medina - , Memorial Sloan-Kettering Cancer Center (Author)
  • Gerardo A Vitiello - , Memorial Sloan-Kettering Cancer Center (Author)
  • Ferdinand Rossi - , Memorial Sloan-Kettering Cancer Center (Author)
  • Jennifer K Loo - , Memorial Sloan-Kettering Cancer Center (Author)
  • Nesteene J Param - , Memorial Sloan-Kettering Cancer Center (Author)
  • Ronald P DeMatteo - , Memorial Sloan-Kettering Cancer Center (Author)

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.

Details

Original languageEnglish
Pages (from-to)114195-114209
Number of pages15
JournalOncotarget
Volume8
Issue number69
Publication statusPublished - 26 Dec 2017
Peer-reviewedYes

External IDs

PubMedCentral PMC5768396
Scopus 85039038222
ORCID /0000-0002-5329-3164/work/147141101

Keywords

Sustainable Development Goals