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.
Highlights
Gastrointestinal stromal tumor (GIST) is the most common subtype of human sarcoma and typically occurs in the stomach or small intestine [1]
ETV4 mRNA expression correlated with tumor mitotic rate in primary and metastatic GIST (Figure 1A, left and middle)
Expression of the GIST lineage survival factor ETV1 did not correlate with mitotic rate or whether a tumor was metastatic (Figure 1A, right), the magnitude of ETV1 mRNA expression was much greater than that of ETV4
Summary
Gastrointestinal stromal tumor (GIST) is the most common subtype of human sarcoma and typically occurs in the stomach or small intestine [1]. The majority of GISTs are driven by an activating mutation in either KIT or PDGFRA [2, 3]. The selective tyrosine kinase inhibitor imatinib has been used as the standard therapy for GIST and dramatically improved survival [4]. Imatinib is rarely curative, and resistance commonly occurs within 2 years of treatment, often via a secondary KIT mutation [5]. Alternative tyrosine kinase inhibitors can overcome imatinib resistance temporarily [6, 7], the vast majority of patients with metastatic GIST develop tumor progression and eventually die. While p16 (CDKN2A) gene deletion and inactivation of myc-associated protein (MAX) are found to be common genetic aberrations in GIST progression [8, 9], a better understanding of the molecular mechanisms www.impactjournals.com/oncotarget responsible for GIST aggressiveness may identify clinical biomarkers or new therapeutic targets
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