Abstract
The biological function of E26 transformation-specific (ETS) transcription factor EHF/ESE-3 in human cancers remains largely unknown, particularly gastric cancer. The aim of this study was to explore the role of EHF in tumorigenesis and its potential as a therapeutic target in gastric cancer. By using quantitative RT-PCR (qRT-PCR), immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) assays, we investigated the expression and copy number of EHF in a cohort of gastric cancers and control subjects. Specific EHF siRNAs was used to determine the biologic impacts and mechanisms of altered EHF expression in vitro and in vivo. Dual-luciferase reporter, chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift assay (EMSA) assays were performed to identify its downstream targets. Our results demonstrated that EHF was significantly upregulated and frequently amplified in gastric cancer tissues as compared with control subjects. Moreover, EHF amplification was positively correlated with its overexpression and significantly associated with poor clinical outcomes of gastric cancer patients. We also found that EHF knockdown notably inhibited gastric cancer cell proliferation, colony formation, migration, invasion and tumorigenic potential in nude mice and induced cell cycle arrest and apoptosis. Importantly, we identified EHF as a new HER2 transcription factor and the modulator of HER3 and HER4 in gastric cancer. Collectively, our findings suggest that EHF is a novel functional oncogene in gastric cancer by regulating the human epidermal growth factor receptor (HER) family of receptor tyrosine kinases and may represent a potential prognostic marker and therapeutic target for this cancer.
Highlights
Gastric cancer is the fourth most common cancer and the second leading cause of cancer-related deaths in the world.[1,2] Given that most of patients are usually diagnosed at advanced stages in developing countries and the outcomes are still poor, the early diagnosis is extremely important for good prognosis.[3,4] Like other cancers, multiple genetic and epigenetic alterations have a critical role in the pathogenesis of gastric cancer
EHF has been demonstrated to function as a potential tumor suppressor gene in prostate cancer and esophageal squamous cell carcinoma (ESCC),[19,22,23] and be frequently downregulated by promoter methylation.[22]
We investigated EHF expression in a total of 384 stomach adenocarcinomas using TCGA data set from the Cancer Browser database.[27]
Summary
Gastric cancer is the fourth most common cancer and the second leading cause of cancer-related deaths in the world.[1,2] Given that most of patients are usually diagnosed at advanced stages in developing countries and the outcomes are still poor, the early diagnosis is extremely important for good prognosis.[3,4] Like other cancers, multiple genetic and epigenetic alterations have a critical role in the pathogenesis of gastric cancer. Like ESE-1 and ESE-2, it is exclusively expressed in a subset of epithelial cells.[18] The previous studies have showed that altered expression of EHF may affect the normal process of epithelial cell differentiation and contribute to cell transformation.[18,19,20] EHF may regulate epithelial growth and differentiation and have an important role in oncogenesis of epithelium-derived tumors.[18,21] EHF has been demonstrated to function as a potential tumor suppressor gene in prostate cancer and esophageal squamous cell carcinoma (ESCC),[19,22,23] and be frequently downregulated by promoter methylation.[22] On the other hand, it is overexpressed in ovarian and mammary cancers[24,25,26] and may be a predictive marker for poor survival in ovarian cancer.[24,25]. EHF downregulation significantly reduced in vitro and in vivo oncogenic potential of gastric cancer cells by regulating HER family of receptor tyrosine kinases
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