Estrogen receptor-related receptor γ uppresses hypoxia-induced angiogenesis by regulating VEGFA in endometrial cancer

Objective: Estrogen receptor-related receptor gamma (ERR gamma), is implicated in cancer cell proliferation and metastasis. The function of ERR gamma in tumor angiogenesis, however, is to be revealed. This study was designed to elaborate the regulatory effect of ERR gamma on angiogenesis in endometrial cancer (EC).Methods: Immunohistochemistry (IHC) was adopted to determine the protein expression of ERR gamma, VEGFA, CD31 and hypoxia-inducible factor-1 (HIF-1) in tumor tissues. HEC-1A cells stably expressing ERR gamma were established bytransfection, and then an endothelial cell tube formation assay was performed. CCK-8 assay was employed for cell viability, and wound healing assay for cell migration ability. Besides, western blot, ELISA and qRT-PCR were used to examine the VEGFA expression. After hypoxia treatment of ERR gamma overexpressing HEC-1A cells, the ERR gamma expression and VEGFA expression were determined by western blot. Finally, EC xenografts in nude mice were constructed by subcutaneous injection of ERR gamma stably expressing HEC-1A cells and control HEC-1A cells.Results: IHC results revealed a negative correlation between the expression of ERR gamma and VEGFA in EC tissues. ERR gamma overexpression significantly decreased the level of HIF-1 in tumor tissue of nude mice. ERR gamma overexpression down-regulated inhibited angiogenesis capability and inhibited the proliferation and migration of HEC-1A cells. Furthermore, ERR gamma expression was suppressed under the condition of hypoxia while restoration of ERR gamma partially inhibited hypoxia-induced VEGFA expression in HEC-1A cells.Conclusions: ERR gamma is an angiogenesis suppressor and involved in hypoxia-induced VEGFA expression in EC. Hence, ERR gamma might be a promising antiangiogenic target for human EC.