Estrogen Promotes the Proliferation and Migration of Endometrial Cancer Through the GPER-Mediated NOTCH Pathway

Abstract

This study aims to investigate the expression of GPER in EC, assess the impact of estrogen on the proliferation and migration of EC via GPER, and examine the potential role of GPER in mediating the NOTCH pathway to influence EC proliferation and migration. The expression of GPER and its correlation with clinicopathological features were investigated using clinical data. Cell proliferation was assessed through MTT and EdU assays, while cell migration ability was evaluated using wound healing and transwell assays. Western blot analysis was conducted to detect proteins associated with the GPER and NOTCH signaling pathways. Additionally, xenograft tumor models were established to investigate the potential role of estrogen in mediating the NOTCH pathway via GPER. The results demonstrated a significant upregulation of GPER expression in EC, which was associated with clinical stage and metastasis. In vitro experiments provided evidence that estrogen promotes EC cell proliferation and metastasis by enhancing the expression levels of GPER, Notch1, and Hes-1 proteins. Conversely, knocking down or suppressing GPER effectively reverses these effects. Furthermore, treatment with JAG-1, an agonist for the NOTCH pathway, counteracts si-GPER's inhibitory impact on both proliferation and migration abilities of EC cells while increasing Notch1 and Hes-1 protein expression levels; however, it does not alter GPER expression. In vivo experiments have substantiated that estrogen facilitates EC proliferation via the GPER-mediated NOTCH pathway.