TET1-GPER-PI3K/AKT pathway is involved in insulin-driven endometrial cancer cell proliferation

Large amount of clinical evidence has demonstrated that insulin resistance is closely related to oncogenesis of endometrial cancer (EC). Despite recent studies showed the up-regulatory role of insulin in G protein-coupled estrogen receptor ( GPER/GPR30) expression, GPERexpression was not decreased compared to control when insulin receptorwas blocked even in insulin treatment. The purpose of this study was to explore the possible mechanism by which insulin up-regulates GPERthat drives EC cell proliferation. For this purpose, we first investigated the GPERexpression in tissues of endometrial lesions, further explored the effect of GPERon EC cell proliferation in insulin resistance context. Then we analyzed the role of Ten-Eleven Translocation 1 (TET1) in insulin-induced GEPR expression and EC cell proliferation. The results showed that GPERwas highly expressed in endometrial atypical hyperplasiaand EC tissues. Mechanistically, insulin up-regulated TET1 expression and the latter played an important role in up-regulating GPERexpression and activating PI3K/AKT signaling pathway. TET1 mediated GPERup-regulation was another mechanism that insulin promotes EC cell proliferation.