title: Increased TET1 Expression in Inflammatory Microenvironment of Hyperinsulinemia Enhances the Response of Endometrial Cancer to Estrogen by Epigenetic Modulation of GPER.
abstract: Background:Insulin resistance (IR) has been well studied in the initiation and development of endometrial endometrioid carcinoma (EEC). As yet, it has been largely neglected for estrogen sensitivity in local endometrium in hyperinsulinemia-induced systemic microenvironment. The aim of this study was to investigate the role of insulin in regulating estrogen sensitivity and explore the potential mechanisms in insulin-driven inflammatory microenvironment.Methods:We first investigated the effect of insulin on estradiol-driven endometrial cancer cells proliferation in vitro to address the roles of insulin in modulating estrogen sensitivity. Then GPER, ERα and TET1 in EEC samples with or without insulin resistance were screened by immunohistochemistry to confirm whether insulin resistance regulates estrogen receptors. Further mechanism analysis was carried out to address whether TET1 was mediated epigenetic modulation of GPER in insulin-induced microenvironment.Results:Insulin enhanced estradiol-driven endometrial cancer cells proliferation by up-regulating G-protein-coupled estrogen receptor (GPER) expression, but not ERα or ERβ. Immunohistochemistry of EEC tissues showed that GPER expression was greatly increased in endometrial tissues from EEC subjects with insulin resistance and was positively correlated with Ten-eleven-translocation 1 (TET1) expression. Mechanistically, insulin up-regulates TET1 expression, and the latter, an important DNA hydroxymethylase, could up-regulate GPER expression through epigenetic modulation.Conclusion:This study identified TET1 as the upstream regulator of GPER expression and provides a possible mechanism that insulin-induced positive regulation of estrogen sensitivity in endometrial cancer cells. Increasing expression of GPER through TET1-mediated epigenetic modulation may emerge as the main regulator to enhance the response of endometrial cancer to estrogen in insulin-driven inflammatory microenvironment.
authors.affiliation: Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200011, China.
authors.forename: Qiao-Ying
authors.initials: QY
authors.lastname: Lv
authors.affiliation: Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200011, China.
authors.forename: Bing-Ying
authors.initials: BY
authors.lastname: Xie
authors.affiliation: Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200011, China.
authors.forename: Bing-Yi
authors.initials: BY
authors.lastname: Yang
authors.affiliation: Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200011, China.
authors.forename: Cheng-Cheng
authors.initials: CC
authors.lastname: Ning
authors.affiliation: Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200011, China.
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Shan
authors.affiliation: Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200011, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Gu
authors.affiliation: Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200011, China.
authors.forename: Xue-Zhen
authors.initials: XZ
authors.lastname: Luo
authors.affiliation: Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200011, China.
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Chen
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University school of medicine, Shanghai, 201620, China.
authors.forename: Zhen-Bo
authors.initials: ZB
authors.lastname: Zhang
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University school of medicine, Shanghai, 201620, China.
authors.forename: You-Ji
authors.initials: YJ
authors.lastname: Feng
keywords: Endometrial endometrioid cancer; GPER/GPR30; Insulin resistance; TET1.; estrogen sensitivity