title: TET1-GPER-PI3K/AKT pathway is involved in insulin-driven endometrial cancer cell proliferation.
abstract: 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, GPER expression was not decreased compared to control when insulin receptor was blocked even in insulin treatment. The purpose of this study was to explore the possible mechanism by which insulin up-regulates GPER that drives EC cell proliferation. For this purpose, we first investigated the GPER expression in tissues of endometrial lesions, further explored the effect of GPER on 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 GPER was highly expressed in endometrial atypical hyperplasia and EC tissues. Mechanistically, insulin up-regulated TET1 expression and the latter played an important role in up-regulating GPER expression and activating PI3K/AKT signaling pathway. TET1 mediated GPER up-regulation was another mechanism that insulin promotes EC cell proliferation.
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: Qiao-Ying
authors.initials: QY
authors.lastname: Lv
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: Bing-Yi
authors.initials: BY
authors.lastname: Yang
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: Ya-Li
authors.initials: YL
authors.lastname: Cheng
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: 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: Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200011, China. Electronic address: xiaojunchen2013@sina.com.
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. Electronic address: xixiaowei66@yahoo.com.cn.
authors.forename: Xiao-Wei
authors.initials: XW
authors.lastname: Xi
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
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016889:Endometrial Neoplasms / Q000378:metabolism / Q000473:pathology*; D004717:Endometrium / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D006899:Mixed Function Oxygenases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C109584:GPER1 protein, human; D007328:Insulin; D011518:Proto-Oncogene Proteins; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D006899:Mixed Function Oxygenases; C462539:TET1 protein, human; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: Endometrial cancer; GPER; Insulin resistance; PI3K/AKT; TET1