机构：[1]School of Medicine, University of Electronic Science and Technology of China, Chengdu, China四川省人民医院[2]Key Laboratory for Human Disease Gene Study, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China四川省人民医院[3]Georgia Cancer Center, Augusta University, Augusta, GA, USA[4]Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, USA.[5]State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Due to its intricate heterogeneity and limited treatment, hepatocellular carcinoma (HCC) has been considered a major cause of cancer-related mortality worldwide. Increasing evidence indicates that G-coupled Estrogen Receptor 1 (GPER1) can promote estrogen-dependent hepatocellular proliferation by activating AKT signaling. The mTOR complex 2 (mTORC2), whose integrity and activity are modulated by its subunit Sin1, controls the activation of AKT by phosphorylation at position S473. In this study, we investigate the modulation of Sin1 and how estrogen signaling may influence the mTORC2-AKT cascade in HCC cells and a DEN-induced mouse model. We have found that estradiol-dependent Sin1 expression is transcriptionally modulated by GPER1 as well as ERα. GPER1 is able to regulate Sin1 stability via nuclear translocation, therefore increasing Sin1-mTORC2-AKT activation. Moreover, Sin1 interacts with ERα and further enhances its transcriptional activity. Sin1 is highly expressed in acute liver injury and in cases of HCC harboring high expression of GPER1 and constitutive activation of mTORC2-AKTsignaling. GPER1 inhibition using the antagonist G-15 reverses DEN-induced acute liver injury by suppressing Sin1 expression and mTORC2-AKT activation. Notably, Sin1 expression varies between male and female mice in the context of both liver injury and liver cancer. Additionally, high SIN1 expression is predictive of good prognosis in both male and female HCC patients who are free from hepatitis virus infection and who report low alcohol consumption. Hence, here we demonstrate that Sin1 can be regulated by GPER1 both through non-genomic and indirect genomic signaling. Implications: This study suggests that Sin1 may be a novel HCC biomarker which is gender-dependent and sensitive to particular risk factor.
基金：
This work was supported by National Key Research and Develop Program of China for Z Yang (grant number: 2016YFC0905200), National Natural Science Foundation of China (grant number: 31601137 and 81790642 for Z Wang, and 81601125 for L Yang) , the Fundamental Research Funds for the Central Universities
(grant number: ZYGX2017KYQD169 for Z Wang and A03019023801206 for L Yang), and Chinese Academy of Medical Sciences (grant number:2019-I2M-5-032 for Z Yang)
第一作者机构：[1]School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
通讯作者：
通讯机构：[1]School of Medicine, University of Electronic Science and Technology of China, Chengdu, China[2]Key Laboratory for Human Disease Gene Study, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China[*1]Shahe Campus of UESTC, No.4, Section 2, North Jianshe Road, Chenghua District, Chengdu, P.R.China, Zip/Postal Code: 610054
推荐引用方式(GB/T 7714)：
Guanying Feng,Jingshu Cai,Yunchuanxiang Huang,et al.G-coupled Estrogen Receptor 1 promotes gender disparities in hepatocellular carcinoma via modulation of SIN1 and mTOR complex 2 activity.[J].MOLECULAR CANCER RESEARCH.2020,18(12):1863-1875.doi:10.1158/1541-7786.MCR-20-0173.
APA：
Guanying Feng,Jingshu Cai,Yunchuanxiang Huang,Xianjun Zhu,Bo Gong...&Ziyan Wang.(2020).G-coupled Estrogen Receptor 1 promotes gender disparities in hepatocellular carcinoma via modulation of SIN1 and mTOR complex 2 activity..MOLECULAR CANCER RESEARCH,18,(12)
MLA：
Guanying Feng,et al."G-coupled Estrogen Receptor 1 promotes gender disparities in hepatocellular carcinoma via modulation of SIN1 and mTOR complex 2 activity.".MOLECULAR CANCER RESEARCH 18..12(2020):1863-1875
