Role Of Sin1 In Hepatocellular Carcinoma And Acute Liver Injury

Liver cancer is the most common malignant tumor worldwide and has a high mortality rate.Chinese liver cancer patients account for about 50% of new cases in the world each year.90% of primary liver cancers are hepatocellular carcinoma(HCC).The occurrence of HCC is associated with chronic liver disease(including hepatitis virus infection,alcohol-related hepatitis,non-alcoholic fatty liver),exposure to carcinogens(such as aflatoxin,etc.)and genetic and other factors.Due to the complex molecular mechanisms of HCC,current clinical therapies still have some limitations.The incidence of HCC has a very notable gender difference.There are many factors contribute to gender differences,among which sex hormone receptors are closely related to the existence and development of liver cancer.Accumulating evidence indicates that G-coupled Estrogen Receptor 1(GPER1)promotes hepatocellular proliferation upon the stimulation of 17?-estradiol(E2).mTOR complex 2(mTORC2)controls AKT full activation,the integrity and activity of which is modulated by its key component Sin1.However,the underlying mechanism of GPER1 regulating HCC through the mTOR-AKT signaling pathway is unknown.We aimed to investigate how Sin1 is modulated by GPER1 and how estrogen signaling talks with mTORC2-AKT signaling in the steroid-depleted HCC cell lines and DEN-induced mouse model.Cell experiments showed that E2 can induce Sin1 expression and dual-luciferase activity assays demonstrated that the transcriptional activity of Sin1 is regulated by GPER1 as well as ER?.In addition,GPER1 regulated Sin1 stability via nuclear translocation,which increased Sin1-mTORC2-AKT activation.CO-IP experiments showed that Sin1 has a strong interaction with ER?,further affecting its transcriptional activity.We found that GPER1 and Sin1 expression were induced in injure liver and tumor.Inhibiting GPER1 by antagonist G-15 reversed DEN-induced acute liver injury by suppressing Sin1 expression and mTORC2-AKT activation.Notably,Sin1 expression had significant difference between male and female in mouse injure liver and tumor.This study shows that Sin1 is regulated by GPER1 through both non-genomic and indirect genomic signaling.GPER1 senses E2 to enhance Sin1 expression,which further activates mTORC2-AKT signaling to increase cell proliferation and liverregeneration.In addition,Sin1-ER? interaction has a vital role in the regulation of ER?-mediated inflammation and hepatocarcinogenesis.Therefore,Sin1 can be a new biomarker for HCC dependent on gender.