Interaction of Hepatitis B Virus X Protein with the Pregnane X Receptor Enhances the Synergistic Effects of Aflatoxin B1 and Hepatitis B Virus on Promoting Hepatocarcinogenesis
作者机构：Department of PharmacologyShantou University Medical CollegeShantouGuangdongChina Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu ProvinceSchool of Life ScienceJiangsu Normal UniversityXuzhouJiangsuChina State Key Laboratory of Oncogenes and Related GenesShanghai Cancer InstituteRenji HospitalShanghai Jiao Tong University School of MedicineShanghaiChina Department of OncologyFirst Affiliated Hospital of Shantou University Medical CollegeShantouGuangdongChina Department of Environmental HygieneSecond Military Medical UniversityShanghaiChina
出 版 物：《Journal of Clinical and Translational Hepatology》 (临床与转化肝病杂志（英文版）)
年 卷 期：2021年第9卷第4期
页 面：466-476页
核心收录：
学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学]
基 金：This study was funded by the National Natural Science Foun-dation of China(Grant Nos.81772972,81672731,81572703,81572451) Natural Science Foundation of Guangdong Prov-ince(Grant Nos.2021A1515010776,2015A030313449) Science and Technology Planning Project of Guangdong Province“Public Research and Capacity Building”Special Project Fund(Grant No.2014A020212285) Department of Education,Guangdong Government under the Toptier University Development Scheme for Research and Control of Infectious Diseases(Grant Nos.2016026,2015060,2015089).
主 题：Liver cancer Hepatitis B virus X protein Pregnane X receptor Aflatoxin B1 Hepatotoxicity
摘 要：Background and Aims:Hepatitis B virus(HBV)infection has been found to increase hepatocellular sensitivity to carcinogenic xenobiotics,by unknown mechanisms,in the generation of hepatocellular carcinoma.The pregnane X receptor(PXR)is a key regulator of the body’s defense against xenobiotics,including xenobiotic carcinogens and clinical drugs.In this study,we aimed to investigate the molecular mechanisms of HBV X protein(HBx)-PXR signaling in the synergistic effects of chemical carcinogens in HBV-associated hepatocarcinogenesis.Methods:The expression profile of PXR-cytochrome p4503A4(CYP3A4)signaling was determined by PCR,western blotting,and tissue microarray.Cell viability and aflatoxin B1(AFB1)cytotoxicity were measured using the cell counting kit-8 assay.Target gene expression was evaluated using transient transfection and real time-PCR.The genotoxicity of AFB1 was assessed in newborn mice with a single dose of AFB1.Results:HBx enhanced the hepatotoxicity of AFB1 by activating CYP3A4 and reducing glutathione Stransferase Mu 1(GSTM1)in cell lines.Activation of PXR by pregnenolone 16α-carbonitrile increased AFB1-induced liver tumor incidence by up-regulating oncogenic KRAS to enhance interleukin(IL)-11:IL-11 receptor subunit alpha-1(IL11RA-1)-mediated inflammation in an HBx transgenic model.Conclusions:Our finding regarding AFB1 toxicity enhancement by an HBx-PXR-CYP3A4/GSTM1-KRASIL11:IL11RA signaling axis provides a rational explanation for the synergistic effects of chemical carcinogens in HBV infection-associated hepatocarcinogenesis.
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