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

被引：12
作者：
Niu, Yongdong [1 ]
Fan, Shaohua [2 ]
Luo, Qin [3 ]
Chen, Liming [4 ]
Huang, Danmei [1 ]
Chang, Wenjun [5 ]
Qin, Wenxin [3 ]
Shi, Ganggang [1 ]
机构：
[1] Shantou Univ, Dept Pharmacol, Med Coll, Shantou, Guangdong, Peoples R China
[2] Jiangsu Normal Univ, Sch Life Sci, Key Lab Biotechnol Med Plants Jiangsu Prov, Xuzhou, Jiangsu, Peoples R China
[3] Shanghai Jiao Tong Univ, Renji Hosp, Shanghai Canc Inst, State Key Lab Oncogenes & Related Genes,Sch Med, Shanghai, Peoples R China
[4] Shantou Univ, Med Coll, Dept Oncol, Affiliated Hosp 1, Shantou, Guangdong, Peoples R China
[5] Second Mil Med Univ, Dept Environm Hyg, Shanghai, Peoples R China
来源：
JOURNAL OF CLINICAL AND TRANSLATIONAL HEPATOLOGY | 2021年 / 9卷 / 04期
基金：
中国国家自然科学基金;
关键词：
Liver cancer; Hepatitis B virus X protein; Pregnane X receptor; Aflatoxin B1; Hepatotoxicity; S-TRANSFERASE GENES; HEPATOCELLULAR-CARCINOMA; HUMAN HEPATOCYTES; B-1; METABOLISM; LIVER-CANCER; CYP3A4; GENE; MICE; INDUCTION; SUSCEPTIBILITY; POLYMORPHISMS;
D O I：
10.14218/JCTH.2021.00036
中图分类号：
R57 [消化系及腹部疾病];
学科分类号：
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 p450 3A4 (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 S-transferase Mu 1 (GSTM1) in cell lines. Activation of PXR by pregnenolone 16 alpha-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-KRAS-IL11:IL11RA signaling axis provides a rational explanation for the synergistic effects of chemical carcinogens in HBV infection-associated hepatocarcinogenesis.
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收藏
页码：466 / 476
页数：11
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