Hepatitis B virus X protein co-activates pregnane X receptor to induce the cytochrome P450 3A4 enzyme, a potential implication in hepatocarcinogenesis

被引：22

作者：

Niu, Yongdong ^{[1
,2
]}

Wu, Zheng ^{[1
]}

Shen, Qiujin ^{[1
]}

Song, Jin ^{[1
]}

Luo, Qin ^{[1
]}

You, Haiyan ^{[1
]}

Shi, Ganggang ^{[2
]}

Qin, Wenxin ^{[1
]}

机构：

[1] Shanghai Jiao Tong Univ, Sch Med, State Key Lab Oncogenes & Related Genes, Shanghai Canc Inst,Renji Hosp, Shanghai 200032, Peoples R China

[2] Shantou Univ, Coll Med, Dept Pharmacol, Shantou, Guangdong, Peoples R China

来源：

DIGESTIVE AND LIVER DISEASE | 2013年 / 45卷 / 12期

基金：

中国博士后科学基金; 中国国家自然科学基金;

关键词：

Cytochrome P450 3A4; Hepatitis B virus X protein; Liver cancer; Pregnane X receptor; FUNCTIONAL CROSS-TALK; HEPATOCELLULAR-CARCINOMA; NUCLEAR RECEPTORS; AFLATOXIN B-1; GENE; ROLES; CANCER; CYP3A4; PROLIFERATION; LIPOGENESIS;

D O I：

10.1016/j.dld.2013.06.004

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

Background: Hepatitis B virus X protein is a key regulator of hepatocarcinogenesis. The pregnane X receptor is a xenobiotic nuclear receptor that plays a role in the regulation of drug-metabolizing enzymes including the cytochrome P450 3A4, an enzyme important for the bioactivation of the liver carcinogen aflatoxin Bl. Aims: To identify novel host factor that interacts with hepatitis B virus X protein and the functional interaction between hepatitis B virus X protein and pregnane X receptor in hepatocarcinogenesis. Methods: Co-immunoprecipitation, glutathione S-transferase pull-down, and chromatin immunoprecipitation were utilized to assess the interaction between hepatitis B virus X protein and pregnane X receptor. The functional relevance of hepatitis B virus X protein-pregnane X receptor interaction was investigated in cell cultures and hepatocellular carcinoma samples. Results: We observed that hepatitis B virus X protein and pregnane X receptor co-localize in hepatic cells. Pregnane X receptor interacted with hepatitis B virus X protein via the ligand-binding domain of pregnane X receptor. Functionally, hepatitis B virus X protein increased the transcriptional activity of pregnane X receptor. Pregnane X receptor was able to recruit hepatitis B virus X protein to the CYP3A4 gene promoter. In clinic samples, the expression of pregnane X receptor was high in hepatitis B virus-associated liver cirrhosis and stage I hepatocellular carcinoma, but low in state II and stage III hepatocellular carcinoma. Conclusion: We revealed a novel function of hepatitis B virus X protein in co-activating pregnane X receptor. The increased expression of pregnane X receptor and its target gene CYP3A4 are potential biomarkers for the early stage of hepatitis B virus-associated hepatocarcinogenesis. (C) 2013 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

引用

页码：1041 / 1048

页数：8

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