title: Hepatitis B virus X protein co-activates pregnane X receptor to induce the cytochrome P450 3A4 enzyme, a potential implication in hepatocarcinogenesis.
abstract: 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 B1.
  
  
  OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Pharmacology, Shantou University Medical College, Guangdong, China. Electronic address: ydniu@126.com.
authors.forename: Yongdong
authors.initials: Y
authors.lastname: Niu
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wu
authors.forename: Qiujin
authors.initials: Q
authors.lastname: Shen
authors.forename: Jin
authors.initials: J
authors.lastname: Song
authors.forename: Qin
authors.initials: Q
authors.lastname: Luo
authors.forename: Haiyan
authors.initials: H
authors.lastname: You
authors.forename: Ganggang
authors.initials: G
authors.lastname: Shi
authors.forename: Wenxin
authors.initials: W
authors.lastname: Qin
mesh_terms: D014408:Biomarkers, Tumor / Q000096:biosynthesis*; D063646:Carcinogenesis / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis* / Q000235:genetics; D004790:Enzyme Induction; D019694:Hepatitis B, Chronic / Q000150:complications; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008103:Liver Cirrhosis / Q000378:metabolism / Q000821:virology; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D000077297:Pregnane X Receptor; D012333:RNA, Messenger / Q000378:metabolism; D011987:Receptors, Steroid / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D054334:Viral Regulatory and Accessory Proteins
chemical_list: D014408:Biomarkers, Tumor; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D011987:Receptors, Steroid; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human
keywords: CYP3A4; ChIP; Cytochrome P450 3A4; DMSO; GST; HBV; HBx; HCC; Hepatitis B virus X protein; Liver cancer; PCN; PXR; Pregnane X receptor; RIF; XREM; chromatin immunoprecipitation; cytochrome P450 3A4; dimethyl sulfoxide; glutathione S-transferase; hepatitis B virus; hepatitis B virus X protein; hepatocellular carcinoma; pregnane X receptor; pregnenolone 16α carbonitrile; rifampicin; xenobiotic responsive enhancer module