title: Inhibition of hepatitis-B-virus core promoter by p53: implications for carcinogenesis in hepatocytes.
abstract: The incidence of hepatocellular carcinoma (HCC) is particularly high in regions of Asia and sub-Saharan Africa where rates of infection with human hepatitis-B virus (HBV) and aflatoxin-B1 contamination of food are high. In HCC tumors occurring in inhabitants of these regions, a G-to-T mutation frequently occurs at position 249 of the tumor-suppressor gene p53. This suggests that HBV and p53 mutation may collaborate in the carcinogenic process in liver. We have examined the effect of the HBV protein HBX in HCC lines with exogenous wild-type p53 or mutated p53 on transactivation of 2 different reporter genes. Transfection of HCC lines with wild-type p53 and a reporter with the promoter from the p53-responsive gene WAF1/p21 resulted in a high level of expression, as expected. When cells were co-transfected with a reporter gene driven by the HBV core promoter and with the HBX gene, expression was enhanced in the Hep 3B, HLE, PLC/PRF/5 and HuH 7 lines, but not in the HuH 1 line. Co-transfection of the reporter with a plasmid containing wild-type p53 resulted in significant inhibition of the HBV core promoter in all of the lines, whereas the mutated p53 gene had no effect. Our results indicate that wild-type p53 can inhibit transcription from the HBV core promoter. In similar experiments, both HBX and p53 were co-transfected into HCC lines with the WAF1/p2l reporter gene. HBX inhibited p53-induced expression in 4 of the 6 lines (Hep 3B, HuH 1, HuH 7 and HLE), there was no effect in one line (HLF), and enhancement was evident in PLC/PRF/5. Our results indicate that inhibition of p53 transcriptional activity by HBX does occur in HCC, but is highly cell-context-dependent. Inhibition of transcription from the HBV core promoter by wild-type p53 appears to be more universal, and may represent a mechanism by which wild-type p53 can protect against the carcinogenic process in liver.
authors.affiliation: Department of Oncology, Nippon Roche Research Center, Kamakura, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Uchida
authors.forename: K
authors.initials: K
authors.lastname: Takahashi
authors.forename: K
authors.initials: K
authors.lastname: Tatsuno
authors.forename: U
authors.initials: U
authors.lastname: Dhingra
authors.forename: J F
authors.initials: JF
authors.lastname: Eliason
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D017930:Genes, Reporter; D006515:Hepatitis B virus / Q000235:genetics*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D014758:Viral Core Proteins / Q000235:genetics*; D054334:Viral Regulatory and Accessory Proteins
chemical_list: D009363:Neoplasm Proteins; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D014758:Viral Core Proteins; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D008156:Luciferases