Retroviral expression of the hepatitis B virus x gene promotes liver cell susceptibility to carcinogen-induced site specific mutagenesis.
Mutational inactivation of the tumor suppressor gene p53 is common in hepatocellular carcinomas (HCC). AGG to AGT transversion in codon 249 of exon 7 of the p53 gene occurs in over 50% of HCC from endemic regions, where both chronic infection with the hepatitis B virus (HBV) and exposure to carcinogens such as aflatoxin B1 (AFB1) prevail. In this study, we report the effect of the HBV x protein (HBx) on carcinogen-induced cytotoxicity and AGG to AGT mutation in codon 249 of the p53 gene in the human liver cell line CCL13. Expression of HBx, as revealed by its transactivation function, results in enhanced cell susceptibility to cytotoxicity induced by the AFB1 active metabolite, AFB1-8,9-epoxide, and benzo(a)pyrene diol-epoxide. Under similar conditions, expression of HBx promotes apoptosis in a subset of cell population. Exposure to AFB1-8, 9-epoxide alone induces a low frequency of AGG to AGT mutation in codon 249 of the p53 gene, as determined by an allele-specific polymerase chain reaction (AS-PCR) assay. However, expression of HBx enhances the frequency of AFB1-epoxide-induced AGG to AGT mutation compared to control cells. In summary, this study demonstrates that expression of HBx enhances liver cell susceptibility to carcinogen-induced mutagenesis, possibly through alteration of the balance between DNA repair and apoptosis, two cellular defense mechanisms against genotoxic stress.
Sohn
S
S
Departments of Medicine, Oncology, Pharmacology and Therapeutics, and Center for Translational Research in Cancer, Lady Davis Institute for Medical Research of the Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
Jaitovitch-Groisman
I
I
Benlimame
N
N
Galipeau
J
J
Batist
G
G
Alaoui-Jamali
M A
MA
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000378:metabolism / Q000633:toxicity; D016604:Aflatoxin B1 / Q000031:analogs & derivatives / Q000378:metabolism / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D002273:Carcinogens / Q000378:metabolism / Q000633:toxicity*; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D003062:Codon / Q000235:genetics; D004252:DNA Mutational Analysis; D004198:Disease Susceptibility; D016158:Genes, p53 / Q000235:genetics; D005822:Genetic Vectors / Q000235:genetics; D006515:Hepatitis B virus / Q000235:genetics / Q000472:pathogenicity; D006801:Humans; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism* / Q000821:virology; D016297:Mutagenesis, Site-Directed / Q000187:drug effects*; D009153:Mutagens / Q000378:metabolism / Q000633:toxicity; D009154:Mutation / Q000235:genetics; D016133:Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014161:Transduction, Genetic; D054334:Viral Regulatory and Accessory Proteins
D002273:Carcinogens; D003062:Codon; D009153:Mutagens; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; C006426:aflatoxin B1-2,3-oxide; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D016604:Aflatoxin B1