Effects of carcinogen-induced transcription factors on the activation of hepatitis B virus expression in human hepatoblastoma HepG2 cells and its implication on hepatocellular carcinomas

To elucidate the molecular mechanisms involved in the action of common carc inogens, which can act as important cofactors in modulating hepatitis B vir us-mediated hepatocellular carcinogenesis, we have investigated the influen ce of aflatoxin B-1 (AFB), a potent liver carcinogen, as well as benzo[a]py rene (BP) and 4-aminobiphenyl (4-ABP), carcinogens in cigarette smoke, on t he induction of various transcription factors in human hepatoblastoma HepG2 cells. DNA electrophoretic mobility shift assays were performed with nucle ar extracts from HepG2 cells treated with 10 mu mol/L AFB, 40 mu mol/L BP, or 300 mu mol/L 4-ABP for 6 and 24 hours. Eight- and 6-fold increases in nu clear transcription factor kappa B (NF-kappa B), and 5- and 10-fold increas es in activated protein (AP-1) transcription factor were observed with 24 h ours AFB and BP treatments, respectively, whereas 4-ABP treatment resulted in an approximately 4-fold induction of both NF-kappa B and AP-1. Moreover, 4-ABP gave the strongest NF-kappa B activation in 6 hours of treatment. Fo ur- and 10-fold activation of stress protein was detected by a consensus he at shock factor (HSF) sequence binding probe, with AFB and BP treatments, r espectively. DNA adducts were observed by immunoassays in HepG2 cells treat ed with AFB and BP but not with 4-ABP. Increased human hepatitis B virus (H BV) surface antigen (HBsAg) synthesis was detected in AFB- and BP-treated H epG2 cells following transfection with recircularized HBV DNA. These data s uggest that certain carcinogen-induced transcription factors may influence viral carcinogenesis and initiate hepatocellular carcinomas (HCC).