SYNERGISM BETWEEN THE HBX GENE AND AFLATOXIN B-1 IN THE DEVELOPMENT OF MURINE LIVER-CANCER

Infection by hepatitis B virus (HBV) and exposure to dietary aflatoxin B-1 (AFB(1)) have both been implicated by epidemiological studies to be important risk factors in the development of hepatocellular carcino ma (HCC). Our ability to derive transgenic mice which develop liver ca ncer as a consequence of the expression of a single gene from HBV, the HBx gene, provides an opportunity to use this animal model to test wh ether AFB(1) can induce p53 mutations, particularly at codon 249, whic h are frequently detected in HCC and, as a result, act synergistically with HBV to accelerate the manifestation of disease. While AFB(1) sig nificantly shortened the latency of tumor development in the HBx trans genic mice, the tumors did not have p53 mutations. As in tumors from t he untreated transgenic mice, the p53 tumor suppressor protein is foun d bound to the HBx protein and sequestered in the cytoplasmic compartm ent of the tumor cell. Despite the frequent involvement of ras mutatio ns in mouse tumors, we also have not detected activation of the ms p21 protein in the tumors from the AFB(1)-treated mice. We conclude that although AFB(1) can act as a co-factor with HBx to induce HCC in mice, its mode of action in vivo remains obscure.