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 carcinoma (HCC). Our ability to derive transgenic mice which develop liver cancer 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 whether AFB(1) can induce p53 mutations, particularly at codon 249, which are frequently detected in HCC and, as a result, act synergistically with HBV to accelerate the manifestation of disease. While AFB(1) significantly shortened the latency of tumor development in the HBx transgenic mice, the tumors did not have p53 mutations. As in tumors from the untreated transgenic mice, the p53 tumor suppressor protein is found bound to the HBx protein and sequestered in the cytoplasmic compartment of the tumor cell. Despite the frequent involvement of ras mutations 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.

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