Two mechanisms of liver cancer development have been proposed for human hepatocellular carcinoma (HCC). One involves the disruption of the Wingless/Wnt signaling pathway by activation of b-catenin, while the other is characterized by genomic instability. We have previously generated a number of transgenic mouse models of liver cancer. Here we investigate the relevance of these two molecular pathways to murine hepatocarcinogenesis. A large number of neoplastic liver lesions from c-myc, TGF-a, E2F-1, c-myc/TGF-a and c-myc/E2F-1 transgenic mice were analyzed for b-catenin mutations and deletions by PCR and sequencing screening. Also, as a measure of b-catenin activation, the subcellular localization of the protein was evaluated by immunohistochemistry. The RAPD method was used to assess the overall genomic instability in preneoplastic and neoplastic lesions and chromosomal loci affected by genomic alterations were determined by microsatellite analysis. Liver tumors from the transgenic mouse lines could be divided in two categories. The first category, best exemplified by the c-myc/E2F-1 transgenic line, was characterized by high frequency of b-catenin activation in the presence of a relatively stable genome. The nuclear accumulation of b-catenin was limited to preneoplastic and neoplastic lesions with a well-differentiated eosinophilic phenotype. The second category, represented by c-myc/TGF-a transgenic line, displayed extensive genomic instability starting from the early dysplastic stage and a low rate of b-catenin activation. Recurrent loss of heterozygosity at chromosomes 1, 2, 4, 5, 6, 7, 8, 9, 12, 14, 15 and X was detected in this model of liver cancer. The data indicate that similar molecular pathways described for human HCC are recapitulated in human HCC.
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