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Hepatocarcinogenesis in Mice with ß-Catenin and Ha-Ras Gene Mutations

¹Banyu Tsukuba Research Institute (Merck), Tsukuba, and ²Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

We have established previously a mouse strain containing a mutant ß-catenin allele of which exon 3 was sandwiched by loxP sequences [Catnb^lox(ex3)]. In this mouse strain, a Wnt-activating ß-catenin mutation alone is insufficient for hepatocarcinogenesis, but additional mutations or epigenetic changes may be required. Here we report that hepatocellular carcinoma develops at the 100% incidence in mice with simultaneous mutations in the ß-catenin and H-ras genes that are introduced by adenovirus-mediated Cre expression. Although H-ras mutation alone rapidly causes large cell dysplasia in the hepatocytes, these cells show no autonomous growth within 1 week after infection of the Cre-adenovirus. However, simultaneous induction of an additional mutation in the ß-catenin gene causes a clonal expansion of such dysplastic cells, followed by nodular formation and development of hepatocellular carcinoma. These results indicate that ß-catenin mutations play a critical role in hepatocarcinogenesis in cooperation with another oncogene and that these mice provide a convenient model to investigate early steps of hepatocarcinogenesis.

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