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Lack of Tumorigenesis in the Mouse Liver after Adenovirus-mediated Expression of a Dominant Stable Mutant of ß-Catenin¹

Banyu Tsukuba Research Institute (Merck), Tsukuba 300-2611 [N. H., H. M., H. O., N. M., M. O., Y. T.]; Laboratory of Biomedical Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033 [M. M. T.]; and Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501 [H. O., M. O., M. M. T.], Japan

Mutations in the glycogen synthase kinase 3ß (GSK3ß) phosphorylation sites of the ß-catenin gene exon 3 are found in 20–30% of human primary hepatocellular carcinoma (HCC), whereas mutations in the APC or AXIN genes are found in other HCC populations. These data strongly suggest that the Wnt signaling pathway is involved in hepatocarcinogenesis. To determine the role of ß-catenin in intestinal tumorigenesis, we earlier constructed a mutant mouse strain Catnb^lox(ex3), in which exon 3 of the ß-catenin gene was sandwiched by loxP sequences. By genetic crosses of these mice with the Fabpl-cre transgenic mice that express the cre gene controlled by the fatty acid binding protein gene promoter, we introduced the ß-catenin stabilizing mutation into the small intestine and liver. Although numerous polyps were formed in the small intestine, we did not find any neoplastic (i.e., dysplastic) foci in the liver, and the mice died in 5 weeks after birth because of acute liver damage accompanying mitochondrial swelling. When a recombinant adenovirus that expresses the cre gene from a human cytomegalovirus early gene promoter was constructed and inoculated at a high multiplicity (10⁹ plaque-forming units/mouse), the Catnb^lox(ex3) mice showed marked hepatomegaly, with similar mitochondrial swelling in the hepatocytes, and died within 3 weeks after infection. On the other hand, when inoculated at lower multiplicities of infection (10⁷ and 10⁸ plaque-forming units/mouse, respectively), the Catnb^lox(ex3) mice survived >6 months without any neoplastic foci in the liver, although the nuclear localization of ß-catenin was found in some hepatocytes even after 6 months. These results suggest that, in contrast to intestinal polyposis, the Wnt pathway activation by stabilized ß-catenin is not sufficient for hepatocarcinogenesis, but additional mutations or epigenetic changes may be required.

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