Phenotype of single hepatocytes expressing an activated version of ß-catenin in liver of transgenic mice.

The gene CTNNB1 encoding ß-catenin is mutated in about 30% of hepatocellular carcinoma, generally often combined with other genetic alterations. In transgenic mice, it has been shown that activation of ß-catenin in more than 70% of all hepatocytes causes immediate proliferation leading to hepatomegaly. In this study we established a novel mouse model where ß-catenin is activated only in individual, dispersed hepatocytes. Hepatocyte-specific expression of activated point-mutated ß-catenin (human ß-catenin(S33Y)) was established using the Cre/loxP system. Expression of several downstream targets of ß-catenin signaling such as glutamine synthetase and several cytochrome P450 isoforms was confirmed by immunostaining. Only a minor portion of hepatocytes expressed the ß-catenin(S33Y) transgene, which were mainly positioned as dispersed individual cells within the normal liver parenchyma. The hepatocytes with activated ß-catenin did not show increased proliferation and the mice did not develop hepatomegaly. In conclusion, activated ß-catenin in single hepatocytes induces a gene expression pattern in hepatocytes which is similar to that of Ctnnb1-mutated mouse liver tumors, but is apparently not sufficient to induce increased cell proliferation. Therefore, onset of proliferation seems to require concomitant activation of ß-catenin in clusters of hepatocytes, suggesting a role of cell-cell communication in this process.