Effect of mutant ß-catenin on liver growth homeostasis and hepatocarcinogenesis in transgenic mice.

ABSTRACT

BACKGROUND: Mutations in the Wnt signalling pathway molecule ß-catenin are associated with liver cancer. AIMS: Our aim was to confirm the effects of stabilized ß-catenin on liver growth, identify whether those effects were reversible and cell autonomous or non-cell autonomous and to model ß-catenin-induced liver cancer in mice. METHODS: Using a liver-specific inducible promoter, we generated transgenic mice in which the expression of mutant ß-catenin can be induced or repressed within hepatocytes in mice of different ages. RESULTS: Similar to other models, the hepatic expression of mutant ß-catenin in our model beginning in utero or induced in quiescent adult liver resulted in a two-fold liver enlargement and development of disease with a latency of 1-5 months, and mice displayed elevated blood ammonia and altered hepatic gene expression. Our model additionally allowed us to discover that molecular and phenotypic abnormalities were reversible following the inhibition of transgene expression. Hepatocyte transplant studies indicated that mutant ß-catenin could not increase the growth of transgene-expressing foci in either growth-permissive or -restrictive hepatic environments, but still directly altered hepatocyte gene expression. Mice with continuous but focal transgene expression developed hepatic neoplasms after the age of 1 year. CONCLUSIONS: Our findings indicate that hepatocyte gene expression is directly affected by mutant ß-catenin in a cell autonomous manner. However, hepatomegaly associated with diffuse hepatocyte-specific expression of mutant ß-catenin is secondary to liver functional alteration or non-cell autonomous. Both phenotypes are reversible. Nevertheless, some foci of transgene-expressing cells progressed to carcinoma, confirming the association of mutant ß-catenin with liver cancer.