Activation of Wnt/β‐catenin pathway during hepatocyte growth factor–induced hepatomegaly in mice†

Abstract

Hepatocyte growth factor (HGF) and β-catenin both play a crucial role in stimulating hepatocyte proliferation, but whether these 2 pathways cooperate in inducing hepatocyte proliferation is unclear. We have previously reported that β-catenin forms a complex with c-Met (HGF receptor) that undergoes dissociation because of β-catenin tyrosine phosphorylation on stimulation by HGF. It is also known that delivery of the human HGF gene cloned in a plasmid under a CMV promoter results in hepatomegaly in mice. In addition, recently characterized β-catenin transgenic mice also showed hepatomegaly. The present study was based on the hypothesis that HGF-induced hepatomegaly is mediated, at least in part, by activation of the Wnt/β-catenin pathway. Here we report that delivery of the human HGF gene delivery in mice led to hepatomegaly via β-catenin activation in the liver in 1- and 4-week studies. The mechanisms of β-catenin activation in the 1-week study included loss of c-Met–β-catenin association as well as canonical β-catenin activation, leading to its nuclear translocation. In the 4-week study, β-catenin activation was observed via canonical mechanisms, whereas the c-Met–β-catenin complex remained unchanged. In both studies there was an associated increase in the E-cadherin–β-catenin association at the membrane. In addition, we generated liver-specific β-catenin knockout mice, which demonstrated significantly smaller livers. HGF gene delivery failed to induce hepatomegaly in these β-catenin conditionally null mice. In conclusion, β-catenin- and HGF-mediated signaling pathways cooperate in hepatocyte proliferation, which may be crucial in liver development, regeneration following partial hepatectomy, and pathogenesis of hepatocellular carcinoma. (HEPATOLOGY 2006;44:992–1002.)