Activation of beta-catenin during hepatocarcinogenesis in transgenic mousemodels: Relationship to phenotype and tumor grade

Mutations affecting phosphorylation sites in the beta -catenin gene have be en implicated in the development of human and rodent hepatocellular carcino mas (HCCs), Tn further investigate the involvement of this gene in hepatoca rcinogenesis, we used several transgenic mouse models of hepatic tumors ind uced by overexpression of c-myc in the liver either alone or in combination with transforming growth factor (TGF) alpha or TGF-beta1. Activation of be ta -catenin, as judged by the presence of mutations and/or nuclear transloc ation of the protein, was most frequent in liver tumors from c-myc (4/17; 2 3.5%) and c-myc/TGF-beta1 (6/18; 33.3%) transgenic mice. However, it was ve ry rare in faster growing and histologically more aggressive HCCs developed in c-myc/TGF-alpha mice (1/20; 5%). Administration of diethylnitrosamine, phenobarbital, or 2-amino-3,8-diethylimidazo[4,5-f]quinoxaline did not sign ificantly affect the occurrence of beta -catenin mutations. Notably, nuclea r accumulation of beta -catenin was observed only in adenomas and highly di fferentiated carcinomas with eosinophilic phenotype, Furthermore, preneopla stic lesions with eosinophilic phenotype frequently displayed focal nuclear positivity, colocalized with areas of high proliferation. In contrast, bas ophilic and clear-cell foci, as well as pseudo-glandular and poorly differe ntiated HCCs, exhibited a normal or reduced membranous immunoreactivity for beta -catenin, These studies suggest that nuclear translocation of beta -c atenin and activation of Wingless/Wnt signaling mag represent an early even t in liver carcinogenesis, providing a growth advantage in a subset of hepa tic tumors with a more differentiated phenotype.