beta-Catenin mutations are frequent in hepatocellular carcinomas but absent in adenomas induced by diethylnitrosamine in B6C3F1 mice

Activating mutations in the region of the beta-catenin gene corresponding t o the NH2-terminal phosphorylation sites of glycogen synthetase kinase 3 be ta have been causally implicated in carcinogenesis, In this study, the beta -catenin exon 3 was examined in hepatic lesions induced by diethylnitrosami ne in B6C3F1 mice, PCR and DNA sequencing detected seven beta-catenin mutat ions in 13 samples dissected from hepatocellular carcinoma tissues, but non e in 14 hepatic adenomas, All of the mutations were Found in codon 41 encod ing a threonine residue, one of the possible glycogen synthetase kinase-3 b eta phosphorylation sites Although beta-catenin protein was immunohistochem ically stained mainly on the cell membrane in preneoplastic hepatocytic foc i and most adenomas, as observed in normal hepatocytes, it was detected in the cytoplasm and nuclei in addition to the cell membrane, indicating stabi lization of the protein in HCCs, This shift in staining was observed not on ly in tumors with mutations, but also in examples lacking exon 3 mutations. Our data demonstrate that beta-catenin alterations may be important for ma lignant progression during multistep hepatic carcinogenesis in mice.