Activation of beta-catenin during hepatocarcinogenesis in transgenic mouse models: relationship to phenotype and tumor grade.
Mutations affecting phosphorylation sites in the beta-catenin gene have been implicated in the development of human and rodent hepatocellular carcinomas (HCCs). To further investigate the involvement of this gene in hepatocarcinogenesis, we used several transgenic mouse models of hepatic tumors induced by overexpression of c-myc in the liver either alone or in combination with transforming growth factor (TGF) alpha or TGF-beta1. Activation of beta-catenin, as judged by the presence of mutations and/or nuclear translocation of the protein, was most frequent in liver tumors from c-myc (4/17; 23.5%) and c-myc/TGF-beta1 (6/18; 33.3%) transgenic mice. However, it was very 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 significantly affect the occurrence of beta-catenin mutations. Notably, nuclear accumulation of beta-catenin was observed only in adenomas and highly differentiated carcinomas with eosinophilic phenotype. Furthermore, preneoplastic lesions with eosinophilic phenotype frequently displayed focal nuclear positivity, colocalized with areas of high proliferation. In contrast, basophilic and clear-cell foci, as well as pseudo-glandular and poorly differentiated HCCs, exhibited a normal or reduced membranous immunoreactivity for beta-catenin. These studies suggest that nuclear translocation of beta-catenin and activation of Wingless/Wnt signaling may represent an early event in liver carcinogenesis, providing a growth advantage in a subset of hepatic tumors with a more differentiated phenotype.
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Division of Basic Sciences, National Cancer Institute, NIH, Bethesda, Maryland 20892-4255, USA.
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D000818:Animals; D003598:Cytoskeletal Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008114:Liver Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D010641:Phenotype; D010766:Phosphorylation; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis; D015534:Trans-Activators; D016211:Transforming Growth Factor alpha / Q000096:biosynthesis / Q000235:genetics; D014407:Tumor Cells, Cultured; D051176:beta Catenin
C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D016271:Proto-Oncogene Proteins c-myc; D015534:Trans-Activators; D016211:Transforming Growth Factor alpha; D051176:beta Catenin