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 to the NH2-terminal phosphorylation sites of glycogen synthetase kinase 3beta have been causally implicated in carcinogenesis. In this study, the beta-catenin exon 3 was examined in hepatic lesions induced by diethylnitrosamine in B6C3F1 mice. PCR and DNA sequencing detected seven beta-catenin mutations in 13 samples dissected from hepatocellular carcinoma tissues, but none in 14 hepatic adenomas. All of the mutations were found in codon 41 encoding a threonine residue, one of the possible glycogen synthetase kinase-3beta phosphorylation sites. Although beta-catenin protein was immunohistochemically stained mainly on the cell membrane in preneoplastic hepatocytic foci and most adenomas, as observed in normal hepatocytes, it was detected in the cytoplasm and nuclei in addition to the cell membrane, indicating stabilization of the protein in HCCs. This shift in staining was observed not only in tumors with mutations, but also in examples lacking exon 3 mutations. Our data demonstrate that beta-catenin alterations may be important for malignant progression during multistep hepatic carcinogenesis in mice.
Ogawa
K
K
Department of Pathology, Asahikawa Medical College, Japan.
Yamada
Y
Y
Kishibe
K
K
Ishizaki
K
K
Tokusashi
Y
Y
D000236:Adenoma / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000032:analysis / Q000235:genetics*; D004052:Diethylnitrosamine; D005091:Exons; D005260:Female; D007150:Immunohistochemistry; D008114:Liver Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators; D051176:beta Catenin
C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D051176:beta Catenin; D004052:Diethylnitrosamine