Mutation of beta-catenin is an early event in chemically induced mouse hepatocellular carcinogenesis.
beta-catenin activation, and subsequent upregulation of Wnt-signaling, is an important event in the development of certain human and rodent cancers. Recently, mutations in the beta-catenin gene in the region of the serine-threonine glycogen kinase (GSK)-3beta phosphorylation target sites have been identified in hepatocellular neoplasms from humans and transgenic mice. In this study we examined 152 hepatocellular neoplasms from B6C3F1 mice included in five chemical treatment groups and controls for mutations in the beta-catenin gene. Twenty of 29 hepatocellular neoplasms from mice treated with methyleugenol had point mutations at codons 32, 33, 34 or 41, sites which are mutated in colon and other cancers. Likewise, nine of 24 methylene chloride-induced hepatocellular neoplasms and 18 of 42 oxazepam-induced neoplasms exhibited similar mutations. In contrast, only three of 18 vinyl carbamate-induced liver tumors, one of 18 TCDD-induced liver tumors, and two of 22 spontaneous liver neoplasms had mutations in beta-catenin. Thus, there appears to be a chemical specific involvement of beta-catenin activation in mouse hepatocellular carcinogenesis. Expression analyses using Western blot and immunohistochemistry indicate that beta-catenin protein accumulates along cell membranes following mutation. The finding of mutations in both adenomas and carcinomas from diverse chemical treatment groups and the immunostaining of beta-catenin protein in an altered hepatocellular focus suggest that these alterations are early events in mouse hepatocellular carcinogenesis.
Devereux
T R
TR
Laboratory of Molecular Carcinogenesis, NIEHS, Research Triangle Park, North Carolina, NC 27709, USA.
Anna
C H
CH
Foley
J F
JF
White
C M
CM
Sills
R C
RC
Barrett
J C
JC
D018248:Adenoma, Liver Cell / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D000818:Animals; D002273:Carcinogens / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005091:Exons; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D051379:Mice; D009153:Mutagens / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D017422:Sequence Analysis, DNA; D015534:Trans-Activators; D051176:beta Catenin
C495267:CTNNB1 protein, mouse; D002273:Carcinogens; D003598:Cytoskeletal Proteins; D009153:Mutagens; D015534:Trans-Activators; D051176:beta Catenin