Cyclin D1 over-expression correlates with beta-catenin activation, but not with H-ras mutations, and phosphorylation of Akt, GSK3 beta and ERK1/2 in mouse hepatic carcinogenesis.
Mutational activation of beta-catenin and cyclin D1 over-expression are a frequent change in mouse hepatic tumors. Although activated beta-catenin may bind to T cell factor (TCF) family members and transcriptionally activate the cyclin D1 gene, either beta-catenin or cyclin D1 may be activated by various pathways independently of beta-catenin mutations. In this study, we investigated beta-catenin activation and mutations, cyclin D1 expression, H-ras mutations and phosphorylation of extracellular signal regulated protein kinases 1/2 (ERK1/2), Akt and glycogen synthetase kinase 3beta (GSK3 beta) in mouse hepatic carcinogenesis. Nuclear/cytoplasmic staining of beta-catenin, a sign of beta-catenin activation, was frequently observed in association with the high nuclear cyclin D1 labeling index in the hepatic tumors at the late stage of carcinogenesis. The beta-catenin activation was further suggested by the fact that all hepatocellular carcinoma (HCC) cell lines examined showed the nuclear beta-catenin/TCF4 complex together with cyclin D1 over-expression. However, the fact that only 31.8% (7/22) of the lesions with the nuclear/cytoplasmic beta-catenin staining showed beta-catenin mutations indicated that beta-catenin was activated not only by its own mutations but also by other reason(s). On the other hand, there was no correlation between the beta-catenin/cyclin D1 activation and the H-ras mutations or phosphorylation of Akt, GSK3 beta and ERK1/2, although GSK3 beta was frequently over-expressed in the tumors. These results indicate that, although beta-catenin and cyclin D1 activation are well correlated, the Akt/GSK3 beta and ras/ERK1/2 pathways may not play a major role in the beta-catenin/cyclin D1 activation.
Gotoh
Junichi
J
Department of Pathology and Department of Surgery, Asahikawa Medical College, 2-1-1-1 East, Midorigaoka, Asahikawa 078-8510, Japan.
Obata
Masahiko
M
Yoshie
Masumi
M
Kasai
Shinichi
S
Ogawa
Katsuhiro
K
D000818:Animals; D001483:Base Sequence; D002471:Cell Transformation, Neoplastic; D019938:Cyclin D1 / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers; D011905:Genes, ras; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D007150:Immunohistochemistry; D008114:Liver Neoplasms, Experimental / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009154:Mutation; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin
C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D017931:DNA Primers; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D051176:beta Catenin; D019938:Cyclin D1; D000071679:Glycogen Synthase Kinase 3 beta; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3