Carcinogenesis, Vol. 24, No. 3, 435-442,
March 2003
© 2003 Oxford University Press
CANCER BIOLOGY |
Cyclin D1 over-expression correlates with ß-catenin activation, but not with H-ras mutations, and phosphorylation of Akt, GSK3ß and ERK1/2 in mouse hepatic carcinogenesis
Department of Pathology and
1 Department of Surgery, Asahikawa Medical College, 2-1-1-1 East, Midorigaoka, Asahikawa 078-8510, Japan
Mutational activation of ß-catenin and cyclin D1 over-expression are a frequent change in mouse hepatic tumors. Although activated ß-catenin may bind to T cell factor (TCF) family members and transcriptionally activate the cyclin D1 gene, either ß-catenin or cyclin D1 may be activated by various pathways independently of ß-catenin mutations. In this study, we investigated ß-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 3ß (GSK3ß) in mouse hepatic carcinogenesis. Nuclear/cytoplasmic staining of ß-catenin, a sign of ß-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 ß-catenin activation was further suggested by the fact that all hepatocellular carcinoma (HCC) cell lines examined showed the nuclear ß-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 ß-catenin staining showed ß-catenin mutations indicated that ß-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 ß-catenin/cyclin D1 activation and the H-ras mutations or phosphorylation of Akt, GSK3ß and ERK1/2, although GSK3ß was frequently over-expressed in the tumors. These results indicate that, although ß-catenin and cyclin D1 activation are well correlated, the Akt/GSK3ß and ras/ERK1/2 pathways may not play a major role in the ß-catenin/cyclin D1 activation.
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