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

• Published in: Carcinogenesis (New York) Vol. 24; no. 3; p. 435
• Main Authors: Gotoh, Junichi, Obata, Masahiko, Yoshie, Masumi, Kasai, Shinichi, Ogawa, Katsuhiro
• Format: Journal Article
• Language: English
• Published: Oxford Oxford Publishing Limited (England) 01-03-2003
• ISSN: 0143-3334; 1460-2180

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 3[beta] (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.