Accumulation of beta-catenin in the cytoplasm and the nuclei during the early hepatic tumorigenesis.

ABSTRACT

Hepatocellular carcinomas (HCCs) are thought to develop as well-differentiated tumors and progress to less-differentiated tumors. However, the genetic changes underlying the development and progression of HCCs are not well understood. Recent studies have shown frequent beta-catenin gene activation in HCCs by somatic alterations involving exon 3, resulting in the activation of the Wnt/Wingless signal transduction pathway. However, the exact process in which activation of Wnt/Wingless signal transduction pathway occurs during hepatic tumorigenesis remains to be elucidated. The aim of the present study was to investigate at what stage of hepatocellular tumorigenesis this pathway was activated. Altered expression of beta-catenin was investigated immunohistochemically with special reference to the grade of histological differentiation in 41 HCCs and eight dysplastic nodules. Mutational analysis of the beta-catenin gene with single-strand conformation polymorphism method and polymerase chain reaction amplification was related with the expression of this protein. beta-Catenin was expressed in the cytoplasm and the nuclei in three cases among eight dysplastic nodules, in four cases among 20 well differentiated HCCs, in five cases among 15 moderately differentiated HCCs, and one case among six poorly differentiated HCCs, respectively. Expression of beta-catenin in the cytoplasm and the nuclei was associated in one case with mutation and two cases without mutation for beta-catenin gene among 11 screened HCCs. It was concluded that beta-catenin was accumulated in the cytoplasm and the nuclei in pre-cancerous lesions of the liver and might contribute, at least in part, to hepatic tumorigenesis.