Altered expression of β-catenin without genetic mutation in intrahepatic cholangiocarcinoma

Abstract

β-catenin which has a role in E-cadherin mediated cell-to-cell adhesion, and is also involved in Wnt signaling pathways as a downstream signaling molecule accumulating in the cytoplasm and nucleus constitutively activates Tcf/LEF-associated transcription of oncogenic genes. We examined the expression pattern and the genetic alteration of β-catenin to determine the role of β-catenin in cancer formation and/or progression in intrahepatic cholangiocarcinoma (ICC). β-catenin expression was immunohistochemically examined in 71 surgically resected ICC samples, and correlation between the expression pattern and clinicopathologic factors was investigated. Mutation analysis of β-catenin exon 3, which included the responsible element for Wnt signaling was done in 55 samples, using PCR-SSCP and direct sequence methods. Immunohistochemical analysis revealed the reduced membranous expression of β-catenin in 58 (82%) ICCs and aberrant nuclear expression in 11 (15%) ICCs. The membranous expression was preserved in 62% of the papillary adenocarcinomas, and was frequently reduced in tumors with a poorer histological differentiation (84%), with a significant difference (P = .01). Genetic analysis showed that none of the 55 ICCs examined carried mutations in β-catenin exon 3. The present study indicates that reduced membranous expression of β-catenin is associated with non-papillary ICCs which have a more malignant behavior, and that nuclear translocation of β-catenin results in oncogenic events. Mutations in β-catenin exon 3 do not appear to be responsible for nuclear translocation of β-catenin in ICCs.