Wnt signaling in hepatocellular carcinoma: Analysis of mutation and expression of beta-catenin, T-cell factor-4 and glycogen synthase kinase 3-beta genes

Authors


Dr Jian Cui, Retinoid Research Group, Department of Food Science and Human Nutrition, Michigan State University, East Lansing, MI 48824, USA. Email: cuij@msu.edu

Abstract

Background and Aims: Hepatocellular carcinoma (HCC) is a common killer cancer in the world. Recently, abnormal activation of the Wnt pathway has been found to be involved in the carcinogenesis of several human cancers including HCC. The goal of the present study was to investigate the mechanism of inappropriate activation of the Wnt pathway in hepatocarcinogenesis.

Methods: We analyzed the alterations of three key components of the Wnt pathway: β-catenin, glycogen synthase kinase (GSK)-3β and T-cell factor (Tcf)-4 in 34 HCC and paracancerous normal liver by immunohistochemistry, polymerase chain reaction (PCR)–single-strand conformation polymorphism (SSCP), direct sequencing, and quantitative real-time reverse transcription (RT)–PCR.

Results: We found that 61.8% (21/34) of all HCC examined showed an abnormal β-catenin protein accumulation in the cytoplasm or nuclei. The RT–PCR–SSCP and direct sequencing showed that β-catenin exon 3 mutations existed in 44.1% (15/34) of the HCC. No mutations of GSK-3β or Tcf-4 were detected in HCC. Moreover, messenger RNA of β-catenin and Tcf-4, but not GSK-3β, was found to be overexpressed in HCC. On analyzing the relationship between alterations of β-catenin or Tcf-4 and C-myc or Cyclin D1 expression, we found that mutations of β-catenin, as well as overexpression of β-catenin or the Tcf-4 gene were independently correlated with C-myc gene overexpression in HCC.

Conclusion: Our present findings strongly suggest that mutations of β-catenin, as well as overexpression of β-catenin and the Tcf-4 gene, independently activate the Wnt pathway in HCC, with the target gene most likely to be C-myc.

Ancillary