Alterations of beta-catenin and Tcf-4 instead of GSK-3beta contribute to activation of Wnt pathway in hepatocellular carcinoma.
- Author:
Jian CUI
1
;
Xinda ZHOU
;
Yinkun LIU
;
Zhaoyou TANG
;
Mahmoud ROMEIH
Author Information
- Publication Type:Journal Article
- MeSH: Carcinoma, Hepatocellular; metabolism; Cytoskeletal Proteins; genetics; physiology; Glycogen Synthase Kinase 3; genetics; physiology; Glycogen Synthase Kinase 3 beta; Humans; Immunohistochemistry; Liver Neoplasms; metabolism; Polymerase Chain Reaction; Polymorphism, Single-Stranded Conformational; Proto-Oncogene Proteins; metabolism; Reverse Transcriptase Polymerase Chain Reaction; TCF Transcription Factors; Trans-Activators; genetics; physiology; Transcription Factor 7-Like 2 Protein; Transcription Factors; genetics; physiology; Wnt Proteins; Zebrafish Proteins; beta Catenin
- From: Chinese Medical Journal 2003;116(12):1885-1892
- CountryChina
- Language:English
-
Abstract:
OBJECTIVEThe goal of this study is to investigate the inappropriate activation of Wnt pathway in the hepatocarcinogenesis.
METHODSWe analyzed the alterations of three key components of Wnt pathway, beta-catenin, glycogen synthase kinase 3beta (GSK-3beta) and T cell factor 4 (Tcf-4), in 34 samples of hepatocellular carcinoma (HCC) and paracancerous normal liver by immunohistochemistry, polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP), direct sequencing, semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) and in situ hybridization.
RESULTSWe found 61.8% (21/34) of all the HCCs examined showed an abnormal beta-catenin protein accumulation in the cytoplasm or nuclei. RT-PCR-SSCP and direct sequencing showed that beta-catenin exon 3 mutations existed in 44.1% (15/34) of the HCCs. No mutations of GSK-3beta or Tcf-4 were detected in HCCs. Moreover, mRNA of beta-catenin and Tcf-4 but not GSK-3beta was found to be over expressed in HCCs. On analyzing the relationship between alterations of beta-catenin or Tcf-4 and C-myc or Cyclin D1 expression, we found that the mutations of beta-catenin as well as over expression of beta-catenin or Tcf-4 gene were independently correlated with C-myc gene over expression in HCCs.
CONCLUSIONSOur present findings strongly suggest mutations of beta-catenin as well as over expression of beta-catenin and Tcf-4 gene activate the Wnt pathway in HCC independently with the target gene most likely to be C-myc.
