Wnt signaling in hepatocellular carcinoma: Analysis of mutation and expression of beta-catenin, T-cell factor-4 and glycogen synthase kinase 3-beta genes
Wnt signaling in hepatocellular carcinoma: Analysis of mutation and expression of beta-catenin, T-cell factor-4 and glycogen synthase kinase 3-beta genes
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DOI：
10.1046/j.1440-1746.2003.02973.x
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发表时间：
2003-03-01
影响因子：
4.1
通讯作者：
Romeih, M
中科院分区：
文献类型：
--
作者：
Cui, J;Zhou, XD;Romeih, M
背景和目的：肝细胞癌（HCC）是世界范围内常见的恶性肿瘤。最近，Wnt通路的异常激活已被发现参与了包括HCC在内的几种人类癌症的致癌作用。本研究的目的是探讨Wnt通路在肝癌发生中的不适当激活机制。方法：我们分析了Wnt通路的三个关键组分的改变：应用免疫组化、聚合酶链反应-单链构象多态性（PCR-SSCP）技术检测34例肝癌及癌旁正常肝组织中β-连环蛋白（β-catenin）、糖原合成酶激酶（GSK）-3 β和T细胞因子（Tcf）-4的表达，结果：61.8%（21/34）的HCC组织中β-catenin蛋白表达异常，主要分布于细胞质或细胞核内。RT-PCR-SSCP和直接测序结果显示44.1%（15/34）的HCC存在β-catenin外显子3突变。在HCC中未检测到GSK-3 β或Tcf-4突变。此外，β-catenin和Tcf-4的信使RNA在HCC中过表达，而GSK-3 β则没有。在分析β-catenin或Tcf-4基因的改变与C-myc或Cyclin D1表达之间的关系时，我们发现β-catenin的突变以及β-catenin或Tcf-4基因的过表达与HCC中C-myc基因的过表达独立相关。我们目前的研究结果有力地表明，β-连环蛋白的突变，以及β-连环蛋白和Tcf-4基因的过度表达，C-myc基因在HCC中独立激活Wnt通路，靶基因最有可能是C-myc。(C)2003年Blackwell Publishing Asia Pty Ltd.
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: beta-catenin, glycogen synthase kinase (GSK)-3beta 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 beta-catenin protein accumulation in the cytoplasm or nuclei. The RT-PCR-SSCP and direct sequencing showed that beta-catenin exon 3 mutations existed in 44.1% (15/34) of the HCC. No mutations of GSK-3beta or Tcf-4 were detected in HCC. Moreover, messenger RNA of beta-catenin and Tcf-4, but not GSK-3beta, was found to be overexpressed in HCC. On analyzing the relationship between alterations of beta-catenin or Tcf-4 and C-myc or Cyclin D1 expression, we found that mutations of beta-catenin, as well as overexpression of beta-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 beta-catenin, as well as overexpression of beta-catenin and the Tcf-4 gene, independently activate the Wnt pathway in HCC, with the target gene most likely to be C-myc. (C) 2003 Blackwell Publishing Asia Pty Ltd.