食管鳞状细胞癌中CDH1基因启动子区甲基化状态与β-catenin异质表达的相关性

郭艳丽; 郭炜; 杨植彬; 邝钢; 董稚明

doi:10.3969/j.issn.1000-8179.2011.01.002

摘要: 目的：研究食管鳞状细胞癌（Esophageal Squamous Cell Cancer， ESCC）中CDH1 （cadherin 1）基因的甲基化状态，探讨其与Wnt中心因子β-catenin表达及与食管鳞癌发生的关系。方法：应用甲基化特异性PCR （MSP）及RT-PCR的方法检测91例食管鳞癌中CDH1基因的甲基化状态及其mRNA表达情况，应用免疫组织化学的方法检测β-catenin蛋白的表达情况，并分析与临床病理参数间的关系。结果：在91例食管鳞癌中，有72例CDH1基因发生了甲基化，甲基化率为79.1%，明显高于癌旁非肿瘤组织（P<0.01）；癌组织中CDH1基因的高甲基化与肿瘤患者的临床分期相关，与病理分级无关；癌组织中该基因mRNA的阳性表达率42.9%，明显低于癌旁非肿瘤组织（97.8%,P<0.01）；癌及癌旁组织中β-catenin蛋白的异质表达率分别为89.0%和24.2%，差异均有统计学意义（P<0.01）；癌组织中CDH1基因mRNA表达及β-catenin蛋白的异质表达均与该基因的甲基化状态明显相关（P<0.05）。结论： CDH1基因启动子区甲基化在食管鳞癌中频繁发生，该基因的高甲基化状态可能是引起食管鳞癌发生的分子机制之一，并有可能通过Wnt/β-catenin信号传导通路发挥作用。

Abstract: Promoter Hypermethylation of CDH1 Gene and Ectopic Expression of β-catenin inEsophageal Squamous Cell CancerYanli GUO, Wei GUO, Zhibin YANG, Gang KUANG, Zhiming DONGCorrespondence to: Zhiming DONG, E-mail: dddzzzmmm@yahoo.com.cnPathology Laboratory of Hebei Cancer Institute, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, He-bei, ChinaThis work was supported by funds of Hebei Planning Program for Key Subjects of Medical Research (No.20090466)Abstract Objective: To investigate promoter methylation of the cadherin 1 (CDH1) gene in esophageal squamouscell cancer (ESCC) and adjacent non-cancerous tissues, and to probe the possible relationship between DNA methylationstatus and pathogenesis of ESCC. Methods: Methylation-specific PCR (MSP) and RT-PCR were used to examine the meth-ylation status of the CDH1 gene and its mRNA expression in samples of 91 ESCC cases and correlated adjacent non-can-cerous tissues. Immunohistochemistry was used to determine the expression of β-catenin protein (key factor of the Wnt sig-nalling pathway), and to analyze the relationship between protein expression and clinicopathologic parameters. Results:Methylation of the CDH1 promoter was found in 72 of the 91 ESCC cases. The frequency of promoter methylation was79.1% in ESCC tumor samples, significantly higher than that in the adjacent non-cancerous tissues ( P < 0.01). Hypermeth-ylation of the CDH1 gene was correlated with clinical stage, but not with pathological grade of ESCC. Furthermore, the posi-tive rate of CDH1 mRNA expression was 42.9% in the cancer tissues, obviously lower than that in the adjacent non-cancer-ous tissues (97.8%, P < 0.01). The ectopic expression rates of β-catenin protein were 89.0% and 24.2% in ESCC and therelated adjacent non-cancerous tissues, respectively, with a significant difference between the two groups ( P < 0.01). Boththe mRNA expression and the ectopic expression of β-catenin protein were correlated with the frequency of CDH1 genepromoter methylation ( P < 0.05). Conclusion: Methylation of the CDH1 promoter region is a frequent event in ESCC. Hy-permethylation may be one of the molecular mechanisms resulting in the pathogenesis of ESCC, perhaps through an aber-rant Wnt/?-catenin signaling pathway.Key words Esophageal squamous cell cancer; Methylation; CDH1 gene