Expression of esophageal cancer related gene 4 (ECRG4), a novel tumor suppressor gene, in esophageal cancer and its inhibitory effect on the tumor growth in vitro and in vivo
Expression of esophageal cancer related gene 4 (ECRG4), a novel tumor suppressor gene, in esophageal cancer and its inhibitory effect on the tumor growth in vitro and in vivo
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DOI：
10.1002/ijc.24513
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发表时间：
2009-10-01
影响因子：
6.4
通讯作者：
Lu, Shih-Hsin
中科院分区：
文献类型：
--
作者：
Li, Lin-Wei;Yu, Xi-Ying;Lu, Shih-Hsin
ECRG4基因最初是在我们实验室从人正常食管上皮中鉴定和克隆的（GenBank登录号AF325503）。组织芯片检测结果显示，68.5%（89/130）的食管鳞癌组织中ECRG4蛋白表达下调。ECRG4蛋白的低表达与食管鳞癌的淋巴结转移、原发灶大小及分期有关（p <0.05）。ECRG4基因启动子甲基化导致ECRG4 mRNA表达下调。用DNA甲基转移酶抑制剂5-氮杂-2'-脱氧胞苷处理恢复了ESCC细胞中ECRG4 mRNA的表达。结果表明，启动子区甲基化可能是导致ECRG4基因沉默的主要机制之一。Kaplan-Meier生存分析显示ECRG4高表达组患者的生存期较ECRG4低表达组延长（p <0.05）。多因素考克斯比例风险回归分析显示ECRG 4蛋白是食管鳞癌的独立预后因素（p <0.05）。ECRG4在ESCC细胞中的恢复表达在体内抑制细胞增殖、集落形成、非贴壁依赖性生长、细胞周期进展和肿瘤生长（p <0.05）。ECRG 4基因转染ESCC细胞后，NF-κ B的表达和核转位受到抑制，NF-κ B靶基因COX-2的表达也受到抑制。综上所述，ECRG4是一个新的候选抑癌基因在ESCC中，ECRG4蛋白是一个候选的ESCC预后标志物。(C)2009年UICC
The ECRG4 gene was initially identified and cloned in our laboratory from human normal esophageal epithelium (GenBank accession no. AF325503). We revealed the expression of ECRG4 protein was downregulated in 68.5% (89/130) ESCC samples using tissue microarray. The low ECRG4 protein expression was significantly associated with regional lymph node metastasis, primary tumor size, and tumor stage in ESCC (p < 0.05). ECRG4 mRNA expression was downregulated in ESCC due to the hypermethylation in the gene promoter. The treatment with 5-aza-2'-deoxycytidine, which is a DNA methyltransferase inhibitor restored ECRG4 mRNA expression in ESCC cells. The result indicated that promoter hypermethylation may be 1 main mechanism leading to the silencing of ECRG4. The high expression of ECRG4 in patients with ESCC was associated with longer survival compared with those with low ECRG4 expression by Kaplan-Meier survival analysis (p < 0.05). ECRG4 protein was an independent prognostic factor for ESCC by multivariable Cox proportional hazards regression analysis (p < 0.05). The restoration of ECRG4 expression in ESCC cells inhibited cell proliferation, colony formation, anchorage-independent growth, cell cycle progression and tumor growth in vivo (p < 0.05). The transfection of ECRG4 gene in ESCC cells inhibited the expression of NF-kappa B and nuclear translocation, in addition to the expression of COX-2, a NF-kappa B target gene, was attenuated. Taken together, ECRG4 is a novel candidate tumor suppressor gene in ESCC, and ECRG4 protein is a candidate prognostic marker for ESCC. (C) 2009 UICC