Hypermethylation-modulated downregulation of claudin-7 expression promotes the progression of colorectal carcinoma
Hypermethylation-modulated downregulation of claudin-7 expression promotes the progression of colorectal carcinoma
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DOI：
10.1159/000124978
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发表时间：
2008-01-01
期刊：
影响因子：
5
通讯作者：
Yokozaki, Hiroshi
中科院分区：
文献类型：
--
作者：
Nakayama, Fumihito;Semba, Shuho;Yokozaki, Hiroshi
目的：研究紧密连接相关跨膜蛋白claudin-7（CLDN 7）在结直肠癌中的表达及其调控机制。研究方法：进行甲基化特异性聚合酶链反应和用去甲基化剂5-氮杂-2 '-脱氧胞苷处理以分析Colo 320 CRC细胞系中CLDN 7启动子区域的甲基化状态。在免疫组化研究中，我们共使用了26例具有腺瘤成分的0期CRC和90例侵袭性CRC（I-IV期）及其相应的淋巴结转移。结果如下：在Colo 320（CLDN 7阴性）细胞中，检测到CLDN 7启动子处的高甲基化，并且用5-氮杂-2 '-脱氧胞苷处理恢复了CLDN 7表达。在结直肠癌组织中，62%的0期和80%的I-IV期结直肠癌组织中CLDN 7的表达较癌旁组织和非肿瘤性上皮组织明显降低，且与肿瘤血管浸润发生率和临床病理分期密切相关。在20%的CLDN 7低表达的CRC中检测到CLDN 7启动子的超甲基化。然而，CLDN 7表达倾向于在其相应的淋巴结转移中重新表达。结论：这些发现表明，CLDN 7基因沉默启动子甲基化和CLDN 7表达的减少可能在CRC的进展中发挥重要作用。版权所有（C）2008 S. Karger AG，巴塞尔。
Objective: The expression of tight junction-related transmembrane protein claudin-7 (CLDN7) and its regulatory mechanism were investigated in colorectal carcinomas (CRCs). Methods: Methylation-specific polymerase chain reaction and treatment with the demethylating agent 5-aza-2'-deoxycytidine were conducted to analyze the methylation status at the CLDN7 promoter region in the Colo320 CRC cell line. We used a total of 26 stage 0 CRCs with an adenoma component and 90 invasive CRCs (stage I-IV), as well as their corresponding lymph node metastases, in an immunohistochemical study. Results: In Colo320 (CLDN7-negative) cells, hypermethylation at the CLDN7 promoter was detected and treatment with 5-aza-2'-deoxycytidine restored CLDN7 expression. In CRC tissues, decreased CLDN7 expression was detected in 62% of stage 0 CRCs and 80% of stage I-IV CRCs, compared with their adjacent adenoma lesions and nonneoplastic epithelia, which had a close correlation with the incidence of vessel infiltration and clinicopathologic stage. Hypermethylation at the CLDN7 promoter was detected in 20% of CRCs with low CLDN7 expression. However, CLDN7 expression tended to be re-expressed in their corresponding lymph node metastases. Conclusion: These findings suggest that the CLDN7 gene silencing by promoter hypermethylation and the resultant reduction of CLDN7 expression may play an important role in the progression of CRCs. Copyright (C) 2008 S. Karger AG, Basel.