Silencing of claudin-11 is associated with increased invasiveness of gastric cancer cells.
Silencing of claudin-11 is associated with increased invasiveness of gastric cancer cells.
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DOI：
10.1371/journal.pone.0008002
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发表时间：
2009-11-24
期刊：
影响因子：
3.7
通讯作者：
Meltzer SJ
中科院分区：
文献类型：
--
作者：
Agarwal R;Mori Y;Cheng Y;Jin Z;Olaru AV;Hamilton JP;David S;Selaru FM;Yang J;Abraham JM;Montgomery E;Morin PJ;Meltzer SJ
紧密连接蛋白是在紧密连接（TJ）的形成和功能中起关键作用的膜蛋白。claudin基因家族的成员已被证明是异常调节的，并参与各种人类癌症的发病机制。在本研究中，我们报告了胃癌中紧密连接蛋白-11（CLDN 11）通过其启动子区域的超甲基化而沉默。分别使用定量甲基化特异性PCR（qMSP）和定量逆转录酶PCR（qRT-PCR）测量原发性胃癌组织、非癌胃粘膜和胃起源细胞系中CLDN 11甲基化和mRNA表达水平。配对胃癌和邻近正常胃组织的分析揭示了胃癌中CLDN 11启动子区域的高甲基化，并且这种高甲基化与CLDN 11表达相对于正常组织的下调显著相关。相对于永生化的正常胃上皮细胞，CLDN 11启动子区域在所有测试的胃癌细胞系中也被高甲基化。此外，CLDN 11 mRNA表达与其甲基化水平呈负相关。用5-氮杂-2 ′-脱氧胞苷处理不表达CLDN 11的胃癌细胞可恢复CLDN 11的表达。此外，siRNA介导的CLDN 11在正常胃上皮细胞中表达的敲低增加了它们的运动性和侵袭性。这些数据表明，CLDN 11的高甲基化导致表达下调，通过增加细胞运动性和侵袭性促进胃癌发生。深入了解claudin蛋白在胃癌发生中的作用机制将有助于发现胃癌诊断和治疗的新方法。
Claudins are membrane proteins that play critical roles in tight junction (TJ) formation and function. Members of the claudin gene family have been demonstrated to be aberrantly regulated, and to participate in the pathogenesis of various human cancers. In the present study, we report that claudin-11 (CLDN11) is silenced in gastric cancer via hypermethylation of its promoter region. Levels of CLDN11 methylation and mRNA expression were measured in primary gastric cancer tissues, noncancerous gastric mucosae, and cell lines of gastric origin using quantitative methylation-specific PCR (qMSP) and quantitative reverse transcriptase-PCR (qRT-PCR), respectively. Analyses of paired gastric cancers and adjacent normal gastric tissues revealed hypermethylation of the CLDN11 promoter region in gastric cancers, and this hypermethylation was significantly correlated with downregulation of CLDN11 expression vs. normal tissues. The CLDN11 promoter region was also hypermethylated in all gastric cancer cell lines tested relative to immortalized normal gastric epithelial cells. Moreover, CLDN11 mRNA expression was inversely correlated with its methylation level. Treatment of CLDN11-nonexpressing gastric cancer cells with 5-aza-2′-deoxycytidine restored CLDN11 expression. Moreover, siRNA-mediated knockdown of CLDN11 expression in normal gastric epithelial cells increased their motility and invasiveness. These data suggest that hypermethylation of CLDN11, leading to downregulated expression, contributes to gastric carcinogenesis by increasing cellular motility and invasiveness. A further understanding of the mechanisms underlying the role of claudin proteins in gastric carcinogenesis will likely help in the identification of novel approaches for diagnosis and therapy of gastric cancer.
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三个紧密连接相关的Maguks ZO-1，ZO-2和ZO-3与Claudins的Cooh Termini直接结合。
DOI：
10.1083/jcb.147.6.1351
发表时间：
1999-12-13
期刊：
The Journal of cell biology
影响因子：
--
作者：
Itoh M;Furuse M;Morita K;Kubota K;Saitou M;Tsukita S
通讯作者：
Tsukita S
影响因子：
3.8
作者：
Cunningham, SC;Kamangar, F;Montgomery, E
通讯作者：
Montgomery, E
影响因子：
3.8
作者：
Hewitt, Kyle J.;Agarwal, Rachana;Morin, Patrice J.
通讯作者：
Morin, Patrice J.
影响因子：
5
作者：
Nakayama, Fumihito;Semba, Shuho;Yokozaki, Hiroshi
通讯作者：
Yokozaki, Hiroshi
影响因子：
64.5
作者：
Gow, A;Southwood, CM;Lazzarini, RA
通讯作者：
Lazzarini, RA