miR-200b and miR-200c as Prognostic Factors and Mediators of Gastric Cancer Cell Progression
miR-200b and miR-200c as Prognostic Factors and Mediators of Gastric Cancer Cell Progression
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miR-200b 和 miR-200c 作为胃癌细胞进展的预后因素和介质
DOI：
10.1158/1078-0432.ccr-13-1326
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发表时间：
2013-10-15
影响因子：
11.5
通讯作者：
Xie, Xiaoming
中科院分区：
文献类型：
--
作者：
Tang, Hailin;Deng, Min;Xie, Xiaoming
目的：本研究的目的是探讨miR-200b和miR-200c在胃癌发生发展中的临床病理意义和潜在作用。实验设计：我们通过实时荧光定量PCR检测了miR-200b和miR-200c在36对正常和胃肿瘤标本以及胃癌细胞系中的表达。此外，采用胃癌组织微阵列，通过ISH检测miR-200b和miR-200c水平，分析miR-200b和miR-200c水平与临床病理因素和预后的关系。荧光素酶测定法进行靶标评价。通过细胞增殖实验和细胞侵袭迁移实验验证了miR-200b和miR-200c对胃癌细胞的功能影响。结果：miR-200b和miR-200c在胃癌标本和细胞系中下调。miR-200b和miR-200c水平与患者的临床分期、T分期、淋巴结转移及生存率有显著相关。异位表达miR-200b和miR-200c会损害细胞的生长和侵袭。此外，当过表达时，miR-200b和miR-200c通常直接靶向DNMT3A、DNMT3B和SP1 （DNMT1基因的转激活子），导致DNA甲基转移酶DNMT1、DNMT3A和DNMT3B在蛋白水平上的表达显著降低。这种效应进而导致p16、RASS1A1和E-cadherin通过启动子DNA低甲基化导致整体DNA甲基化和重表达的减少。结论：我们的研究结果提示miR-200b和miR-200c作为胃癌预后的有价值的标志物，可能是人类胃癌治疗的一个有希望的途径。(c) 2013年aacr。
Purpose: The purpose of this study was to investigate the clinicopathologic significance and potential role of miR-200b and miR-200c in the development and progression of gastric cancer.Experimental Design: We examined miR-200b and miR-200c expression in 36 paired normal and stomach tumor specimens, as well as gastric cancer cell lines, by quantitative real-time PCR. In addition, miR-200b and miR-200c were detected by ISH using gastric cancer tissue microarrays, and the association between miR-200b and miR-200c levels and clinicopathologic factors and prognosis were analyzed. A luciferase assay was conducted for target evaluation. The functional effects of miR-200b and miR-200c on gastric cancer cells were validated by a cell proliferation assay and cell invasion and migration assays.Results: miR-200b and miR-200c were downregulated in the gastric cancer specimens and cell lines tested. miR-200b and miR-200c levels were significantly correlated with the clinical stage, T stage, lymph node metastasis, and survival of patients. Ectopic expression of miR-200b and miR-200c impaired cell growth and invasion. In addition, when overexpressed, miR-200b and miR-200c commonly directly targeted DNMT3A, DNMT3B, and SP1 (a transactivator of the DNMT1 gene), which resulted in marked reduction of the expression of DNA methyltransferases DNMT1, DNMT3A, and DNMT3B at the protein level. This effect, in turn, led to a decrease in global DNA methylation and reexpression of p16, RASS1A1, and E-cadherin via promoter DNA hypomethylation.Conclusion: Our findings suggest that miR-200b and miR-200c, as valuable markers of gastric cancer prognosis, may be a promising approach to human gastric cancer treatment. (C) 2013 AACR.