Regulation of ovarian cancer progression by microRNA-187 through targeting Disabled homolog-2
Regulation of ovarian cancer progression by microRNA-187 through targeting Disabled homolog-2
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DOI：
10.1038/onc.2011.269
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发表时间：
2012-02-01
期刊：
影响因子：
8
通讯作者：
Lai, C-H
中科院分区：
文献类型：
--
作者：
Chao, A.;Lin, C-Y;Lai, C-H
MicroRNAs(MiRNAs)通过调控癌基因和抑癌基因在肿瘤发生中发挥重要作用。本研究发现miR-187和miR-200a在卵巢癌中的表达水平高于良性肿瘤。然而，在卵巢癌患者中，miR-187和miR-200a的高水平表达与更好的OS和无复发生存率之间存在矛盾的关系。多因素分析显示miR-187是卵巢癌患者的独立预后因素(n=176)。计算预测和微阵列结果表明，miR-187直接靶向DAB2，荧光素酶报告基因分析证实miR-187的靶点位于DAB2基因的3‘端非编码区。DAB2通常被认为是一种肿瘤抑制基因，实际上可能通过上皮向间充质转化(EMT)促进晚期癌症的肿瘤进展。在癌细胞中异位表达miR-187促进细胞增殖，但持续过表达miR-187抑制DAB2并抑制迁移。抑制miR-187上调DAB2，DAB2通过抑制E-钙粘附素水平，同时刺激波形蛋白和磷酸化FAK水平，促进EMT。卵巢癌DAB2组织分数降低与miR-187水平升高和患者预后改善相关。总而言之，这些结果表明DAB2在细胞增殖和肿瘤进展中具有明显的双重作用。在肿瘤发生的最初阶段，上调的miR-187抑制DAB2，促进细胞增殖。然而，在后期，miR-187水平的持续增加抑制了与肿瘤侵袭性相关的DAB2依赖的EMT，这被认为是为什么miR-187水平高的癌症与更好的生存相关的原因。Oncogene(2012年)31764775；doi：10.1038/onc.2011.269；2011年7月4日在线发布
MicroRNAs (miRNAs) play important roles in tumorigenesis by regulating oncogenes and tumor-suppressor genes. In this study, miR-187 and miR-200a were found to be expressed at higher levels in ovarian cancers than in benign tumors. In patients with ovarian cancer, however, higher levels of miR-187 and miR-200a expression were paradoxically associated with better OS and recurrence-free survival. Further, multivariate analysis showed that miR-187 served as an independent prognostic factor for patients with ovarian cancer (n = 176). Computational prediction and microarray results indicated that miR-187 directly targeted Disabled homolog-2 (Dab2), and luciferase reporter assays confirmed that the target site of miR-187 was located at the 3'-UTR of the Dab2 gene. Generally considered as a tumor-suppressor gene, Dab2 may actually promote tumor progression in advanced cancers through epithelial-to-mesenchymal transition (EMT). Ectopic expression of miR-187 in cancer cells promoted cell proliferation, but continued overexpression of miR-187 suppressed Dab2 and inhibited migration. Suppression of miR-187 upregulated Dab2, which, by inhibiting E-cadherin levels while stimulating vimentin and phospho-FAK levels, promoted EMT. Reduced ovarian cancer Dab2 histoscores correlated with high miR-187 levels and improved outcomes of patients. Collectively, these results demonstrate distinct dual roles of Dab2 in cell proliferation and tumor progression. In the initial steps of tumorigenesis, upregulated miR-187 suppresses Dab2, promoting cell proliferation. During the later stages, however, continued increased levels of miR-187 inhibits the Dab2-dependent EMT that is associated with tumor invasiveness, which is presumed to be the reason why cancers with high miR-187 levels were associated with better survivals. Oncogene (2012) 31, 764-775; doi:10.1038/onc.2011.269; published online 4 July 2011