DNA Methylation-Mediated Repression of miR-886-3p Predicts Poor Outcome of Human Small Cell Lung Cancer
DNA Methylation-Mediated Repression of miR-886-3p Predicts Poor Outcome of Human Small Cell Lung Cancer
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DOI：
10.1158/0008-5472.can-12-3055
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发表时间：
2013-06-01
期刊：
影响因子：
11.2
通讯作者：
Zhan, Qimin
中科院分区：
文献类型：
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作者：
Cao, Jianzhong;Song, Yongmei;Zhan, Qimin
小细胞肺癌（SCLC）是最具侵袭性的癌症类型之一，但其破坏性临床结果的病理机制仍然难以捉摸。在这份报告中，我们调查了42例SCLC患者福尔马林固定石蜡包埋标本中924个miRNA（miR）的表达，发现下调的miR-886- 3 p与SCLC的生存期缩短密切相关。另外40例病例证实了这种相关性。进一步发现，在培养的SCLC细胞和肿瘤样品中，miR-886- 3 p表达的丧失由其启动子的DNA超甲基化介导。此外，miR-886- 3 p通过在转录后水平抑制其靶基因PLK 1和TGF-β 1的表达，有效抑制细胞培养物中NCI-H446细胞的细胞增殖、迁移和侵袭。miR-886- 3 p的强制上调极大地抑制了NCI-H446细胞的体内肿瘤生长、骨/肌肉侵袭和肺转移。这种新鉴定的调节SCLC侵袭性的miR-886- 3 p-PLK 1/TGF-β 1关系表明，miR-886- 3 p表达的缺失和miR-886启动子的超甲基化是SCLC不良结局的有希望的指标以及新的治疗靶点。(C)2013年AACR。
Small cell lung cancer (SCLC) is one of the most aggressive types of cancer, yet the pathologic mechanisms underlying its devastating clinical outcome remain elusive. In this report, we surveyed 924 miRNA (miR) for their expressions in the formalin-fixed paraffin-embedded specimens from 42 patients with SCLC, and found that the downregulated miR-886-3p is closely correlated with the shorter survival of SCLC. This correlation was validated with another 40 cases. It was further discovered that loss of miR-886-3p expression was mediated by DNA hypermethylation of its promoter in both cultured SCLC cells and tumor samples. Moreover, miR-886-3p potently repressed cell proliferation, migration, and invasion of NCI-H446 cell in cell culture via suppression of the expression of its target genes: PLK1 and TGF-beta 1 at posttranscription levels. Forced upregulation of miR-886-3p greatly inhibited in vivo tumor growth, bone/muscle invasion, and lung metastasis of NCI-H446 cells. This newly identified miR-886-3p-PLK1/TGF-beta 1 nexus that modulates SCLC aggression suggests that both loss of miR-886-3p expression and hypermethylation of the miR-886 promoter are the promising indicators for poor outcome of as well as new therapeutic targets for SCLC. (C) 2013 AACR.