Genome-wide pharmacologic unmasking identifies tumor suppressive microRNAs in multiple myeloma.
Genome-wide pharmacologic unmasking identifies tumor suppressive microRNAs in multiple myeloma.
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DOI：
10.18632/oncotarget.4769
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发表时间：
2015-09-22
期刊：
影响因子：
--
通讯作者：
Chng WJ
中科院分区：
文献类型：
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作者：
Bi C;Chung TH;Huang G;Zhou J;Yan J;Ahmann GJ;Fonseca R;Chng WJ
表观遗传改变已成为 microRNA (miRNA) 失调的重要原因。在多发性骨髓瘤（MM）中，已经报道了一些因DNA高甲基化而沉默的肿瘤抑制miRNA，但迄今为止，对表观遗传学沉默的miRNA的系统研究还很少。我们对 MM 中表观遗传沉默的肿瘤抑制 miRNA 进行了全基因组筛选。用去甲基化剂 5'氮杂胞苷 (5'aza) 处理四种人 MM 细胞系。持续上调的 miRNA 包括 miR-155、miR-198、miR-135a*、miR-200c、miR-125a-3p、miR-188-5p、miR-483-5p、miR-663 和 miR-630。甲基化芯片分析显示 MM 患者中 miRNA 相关 CpG 岛或其附近的甲基化增加。 miR-155、miR-198、miR-135a*、miR-200c、miR-663 和 miR-483-5p 的异位恢复显着抑制 MM 细胞增殖、迁移和集落形成。此外，我们从预测的 miRNA 靶基因中得出了 33 个基因特征，这些基因在 MM 患者中也上调，并且在三个独立的骨髓瘤数据集中与患者生存相关。总之，我们通过药理逆转表观遗传沉默揭示了重要的、表观遗传沉默的肿瘤抑制 miRNA。
Epigenetic alterations have emerged as an important cause of microRNA (miRNA) deregulation. In Multiple Myeloma (MM), a few tumor suppressive miRNAs silenced by DNA hypermethylation have been reported, but so far there are few systemic investigations on epigenetically silenced miRNAs. We conducted genome-wide screening for tumor suppressive miRNAs epigenetically silenced in MM. Four Human MM Cell lines were treated with demethylating agent 5′azacytidine (5′aza). Consistently upregulated miRNAs include miR-155, miR-198, miR-135a*, miR-200c, miR-125a-3p, miR-188-5p, miR-483-5p, miR-663, and miR-630. Methylation array analysis revealed increased methylation at or near miRNA-associated CpG islands in MM patients. Ectopic restoration of miR-155, miR-198, miR-135a*, miR-200c, miR-663 and miR-483-5p significantly repressed MM cell proliferation, migration and colony formation. Furthermore, we derived a 33-gene signature from predicted miRNA target genes that were also upregulated in MM patients and associated with patient survival in three independent myeloma datasets. In summary, we have revealed important, epigenetically silenced tumor suppressive miRNAs by pharmacologic reversal of epigenetic silencing.