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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >A microRNA DNA methylation signature for human cancer metastasis
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A microRNA DNA methylation signature for human cancer metastasis

机译：microRNA DNA甲基化标志物转移人类癌症

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MicroRNAs (miRNAs) are small, noncoding RNAs that can contribute to cancer development and progression by acting as oncogenes or tumor suppressor genes. Recent studies have also linked different sets of miRNAs to metastasis through either the promotion or suppression of this malignant process. Interestingly, epigenetic silencing of miRNAs with tumor suppressor features by CpG island hypermethylation is also emerging as a common hallmark of human tumors. Thus, we wondered whether there was a miRNA hypermethylation profile characteristic of human metastasis. We used a pharmacological and genomic approach to reveal this aberrant epigenetic silencing program by treating lymph node metastatic cancer cells with a DNA demethylating agent followed by hybridization to an expression microarray. Among the miRNAs that were reactivated upon drug treatment, miR-148a, miR-34b/c, and miR-9 were found to undergo specific hypermethylation-associated silencing in cancer cells compared with normal tissues. The reintroduction of miR-148a and miR-34b/c in cancer cells with epigenetic inactivation inhibited their motility, reduced tumor growth, and inhibited metastasis formation in xenograft models, with an associated down-regulation of the miRNA oncogenic target genes, such as C-MYC, E2F3, CDK6, and TGIF2. Most important, the involvement of miR-148a, miR-34b/c, and miR-9 hypermethylation in metastasis formation was also suggested in human primary malignancies (n = 207) because it was significantly associated with the appearance of lymph node metastasis. Our findings indicate that DNA methylation-associated silencing of tumor suppressor miRNAs contributes to the development of human cancer metastasis.
机译：微小RNA（miRNA）是小的非编码RNA，可通过充当癌基因或抑癌基因来促进癌症的发展和进展。最近的研究还通过促进或抑制这种恶性过程将不同组的miRNA与转移联系起来。有趣的是，通过CpG岛超甲基化具有肿瘤抑制功能的miRNA的表观遗传沉默也正在成为人类肿瘤的共同特征。因此，我们想知道是否存在人类转移的特征性miRNA高甲基化谱。我们使用药理学和基因组学方法来揭示这种异常的表观遗传沉默程序，方法是用DNA去甲基化剂处理淋巴结转移性癌细胞，然后与表达微阵列杂交。在药物治疗后重新激活的miRNA中，与正常组织相比，发现miR-148a，miR-34b / c和miR-9在癌细胞中经历了特定的高甲基化相关沉默。在表观遗传失活的癌细胞中重新引入miR-148a和miR-34b / c抑制了它们的运动能力，减少了肿瘤的生长并抑制了异种移植模型中的转移形成，并伴随着miRNA致癌靶基因（如C）的下调-MYC，E2F3，CDK6和TGIF2。最重要的是，在人类原发性恶性肿瘤（n = 207）中也暗示了miR-148a，miR-34b / c和miR-9甲基化参与转移形成，因为它与淋巴结转移的出现密切相关。我们的发现表明，肿瘤抑制miRNA的DNA甲基化相关沉默有助于人类癌症转移的发展。

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