Epigenetic inactivation of microRNA gene hsa-mir-9-1 in human breast cancer
Epigenetic inactivation of microRNA gene hsa-mir-9-1 in human breast cancer
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DOI：
10.1002/path.2251
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发表时间：
2008-01-01
影响因子：
7.3
通讯作者：
Kreipe, H.
中科院分区：
文献类型：
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作者：
Lehmann, U.;Hasemeier, B.;Kreipe, H.
microRNA（miRNAs）是一类新的非编码小RNA，通过诱导RNA降解或干扰翻译来调控基因表达。已经描述了几种人类恶性肿瘤的异常miRNA表达，并且已经将肿瘤抑制功能归因于这类新的小调控RNA。因此，在人类恶性肿瘤中发现了由于缺失或突变引起的失活。在这里，我们描述了异常甲基化作为人类乳腺癌中miRNA基因失活的额外机制的作用。在一系列71例原发性人乳腺癌标本中，34-86%的病例显示mir-9-1、mir-124 a3、mir-148、mir-152和mir-663异常高甲基化。对于全面的甲基化分析，采用组合的亚硫酸氢盐限制性分析、亚硫酸氢盐测序和焦磷酸测序（TM）。miRNA基因甲基化与已知肿瘤抑制基因的甲基化密切相关（p=0.003）。在用去甲基化剂5-氮杂-2 '-脱氧胞苷处理各种乳腺癌细胞系后，可以观察到mir-9-1基因甲基化的降低和伴随的表达再活化。对于mir-9-1基因，其在浸润前导管内病变中已经高甲基化，在原发性人乳腺癌样本的子集中可以证明定量甲基化水平和表达减少之间的良好相关性（r=0.8）。总之，这项研究表明，各种microRNA基因也受到异常高甲基化引起的表观遗传失活的影响，这是乳腺癌发展中的早期和频繁事件。版权所有（c）2007大不列颠和爱尔兰病理学会。出版社：John Wiley & Sons公司
MicroRNAs (miRNAs) represent a new class of small non-coding RNAs regulating gene expression by inducing RNA degradation or interfering with translation. Aberrant miRNA expression has been described for several human malignancies and tumour suppressor functions have been ascribed to this new class of small regulatory RNAs. Accordingly, inactivation due to deletion or mutation has been found in human malignancies. Here, we describe the role of aberrant hypermethylation as an additional mechanism for miRNA gene inactivation in human breast cancer. Aberrant hypermethylation was shown for mir-9-1, mir-124a3, mir-148, mir-152, and mir-663 in 34-86% of cases in a series of 71 primary human breast cancer specimens. For comprehensive methylation analysis, combined bisulphite restriction analysis, bisulphite sequencing, and Pyrosequencing (TM) were employed. miRNA gene hypermethylation correlated strongly with methylation of known tumour suppressor genes (p=0.003). After treatment of various breast cancer cell lines with the demethylating agent 5-aza-2'-deoxycytidine, reduction of mir-9-1 gene methylation and concomitant reactivation of expression could be observed. For the mir-9-1 gene, which is already hypermethylated in pre-invasive intraductal lesions, a good correlation between quantitative methylation level and reduction of expression could be demonstrated in a subset of primary human breast cancer specimen (r=0.8). In conclusion, this study demonstrates that various microRNA genes are also affected by epigenetic inactivation due to aberrant hypermethylation and that this is an early and frequent event in breast cancer development. Copyright (c) 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons., Ltd.