MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B
MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B
复制标题
DOI：
10.1073/pnas.0707628104
复制
发表时间：
2007-10-02
影响因子：
11.1
通讯作者：
Croce, Carlo M.
中科院分区：
文献类型：
--
作者：
Fabbri, Muller;Garzon, Ramiro;Croce, Carlo M.
microRNA（miRNAs）是一类小的非编码RNA，可调控多种基因的表达。最近的研究表明miRNA在肿瘤发生中的作用。我们和其他人已经表明，miRNA的表达谱在肺癌与正常肺中是不同的，尽管这种异常表达的意义知之甚少。在已报道的肺癌中下调的miRNA中，miRNA（miR）-29家族（29 a、29 b和29 c）与DNA甲基转移酶（DNMT）3A和-3B（从头甲基转移酶）的3 '-UTR具有有趣的互补性，DNMT 3A和-3B是参与DNA甲基化的两种关键酶，其在肺癌中频繁上调并与不良预后相关。我们研究了miR-29 s是否可以靶向DNMT 3A和-B，以及miR-29 s的恢复是否可以使非小细胞肺癌中异常的甲基化模式正常化。在这里，我们发现miR-29 s的表达与肺癌组织中的DNMT 3A和-3B呈负相关，并且miR-29 s直接靶向DNMT 3A和-3B。肺癌细胞系中miR-29的强制表达恢复了DNA甲基化的正常模式，诱导甲基化沉默的肿瘤抑制基因（如FHIT和WWOX）的再表达，并抑制体外和体内致瘤性。这些发现支持miR-29在NSCLC表观遗传正常化中的作用，为开发基于miRNA的肺癌治疗策略提供了理论基础。
MicroRNAs (miRNAs) are small, noncoding RNAs that regulate expression of many genes. Recent studies suggest roles of miRNAs in carcinogenesis. We and others have shown that expression profiles of miRNAs are different in lung cancer vs. normal lung, although the significance of this aberrant expression is poorly understood. Among the reported down-regulated miRNAs in lung cancer, the miRNA (miR)-29 family (29a, 29b, and 29c) has intriguing complementarities to the 3'-UTRs of DNA methyltransferase (DNMT)3A and -3B (de novo methyltransferases), two key enzymes involved in DNA methylation, that are frequently up-regulated in lung cancer and associated with poor prognosis. We investigated whether miR-29s could target DNMT3A and -B and whether restoration of miR-29s could normalize aberrant patterns of methylation in non-small-cell lung cancer. Here we show that expression of miR-29s is inversely correlated to DNMT3A and -3B in lung cancer tissues, and that miR-29s directly target both DNMT3A and -3B. The enforced expression of miR-29s in lung cancer cell lines restores normal patterns of DNA methylation, induces reexpression of methylation-silenced tumor suppressor genes, such as FHIT and WWOX, and inhibits tumorigenicity in vitro and in vivo. These findings support a role of miR-29s in epigenetic normalization of NSCLC, providing a rationale for the development of miRNA-based strategies for the treatment of lung cancer.