Molecular mechanisms of regulation and action of microRNA-199a in testicular germ cell tumor and glioblastomas.
Molecular mechanisms of regulation and action of microRNA-199a in testicular germ cell tumor and glioblastomas.
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DOI：
10.1371/journal.pone.0083980
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Chan WY
中科院分区：
文献类型：
--
作者：
Gu S;Cheung HH;Lee TL;Lu G;Poon WS;Chan WY
MicroRNA-199a（miRNA-199a）已被证明具有全面的功能，并且在不同的系统和疾病中表现不同。它由人类基因组中的两个基因座编码，即 19 号染色体上的 miR-199a-1 和 1 号染色体上的 miR-199a-2。两个基因座产生相同的 miRNA（miR-199a-5p 和 miR-199a-3p）。 miRNA在不同系统中发挥不同作用的原因尚不清楚。然而，这可能是由于不同细胞和组织中两个基因组位点的不同调控以及 miRNA 的不同靶点所致。在这里，我们研究了睾丸生殖细胞肿瘤（TGCT）和胶质母细胞瘤（胶质瘤）中miR-199a的启动子甲基化，发现miR-199a-1和-2在TGCT中的高甲基化导致其表达降低，而胶质瘤中miR-199a-2而不是-1的低甲基化可能与其表达升高有关。我们还鉴定了一个共同的调节因子 REST，它优先与 miR-199a-1 和 miR-199a-2 的甲基化启动子结合。 miR-199a 的作用取决于其下游靶标。我们将 MAFB 确定为 TGCT 中 miRNA-199a-5p 的推定靶标，并证实 microRNA 的肿瘤抑制活性是由其靶标 MAFB 介导的。通过研究控制miR-199a及其各种下游靶标表达的机制，我们希望以miR-199a作为模型来理解miRNA生物学的复杂性。
MicroRNA-199a (miRNA-199a) has been shown to have comprehensive functions and behave differently in different systems and diseases. It is encoded by two loci in the human genome, miR-199a-1 in chromosome 19 and miR-199a-2 in chromosome 1. Both loci give rise to the same miRNAs (miR-199a-5p and miR-199a-3p). The cause of the diverse action of the miRNA in different systems is not clear. However, it is likely due to different regulation of the two genomic loci and variable targets of the miRNA in different cells and tissues. Here we studied promoter methylation of miR-199a in testicular germ cell tumors (TGCTs) and glioblastomas (gliomas) and discovered that hypermethylation in TGCTs of both miR-199a-1 and -2 resulted in its reduced expression, while hypomethylation of miR-199a-2 but not -1 in gliomas may be related to its elevated expression. We also identified a common regulator, REST, which preferentially bound to the methylated promoters of both miR-199a-1 and miR-199a-2. The action of miR-199a is dependent on its downstream targets. We identified MAFB as a putative target of miRNA-199a-5p in TGCTs and confirmed that the tumor suppression activity of the microRNA is mediated by its target MAFB. By studying the mechanisms that control the expressions of miR-199a and its various downstream targets, we hope to use miR-199a as a model to understand the complexity of miRNA biology.
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