Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
PLoS One. 2013 May 8;8(5):e62589. doi: 10.1371/journal.pone.0062589. Print 2013.
MicroRNAs (miRNAs) act as transcriptional regulators and play pivotal roles in carcinogenesis. According to miRNA target databases, one miRNA may regulate many genes as its targets, while one gene may be targeted by many miRNAs. These findings indicate that relationships between miRNAs and their targets may not be one-to-one. However, many reports have described only a one-to-one, one-to-multiple or multiple-to-one relationship between miRNA and its target gene in human cancers. Thus, it is necessary to determine whether or not a combination of some miRNAs would regulate multiple targets and be involved in carcinogenesis. To find some groups of miRNAs that may synergistically regulate their targets in human gastric cancer (GC), we re-analyzed our previous miRNA expression array data and found that 50 miRNAs were up-regulated on treatment with 5-aza-2'-deoxycytidine in a GC cell line. The "TargetScan" miRNA target database predicted that some of these miRNAs have common target genes. We also referred to the GEO database for expression of these common target genes in human GCs, which might be related to gastric carcinogenesis. In this study, we analyzed two miRNA combinations, miR-224 and -452, and miR-181c and -340. Over-expression of both miRNA combinations dramatically down-regulated their target genes, DPYSL2 and KRAS, and KRAS and MECP2, respectively. These miRNA combinations synergistically decreased cell proliferation upon transfection. Furthermore, we revealed that these miRNAs were down-regulated through promoter hypermethylation in GC cells. Thus, it is likely that the relationships between miRNAs and their targets are not one-to-one but multiple-to-multiple in GCs, and that these complex relationships may be related to gastric carcinogenesis.
微小 RNA（miRNAs）作为转录调控因子，在肿瘤发生中发挥关键作用。根据 miRNA 靶标数据库，一个 miRNA 可能作为其靶标调节许多基因，而一个基因可能被许多 miRNA 靶向。这些发现表明 miRNA 与其靶标之间的关系可能不是一对一的。然而，许多报道仅描述了 miRNA 与其靶基因在人类癌症中的一对一、一对多或多对一关系。因此，有必要确定一些 miRNA 的组合是否可以调节多个靶标并参与肿瘤发生。为了在人类胃癌（GC）中找到一些可能协同调节其靶标的 miRNA 组，我们重新分析了之前的 miRNA 表达谱数据，发现 5-aza-2'-脱氧胞苷处理 GC 细胞系后有 50 个 miRNA 上调。“TargetScan”miRNA 靶标数据库预测其中一些 miRNA 具有共同的靶基因。我们还参考了 GEO 数据库中这些共同靶基因在人类 GC 中的表达情况，这些表达可能与胃癌发生有关。在这项研究中，我们分析了两个 miRNA 组合，miR-224 和 -452，以及 miR-181c 和 -340。两个 miRNA 组合的过表达均显著下调了它们的靶基因 DPYSL2 和 KRAS，以及 KRAS 和 MECP2。这些 miRNA 组合在转染后协同降低细胞增殖。此外，我们揭示了这些 miRNA 在 GC 细胞中通过启动子超甲基化而被下调。因此，miRNA 与其靶标之间的关系可能不是一对一，而是 GC 中的多对多，并且这些复杂的关系可能与胃癌发生有关。
