Multiple-to-multiple relationships between microRNAs and target genes in gastric cancer.
Multiple-to-multiple relationships between microRNAs and target genes in gastric cancer.
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DOI：
10.1371/journal.pone.0062589
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Yuasa Y
中科院分区：
文献类型：
--
作者：
Hashimoto Y;Akiyama Y;Yuasa Y
MicroRNAs （miRNAs）作为转录调控因子在癌变过程中发挥着关键作用。根据miRNA靶点数据库，一个miRNA可能调控多个基因作为其靶点，而一个基因可能被多个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，在人类癌症中，许多报道只描述了miRNA与其靶基因之间的一对一、一对多或多对一关系。因此，有必要确定一些mirna的组合是否会调节多个靶点并参与癌变。为了寻找在人胃癌（GC）中可能协同调节其靶点的miRNA群，我们重新分析了我们之前的miRNA表达阵列数据，发现在胃癌细胞系中，5-aza-2'-脱氧胞苷处理后，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，寻找这些可能与胃癌发生有关的人类胃癌中常见靶基因的表达。在这项研究中，我们分析了两种miRNA组合，miR-224和-452，miR-181c和-340。这两种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，我们发现这些mirna在GC细胞中通过启动子超甲基化而下调。因此，在胃癌中，mirna与其靶点之间的关系很可能不是一对一的，而是多对多的，这些复杂的关系可能与胃癌发生有关。
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.
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