Multiple-to-Multiple Relationships between MicroRNAs and Target Genes in Gastric Cancer

Hiromu Suzuki,Yasuhito Yuasa,Yoshimitsu Akiyama,Yutaka Hashimoto

doi:10.1371/journal.pone.0062589

Hiromu Suzuki, Yasuhito Yuasa + Show 2 more

Open Access

https://doi.org/10.1371/journal.pone.0062589

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Journal: PLoS ONE	Publication Date: May 8, 2013
Citations: 195	License type: CC BY 4.0

Affiliation: Tokyo Medical and Dental University

Abstract

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.

Highlights

MicroRNAs, a class of small non-protein-coding RNAs, have been identified as a new type of gene regulator that bind to the 3’-untranslated regions (UTRs) of target mRNA, thereby resulting in mRNA degradation or the blockade of mRNA translation [1]
To validate multiple-to-multiple relationships between miRNAs and targets in cancer cells, we demonstrated that two pairs of multiple miRNAs, miR-224 and -452, and miR181c and -340, had multiple target genes and synergistically decreased cell proliferation through regulation of their targets in human gastric cancer (GC) cells
50 miRNAs were up-regulated in a GC Cell Line, KATO-III, after 5-aza-2’-deoxycytidine Treatment

Summary

Introduction

MicroRNAs (miRNAs), a class of small non-protein-coding RNAs, have been identified as a new type of gene regulator that bind to the 3’-untranslated regions (UTRs) of target mRNA, thereby resulting in mRNA degradation or the blockade of mRNA translation [1]. 50 miRNAs were up-regulated in a GC Cell Line, KATO-III, after 5-aza-2’-deoxycytidine Treatment We examined the involvement of epigenetic changes in downregulation of the miRNAs. The expression of miR-224, -340 and 152 was increased by 5-aza-CdR treatment in several GC cell lines (Figure 1B).

Results

Conclusion