Targeting of YAP1 by microRNA-15a and microRNA-16-1 exerts tumor suppressor function in gastric adenocarcinoma.

Wei Kang,Jesse Cs Pang,Li Zhang,Yi Pan,Qiaoyi Liang,Weiqin Yang,Ka Fai To,Yujuan Dong,Joanna Hm Tong,Raymond Wm Lung,Junhong Zhao,Jun Yu,Alfred Sl Cheng

doi:10.1186/s12943-015-0323-3

Abstract

BackgroundMicroRNAs (miRNAs) have been reported to play an important role in tumorigenesis. In this study, the role of miR-15a and miR-16-1 in gastric adenocarcinoma (GAC) was investigated.MethodsThe expression of miR-15a and miR-16-1 in cell lines and primary tumors was examined by miRNA qRT-PCR. Proliferative assays, colony formation, cell invasion and migration, flow cytometry analysis and in vivo study were performed by ectopic expression of miR-15a and miR-16-1. The putative target genes of miR-15a and miR-16-1 were explored by TargetScan and further validated.ResultsWe found that miR-15a and miR-16-1 were down-regulated in GAC cell lines and primary tumor samples compared with normal gastric epithelium. Functional study demonstrated that ectopic expression of miR-15a and miR-16-1 suppressed cell proliferation, monolayer colony formation, invasion and migration, and xenograft formation in vivo. In addition, miR-15a and miR-16-1 induced G0/G1 cell cycle arrest which was further confirmed by Western blot and qRT-PCR of related cell cycle regulators. YAP1 was confirmed to be a functional target of miR-15a and miR-16-1 in GAC. YAP1 re-expression partly abrogated the inhibitory effect of miR-15a and miR-16-1 in GAC cells. In clinical samples, YAP1 protein expression shows negative correlation with miR-15a and miR-16-1 expression.ConclusionIn conclusion, targeting YAP1 by tumor suppressor miRNA miR-15a and miR-16-1 plays inhibitory effect and this might have a therapeutic potential in GAC.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0323-3) contains supplementary material, which is available to authorized users.

Highlights

MicroRNAs have been reported to play an important role in tumorigenesis
Results miR-15a and miR-16-1 are down-regulated in gastric adenocarcinoma (GAC) miR-15a and miR-16-1 showed decreased expression in 7 and 9 gastric cancer cell lines respectively compared with immortalized gastric epithelium cell lines GES-1 (Figure 1A)
In 60 paired primary GAC samples, miR15a and miR-16-1 showed downregulation in adenocarcinoma compared with corresponding adjacent nontumorous mucosae

Summary

Introduction

MicroRNAs (miRNAs) have been reported to play an important role in tumorigenesis. In this study, the role of miR-15a and miR-16-1 in gastric adenocarcinoma (GAC) was investigated. MicroRNAs (miRNAs) recently have been identified as one of the crucial players in carcinogenesis through post-transcriptional regulation of their target genes [6]. MiRNA is a class of small non-coding RNAs which function as regulators of gene expression through specific binding to the miRNA recognition elements (MREs) on the 3′ untranslated regions (UTRs) of target mRNAs. MicroRNAs (miRNAs) recently have been identified as one of the crucial players in carcinogenesis through post-transcriptional regulation of their target genes [6]. MiRNA is a class of small non-coding RNAs which function as regulators of gene expression through specific binding to the miRNA recognition elements (MREs) on the 3′ untranslated regions (UTRs) of target mRNAs This results in mRNA degradation or translational repression. Emerging evidence shows that miRNAs are abnormally expressed in various cancers and the

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