MicroRNA-188 suppresses G1/S transition by targeting multiple cyclin/CDK complexes.

Jiangbin Wu,Weidong Xie,Yaou Zhang,Qing Lv,Nunu Huang,Haoxiang Zhang,Kai Cui,Xueshuang Mei,Jie He,Naihan Xu

doi:10.1186/s12964-014-0066-6

Abstract

BackgroundAccelerated cell cycle progression is the common feature of most cancers. MiRNAs can act as oncogenes or tumor suppressors by directly modulating cell cycle machinery. It has been shown that miR-188 is upregulated in UVB-irradiated mouse skin and human nasopharyngeal carcinoma CNE cells under hypoxic stress. However, little is known about the function of miR-188 in cell proliferation and growth control.ResultsOverexpression of miR-188 inhibits cell proliferation, tumor colony formation and G1/S cell cycle transition in human nasopharyngeal carcinoma CNE cells. Using bioinformatics approach, we identify a series of genes regulating G1/S transition as putative miR-188 targets. MiR-188 inhibits both mRNA and protein expression of CCND1, CCND3, CCNE1, CCNA2, CDK4 and CDK2, suppresses Rb phosphorylation and downregulates E2F transcriptional activity. The expression level of miR-188 also inversely correlates with the expression of miR-188 targets in human nasopharyngeal carcinoma (NPC) tissues. Moreover, studies in xenograft mouse model reveal that miR-188 is capable of inhibiting tumor initiation and progression by suppressing target genes expression and Rb phosphorylation.ConclusionsThis study demonstrates that miR-188 exerts anticancer effects, via downregulation of multiple G1/S related cyclin/CDKs and Rb/E2F signaling pathway.Electronic supplementary materialThe online version of this article (doi:10.1186/s12964-014-0066-6) contains supplementary material, which is available to authorized users.

Highlights

Accelerated cell cycle progression is the common feature of most cancers
Inverse correlation of miR-188 and its target genes in NPC tissues To define the clinical relevance of our findings that miR188 suppressed the expression of G1/S related cyclin/ Cyclin dependent kinase (CDK), we showed that miR-188 expression was possibly associated with human nasopharyngeal carcinoma
Since we have shown that miR-188 downregulates the expression of Cyclin D/CDK4 and Cyclin E/CDK2 complexes, we wanted to ask whether overexpression of miR-188 would have an impact on Retinoblastoma protein (Rb) phosphorylation

Summary

Introduction

Accelerated cell cycle progression is the common feature of most cancers. MiRNAs can act as oncogenes or tumor suppressors by directly modulating cell cycle machinery. MiRNAs are important regulators of various biological and pathological processes, including cell proliferation, differentiation, apoptosis, metabolism and cancer [2,3,4,5,6,7,8,9,10,11]. G1 to S phase progression is regulated by the Retinoblastoma protein (Rb). Rb is a tumor suppressor protein that plays a pivotal role in the negative control of cell cycle and in tumor progression [21,22]. When it is time for a cell to enter S phase, the inactivating phosphorylation of Rb by the G1/S CDKs results in the release of Rb from E2F-DP1 and allows for the activation of E2F target genes that are responsible for facilitating G1/S transition and S phase progression

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