MiR-497 and miR-34a retard lung cancer growth by co-inhibiting cyclin E1 (CCNE1).

Yiguo Jiang,Jianjun Wu,Binbin Liu,Yanbin Zhang,Qiaoyuan Yang,Yajie Zhang,Zhiyuan Han,Chengfeng Yang

doi:10.18632/oncotarget.3693

Abstract

Cyclin E1, encoded by the CCNE1 gene, promotes G1/S transition, chromosome instability, and oncogenesis. Here, we show that miR-497 and miR-34a target the 3'-UTR of CCNE1. miR-497 and miR-34a are downregulated in cancer cells and their ectopic expression inhibited cell proliferation and colony formation in vitro, and inhibited tumor growth in a xenograft model. The effect of simultaneous overexpression of miR-497 and miR-34a on the inhibition of cell proliferation, colony formation, and tumor growth, and the downregulation of cyclin E1 was stronger than the effect of each miRNA alone. The synergistic actions of miR-497 and miR-34a partly correlated with cyclin E1 levels. When cells stably expressing CCNE1 were transfected with the Hi-miR-497/34a plasmid, there was no effect on colony formation, compared with that of cells transfected with either Hi-miR497 or Hi-miR34a. These results indicate cyclin E1 is downregulated by both miR-497 and miR-34a, which synergistically retard the growth of human lung cancer cells.

Highlights

Cancer is a complex disease caused by the progressive accumulation of genetic and epigenetic alterations in cells, which allow the cells to evade normal and environmental controls
Results miR-497 and miR-34a inhibit the proliferation of human lung cancer cells miR-34a is downregulated in lung cancer tissues and cells [23, 24]; few reports have examined the expression of miR-497 in lung cancer
Our study extends the results of others by showing that miR-34a and miR-497 cotarget CCNE1 in lung cancer cells

Summary

Introduction

Cancer is a complex disease caused by the progressive accumulation of genetic and epigenetic alterations in cells, which allow the cells to evade normal and environmental controls. A wide range of biological functions are controlled by miRNAs, including cell proliferation, differentiation, and apoptosis [4,5,6]. In an attempt to understand the mechanisms underlying cancer, an increasing number of studies have reported that individual miRNAs exert their functions in specific cancers. Many recent studies reported that some miRNAs cooperatively control a variety of biological processes, including cell development and differentiation, apoptosis, and the cell cycle [7,8,9,10]. When an mRNA or several different mRNAs involved in a specific biological process are targeted by several miRNAs, the miRNAs act cooperatively. Ventura et al reported that miR-17-92 and miR-106b-25 double-knockout mice have a more severe phenotype than miR-17-92 single-knockout mice [16]

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Conclusion