MicroRNA-503 inhibits the G1/S transition by downregulating cyclin D3 and E2F3 in hepatocellular carcinoma

Fenqiang Xiao,Shusen Zheng,Songming Ding,Wu Zhang,Haiyang Xie,Fei Chen,Xiaobo Yu,Haijun Guo,Chunyang Xing,Kangjie Chen,Jun Cheng,Lin Zhou,Liming Chen

doi:10.1186/1479-5876-11-195

Abstract

BackgroundIncreasing evidence indicates that deregulation of microRNAs (miRNAs) is involved in tumorigenesis. Downregulation of microRNA-503 has been observed in various types of diseases, including cancer. However, the biological function of miR-503 in hepatocellular carcinoma (HCC) is still largely unknown. In this study we aimed to elucidate the prognostic implications of miR-503 in HCC and its pathophysiologic role.MethodsQuantitative reverse transcriptase polymerase chain reaction was used to evaluate miR-503 expression in HCC tissues and cell lines. Western blotting was performed to evaluate the expression of the miR-503 target genes. In vivo and in vitro assays were performed to evaluate the function of miR-503 in HCC. Luciferase reporter assay was employed to validate the miR-503 target genes.ResultsmiR-503 was frequently downregulated in HCC cell lines and tissues. Low expression levels of miR-503 were associated with enhanced malignant potential such as portal vein tumor thrombi, histologic grade, TNM stage, AFP level and poor prognosis. Multivariate analysis indicated that miR-503 downregulation was significantly associated with worse overall survival of HCC patients. Functional studies showed miR-503 suppressed the proliferation of HCC cells by induction of G1 phase arrest through Rb-E2F signaling pathways, and thus may function as a tumor suppressor. Further investigation characterized two cell cycle-related molecules, cyclin D3 and E2F3, as the direct miR-503 targets.ConclusionOur data highlight an important role for miR-503 in cell cycle regulation and in the molecular etiology of HCC, and implicate the potential application of miR-503 in prognosis prediction and miRNA-based HCC therapy.

Highlights

Increasing evidence indicates that deregulation of microRNAs is involved in tumorigenesis
One-third of protein-coding genes in humans are reportedly regulated by miRNAs [8]. miRNAs are involved in the regulation of various biological processes, such as development [9], cell proliferation, apoptosis [10], and differentiation [11]
The expression profile of miR-503 in hepatocellular carcinoma (HCC) cell lines and tissues and the clinicopathologic significance of miR-503 expression in HCC To investigate the expression pattern of miR-503 in HCC, we detected the expression of miR-503 in 125 paired HCC and adjacent noncancerous liver tissues by real-time qRTPCR

Summary

Introduction

Increasing evidence indicates that deregulation of microRNAs (miRNAs) is involved in tumorigenesis. The biological function of miR-503 in hepatocellular carcinoma (HCC) is still largely unknown. The development and progression of HCC is a multistage process involving the deregulation of genes that are crucial to cellular processes, such as cell cycle control, cell growth, apoptosis miRNAs are a class of short, endogenous, non-coding RNAs known to negatively regulate the expression of protein-coding genes through binding to the 3′ untranslated regions (3′ UTRs) of target genes [6,7]. MiRNAs are involved in the regulation of various biological processes, such as development [9], cell proliferation, apoptosis [10], and differentiation [11]. Liu et al reported that the miR-16 family induces cell cycle arrest by downregulating the expression of CCND3, CCNE1 and CDK6 [17]. The specific signaling pathways regulated by miR-503 and the detailed mechanisms in tumorigenesis are still unknown

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