MicroRNA-92a contributes to tumor growth of human hepatocellular carcinoma by targeting FBXW7.

Wei Yang,Yufeng Wang,Xin Zheng,Chao Li,Changwei Dou,Yuli Jia,Kangsheng Tu

doi:10.3892/or.2015.4210

Abstract

Deregulation of microRNA-92a (miR-92a) has been reported in several human cancers and is associated with prognosis of patients. However, the clinical significance of miR-92a and the underlying mechanisms involved in hepatocarcinogenesis remain to be determined. The aim of the present study was to determine the role of miR-92a in hepatocellular carcinoma (HCC). The results showed that the expression of miR-92a was upregulated in HCC tissues as compared with matched tumor-adjacent tissues. A high expression of miR-92a was observed in HCC cell lines as compared with a non-transformed hepatic cell line. The gain- and loss-of-function studies revealed that miR-92a significantly promoted proliferation and cell cycle transition from G1 to Sphase, and inhibited apoptosis of HCC cell in vitro. In tumor‑bearing nude mice, the downregulation of miR-92a suppressed tumor growth of HCC invivo. miR-92a was inversely correlated with F-box and WD repeat domain-containing 7 (FBXW7) expression in HCC tissues. Furthermore, miR-92a negatively regulated FBXW7 abundance in HCC cells. In the present study, FBXW7 was identified as a direct target of miR-92a. Notably, alterations of FBXW7 expression abrogated the effects of miR-92a on HCC cell proliferation, cell cycle and apoptosis. Clinical association analysis revealed that a high expression of miR-92a was correlated with poor prognostic characteristics of HCC. Notably, the high expression of miR-92a conferred a reduced 5-year overall survival (OS) and recurrence-free survival (RFS) of HCC patients. The multivariate Cox regression analysis demonstrated that miR-92a expression was an independent prognostic marker for predicting survival of HCC patients. In conclusion, the results of the present study suggested that miR-92a promotes the tumor growth of HCC by targeting FBXW7 and may serve as a novel prognostic biomarker and therapeutic target for HCC.

Highlights

MicroRNAs are a group of endogenous small non‐coding RNA molecules, which regulate protein-coding gene expression by interacting with complementary sites within the 3'-untranslated region (UTR) of target mRNAs and targeting mRNAs for cleavage or translational repression [1]
The results showed that the expression of miR-92a was upregulated in hepatocellular carcinoma (HCC) tissues. miR-92a promoted proliferation, cell cycle and apoptosis resistance in vitro
The results showed that the mean level of miR-92a expression in HCC tissues was significantly higher than that in the non-tumor tissues (P

Summary

Introduction

MicroRNAs (miRNAs) are a group of endogenous small non‐coding RNA molecules, which regulate protein-coding gene expression by interacting with complementary sites within the 3'-untranslated region (UTR) of target mRNAs and targeting mRNAs for cleavage or translational repression [1]. MiR-92a, which belongs to the miR-17-92 cluster, plays a critical role in the progression of lung cancer [6], esophageal squamous cell carcinoma [7], colorectal [8], breast [9], ovarian [10] and cervical cancer [11]. MiR-92a promotes lung cancer cell invasion by targeting reversion‐inducing-cysteine-rich protein with Kazal motifs (RECK) and a high expression of miR-92a is associated with the poor survival rate of lung cancer patients [6,13]. Upregulation of miR-92a inhibits ovarian cancer cell adhesion, invasion and proliferation by suppressing integrin α5 expression [10]. The proliferation of HCC-derived cell lines was enhanced by the upregulation of miR-92a and inhibited by the downregulation of miR-92a [16]. Yang et al: miR-92a promotes HCC by targeting FBXW7 the clinical significance of miR-92a and the underlying mechanisms involved in the development of HCC remain to be investigated

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Conclusion