Abstract

Recent studies have shown that miR-564 is closely related to the development of various tumors, including breast cancer, lung cancer and glioma. However, few studies have examined miR-564 in hepatocellular carcinoma (HCC). Here, we demonstrated that miR-564 expression in HCC tissues was lower than that in adjacent noncancerous tissues and that miR-564 expression was associated with tumor size, tumor number and vein invasion. Bioinformatics analyses showed that low levels of miR-564 were correlated with poor prognosis. Furthermore, upregulation of miR-564 impaired SMCC7721 and MHCC97H cell proliferation, migration and invasion in vitro and reduced tumorigenesis in vivo. Next, we found that GRB2 was a direct target gene of miR-564 in the HCC cell lines. GRB2 was highly expressed in HCC tissues and negatively correlated with miR-564 expression levels. When GRB2 was downregulated by GRB2-siRNA, HCC cell proliferation, invasion and metastasis were impaired, and restoring GRB2 expression partially reversed the inhibitory effects of miR-564. Western blot analysis showed that miR-564 overexpression reduced GRB2 expression in HCC cell lines and inhibited ERK1/2 and AKT phosphorylation. miR-564 overexpression also upregulated the epithelial-like cell marker E-cadherin and downregulated the interstitial cell-like markers N-cadherin and vimentin. These results suggest that miR-564 inhibits the malignant phenotype of HCC cells by targeting the GRB2-ERK1/2-AKT axis. Consequently, miR-564 may be used as a prognostic marker and therapeutic target for HCC.

Highlights

  • Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world

  • GRB2 was highly expressed in hepatocellular carcinoma (HCC) tissues and negatively correlated with miR-564 expression levels

  • Our results demonstrate that miR-564 was downregulated in HCC and that low expression levels of miR-564 were closely related to tumor size, tumor number and vein invasion, which are indicators of poor prognosis

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Summary

Introduction

GLOBALCAN data show that the number of new cases of global HCC was 782,000 in 2012; HCC has an incidence rate of 83% in non-developed areas and 50% in China [1]. China is an area of high incidence of liver cancer. The incidence of liver cancer in 2015 was 466,100, and the number of deaths was 422,000 [2]. The main reasons for the poor prognosis of HCC is that early diagnosis of liver cancer is difficult and that liver cancer is prone to recurrence and metastasis [3,4,5]. There is a lack of biomarkers for early diagnosis and prognosis prediction.

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