MicroRNA-1296 inhibits metastasis and epithelial-mesenchymal transition of hepatocellular carcinoma by targeting SRPK1-mediated PI3K/AKT pathway

Lijie Li,Hangxing Bao,Qiuran Xu,Xin Liu,Zhikui Liu,Jianfeng Tu,Yufeng Wang,Zhenyu Zhou,Liu Yang,Kangsheng Tu

doi:10.1186/s12943-017-0675-y

Abstract

BackgroundIncreasing evidences demonstrate that miRNAs contribute to development and progression of hepatocellular carcinoma (HCC). Underexpression of miR-1296 is recently reported to promote growth and metastasis of human cancers. However, the expression and role of miR-1296 in HCC remain unknown.MethodsThe levels of miR-1296 in HCC tissues and cells were detected by qRT-PCR. Immunoblotting and immunofluorescence were used for detection of epithelial-to-mesenchymal transition (EMT) progression in HCC cells. Transwell assays were performed to determine migration and invasion of HCC cells. A lung metastasis mouse model was used to evaluated metastasis of HCC in vivo. The putative targets of miR-1296 were disclosed by public databases and a dual-luciferase reporter assay.ResultsWe found that the expression of miR-1296 was reduced in HCC tissues and cell lines, and it was associated with metastasis and recurrence of HCC. Notably, miR-1296 overexpression inhibited migration, invasion and EMT progress of HCCLM3 cells, while miR-1296 loss facilitated these biological behaviors of Hep3B cells in vitro and in vivo. In addition, miR-1296 inversely regulated SRPK1 abundance by directly binding to its 3′-UTR, which subsequently resulted in suppression of p-AKT. Either SRPK1 re-expression or PI3K/AKT pathway activation, at least partially, abolished the effects of miR-1296 on migration, invasion and EMT progress of HCC cells. Furthermore, miR-1296 and SRPK1 expression were markedly correlated with adverse clinical features and poor prognosis of HCC patients. We showed that hypoxia was responsible for the underexpression of miR-1296 in HCC. And the promoting effects of hypoxia on metastasis and EMT of HCC cells were reversed by miR-1296.ConclusionsUnderexpression of miR-1296 potentially serves as a prognostic biomarker in HCC. Hypoxia-induced miR-1296 loss promotes metastasis and EMT of HCC cells probably by targeting SRPK1/AKT pathway.

Highlights

Increasing evidences demonstrate that miRNAs contribute to development and progression of hepatocellular carcinoma (HCC)
We found that miR-1296 was obviously decreased in aggressive HCC tissues compare to non-aggressive tissues (P < 0.05, Fig. 1b)
A mechanism by which miR1296 inhibits epithelial-to-mesenchymal transition (EMT) and metastasis probably by targeting serine-arginine protein kinase 1 (SRPK1)-mediated PI3K/AKT pathway plays an important role in this process

Summary

Introduction

Increasing evidences demonstrate that miRNAs contribute to development and progression of hepatocellular carcinoma (HCC). It is critical to identify the potential molecular mechanisms underlying the progression and metastasis in HCC and provide novel therapeutic targets for cancer treatment. Numerous evidences confirm that aberrantly expressed miRNAs play critical roles in multiple biological progresses in HCC [7,8,9,10], including cell proliferation, apoptosis, drug-resistance, metastasis and stem cell renewal, and have been identified as promising therapeutic and prognostic biomarkers in HCC diagnosis and treatment. MiR-1296 increased resistance to chemotherapeutic treatment and could be used as a new potential biomarker for breast cancer stem cell diagnosis [16]. These data suggest that miR-1296 plays a tumor suppressive role in malignancies. The function of miR-1296 and its underlying molecular mechanisms in HCC remain unknown

Methods

Results

Discussion

Conclusion