MiRNA-148b suppresses hepatic cancer stem cell by targeting neuropilin-1.

Qinying Liu,Qiuhong Zheng,Li Chen,Shenghong Wei,Tong Zhou,Yangmei Xu,Zhen Wang,Mingang Ying,Wei Gao

doi:10.1042/bsr20150084

Qinying Liu, Qiuhong Zheng + Show 7 more

Open Access

https://doi.org/10.1042/bsr20150084

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Abstract

The existence of cancer stem cells (CSCs) is considered as a direct reason for the failure of clinic treatment in hepatocellular carcinoma (HCC). Growing evidences have demonstrated that miRNAs play an important role in regulation of stem cell proliferation, differentiation and self-renewal and their aberrances cause the formation of CSCs and eventually result in carcinogenesis. We recently identified miRNA-148b as one of the miRNAs specifically down-regulated in side population (SP) cells of PLC/PRF/5 cell line. However, it remains elusive how miRNA-148b regulates CSC properties in HCC. In the present study, we observed that overexpression or knockdown of miR-148b through lentiviral transfection could affect the proportion of SP cells as well as CSC-related gene expression in HCC cell lines. In addition, miR-148b blocking could stimulate cell proliferation, enhance chemosensitivity, as well as increase cell metastasis and angiogenesis invitro. More importantly, miR-148b could significantly suppress tumorigenicity invivo. Further studies revealed that Neuropilin-1 (NRP1), a transmembrane co-receptor involved in tumour initiation, metastasis and angiogenesis, might be the direct target of miRNA-148b. Taking together, our findings define that miR-148b might play a critical role in maintenance of SP cells with CSC properties by targeting NRP1in HCC. It is the potential to develop a new strategy specifically targeting hepatic CSCs (HCSCs) through restoration of miR-148b expression in future therapy.

Highlights

Hepatocellular carcinoma (HCC) is known as the fifth most common cancer and the third cause of cancer-related mortality in the world
side population (SP) cells of HCC cell lines harbour cancer stem cell-like properties SP cell assay based on actively efflux of Hoechst 33342 dye was reported to be an effective method to identify CSCs in HCC [5]
We further tested the expression of HCC-related CSC markers, including CD90, cluster of differentiation 133 (CD133), CD44, epithelial cell adhesion molecule (EpCAM) and ABCG2, on the surface of SP and NSP cells by flow cytometry

Summary

Introduction

Hepatocellular carcinoma (HCC) is known as the fifth most common cancer and the third cause of cancer-related mortality in the world. Increasing evidences have suggested that many miRNAs play critical roles in controlling the selfrenewal and differentiation of stem cell and some of them were proved to express abnormally in HCSCs and regulate the key biological characteristics of HCSCs [2]. It suggests a new clue to conquer HCC by directly targeting and eradicating HCSCs through related-miRNA regulation [3]. It remains unclear the detailed mechanism about how miRNAs regulate the formation of HCSCs and maintain the properties of HCSCs. c 2015 Authors.

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