MiR-451 acts as a suppressor of angiogenesis in hepatocellular carcinoma by targeting the IL-6R-STAT3 pathway.

Xuemin Liu,Xufeng Zhang,Junxi Xiang,Anpeng Zhang,Yi Lv

doi:10.3892/or.2016.4971

Abstract

Hepatocellular carcinoma(HCC) is a highly vascularized tumor and the third ranking contributor of tumor-associated death. Our previous study corroborated the inhibitory roles of miRNA-451(miR-451) in HCC cell growth and invasion. However, its effect on angiogenesis in HCC remains poorly elucidated. In this study, overexpression of miR-451 clearly attenuated the promoting effects of HCC cells on cell proliferation, migration and tube formation of human umbilical vein endothelial cells(HUVECs). Importantly, ectopic expression of miR‑451 also attenuated tumor growth and angiogenesis in nude mice. Invitro, the expression of IL‑6 receptor(IL‑6R) was reduced and identified as a direct target of miR‑451 by bioinformatics and a dual‑firefly luciferase reporter assay. Moreover, upregulation of IL‑6R strikingly ameliorated the inhibitory function of conditioned medium from miR‑451‑transfected HCC cells in HUVEC proliferation, migration and tube formation. Further mechanistic assay substantiated that miR‑451 restrained vascular endothelial growth factor(VEGF) production of HCC cells by targeting IL‑6R‑STAT3 signaling as evidenced that IL‑6R upregulation induced the increase in VEGF levels and interrupting signal transducer and activator of transcription3(STAT3) signaling with ectopic expression of dominant-negative STAT3(STAT3D) markedly decreased VEGF expression. Additionally, conditioned medium of miR-451-overexpressed HCC also impaired the VEGF receptor2(VEGFR2) signaling in HUVECs. Accordingly, miR-451 may function as a potential suppressor of tumor angiogenesis in HCC by targeting IL-6R-STAT3-VEGF signaling, suggesting a promising therapeutic avenue for managing HCC.

Highlights

Hepatocellular carcinoma (HCC), a common aggressive carcinoma of the liver, ranks as the third contributor for tumor‐associated death around the world [1,2]
The expression of proliferating cell nuclear antigen (PCNA), a marker for cell proliferation, was downregulated in human umbilical vein endothelial cells (HUVECs) when treated with the tumor‐conditioned medium (TCM) (Fig. 1C)
Overexpression of IL‐6 receptor (IL‐6R) could remarkably restore the reduction of vascular endothelial growth factor (VEGF) levels in TCM from miR‐451‐transfected HCC cells, which ameliorated the inhibitory effect on the phosphorylation of VEGF receptor 2 (VEGFR2) and p‐ERK in HUVECs (Fig. 5C). These results demonstrated that miR‐451 could block the VEGFR2 pathway in HUVECs, which will lead to reduction in angiogenesis

Summary

Introduction

Hepatocellular carcinoma (HCC), a common aggressive carcinoma of the liver, ranks as the third contributor for tumor‐associated death around the world [1,2]. During the past few years, increasing evidence has identified HCC as a highly vascularized tumor with high invasion and metastasis, which contributes to tumor recurrence and poor survival of HCC patients [4,5]. It is widely accepted that angiogenesis is a prerequisite for the development and metastasis of carcinoma by supplying nutrients and oxygen [6,7]. A great number of factors have been reported to be involved in tumor angiogenesis, especially the vascular endothelial growth factor (VEGF) [8,9]. Targeting cancer vasculature to ‘starve a tumor to death’ has become a new approach for carcinoma therapy [7,10]. It is urgent to develop more effective therapy against HCC

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