miR-451 acts as a suppressor of angiogenesis in hepatocellular carcinoma by targeting the IL-6R-STAT3 pathway
Open Access
- 25 July 2016
- journal article
- Published by Spandidos Publications in Oncology Reports
- Vol. 36 (3), 1385-1392
- https://doi.org/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. In vitro, 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 transcription 3 (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 receptor 2 (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.Keywords
This publication has 29 references indexed in Scilit:
- Interleukin-37 suppresses tumor growth through inhibition of angiogenesis in non-small cell lung cancerJournal of Experimental & Clinical Cancer Research, 2016
- A Huaier polysaccharide restrains hepatocellular carcinoma growth and metastasis by suppression angiogenesisInternational Journal of Biological Macromolecules, 2015
- Sustained Endothelial Expression of HoxA5 In Vivo Impairs Pathological Angiogenesis And Tumor ProgressionPLOS ONE, 2015
- Recent molecular discoveries in angiogenesis and antiangiogenic therapies in cancerJCI Insight, 2013
- Hepatocellular carcinoma: ESMO–ESDO Clinical Practice Guidelines for diagnosis, treatment and follow-upAnnals of Oncology, 2012
- Long noncoding RNA associated with microvascular invasion in hepatocellular carcinoma promotes angiogenesis and serves as a predictor for hepatocellular carcinoma patients' poor recurrence-free survival after hepatectomyHepatology, 2012
- Rapid Decrease in Delivery of Chemotherapy to Tumors after Anti-VEGF Therapy: Implications for Scheduling of Anti-Angiogenic DrugsCancer Cell, 2012
- Hepatocellular carcinoma: a global viewNature Reviews Gastroenterology & Hepatology, 2010
- Hepatocellular Carcinoma Incidence, Mortality, and Survival Trends in the United States From 1975 to 2005Journal of Clinical Oncology, 2009
- Interleukin-6 promotes cervical tumor growth by VEGF-dependent angiogenesis via a STAT3 pathwayOncogene, 2003