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

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.