title: miR-451 acts as a suppressor of angiogenesis in hepatocellular carcinoma by targeting the IL-6R-STAT3 pathway.
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.
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors.forename: Xuemin
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors.forename: Anpeng
authors.initials: A
authors.lastname: Zhang
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors.forename: Junxi
authors.initials: J
authors.lastname: Xiang
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Lv
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors.forename: Xufeng
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D057809:HEK293 Cells; D056945:Hep G2 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000473:pathology; D019947:Receptors, Interleukin-6 / Q000235:genetics*; D050796:STAT3 Transcription Factor / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: C508603:IL6R protein, human; D015850:Interleukin-6; C531201:MIRN451 microRNA, human; D035683:MicroRNAs; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D042461:Vascular Endothelial Growth Factor A