title: MicroRNA-214 downregulation contributes to tumor angiogenesis by inducing secretion of the hepatoma-derived growth factor in human hepatoma.
abstract: OBJECTIVE
  Unusual hypervascularity is a hallmark of human hepatocellular carcinoma (HCC). Although microRNA-214 (miR-214) is upregulated in other human cancers, it is downregulated in HCC. We elucidated the biological and clinical significance of miR-214 downregulation in HCC.
  
  
  METHODS
  MicroRNAs deregulated in HCC were identified using array-based microRNA profiling. A luciferase reporter assay confirmed target association between miR-214 and the hepatoma-derived growth factor (HDGF). Tube formation and in vivo angiogenesis assays validated the roles of miR-214/HDGF in angiogenesis.
  
  
  RESULTS
  miR-214 downregulation was associated with higher tumor recurrence and worse clinical outcomes. Ectopic expression of miR-214 suppressed xenograft tumor growth and microvascularity of the tumors and their surrounding tissues. The genes downregulated by ectopic expression of miR-214 were involved in the regulation of apoptosis, cell cycle, and angiogenesis. Integrated analysis disclosed HDGF as a downstream target of miR-214. Conditioned medium of HCC cells contained bioactivity to stimulate tube formation of human umbilical vein endothelial cells, which was abolished by pretreatment of the conditioned media with HDGF antibodies, suppression of HDGF expression or ectopic expression of miR-214 in the donor HCC cells. The angiogenic activity of the conditioned media, lost by ectopic expression of miR-214 in the donor cells, was restored by supplementation with recombinant HDGF. In vivo tumor angiogenesis assays showed significant suppression of tumor vascularity by ectopic expression of miR-214.
  
  
  CONCLUSIONS
  A novel role of microRNA in tumorigenesis is identified. Downregulation of miR-214 contributes to the unusual hypervascularity of HCC via activation of the HDGF paracrine pathway for tumor angiogenesis.
authors.affiliation: Liver Research Unit, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Tsung-Chieh
authors.initials: TC
authors.lastname: Shih
authors.forename: Yin-Jing
authors.initials: YJ
authors.lastname: Tien
authors.forename: Chih-Jen
authors.initials: CJ
authors.lastname: Wen
authors.forename: Ta-Sen
authors.initials: TS
authors.lastname: Yeh
authors.forename: Ming-Chin
authors.initials: MC
authors.lastname: Yu
authors.forename: Chia-Hao
authors.initials: CH
authors.lastname: Huang
authors.forename: Yun-Shien
authors.initials: YS
authors.lastname: Lee
authors.forename: Tzu-Chen
authors.initials: TC
authors.lastname: Yen
authors.forename: Sen-Yung
authors.initials: SY
authors.lastname: Hsieh
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000098:blood supply* / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D018450:Disease Progression; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000098:blood supply* / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009364:Neoplasm Recurrence, Local / Q000378:metabolism*; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D019899:Paracrine Communication; D011379:Prognosis
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; C547397:MIRN214 microRNA, human; D035683:MicroRNAs; C051610:hepatoma-derived growth factor