title: Inhibition of tumour angiogenesis and growth by small hairpin HIF-1α and IL-8 in hepatocellular carcinoma.
abstract: OBJECTIVE
  Hypoxia-inducible factor-1α (HIF-1α), a key transcription factor in the cellular response to hypoxia, and interleukin 8 (IL-8), a key mediator of angiogenesis, are important in cancerous tumour growth. In this study, we evaluated the effects of HIF-1α and IL-8 knockdown on angiogenesis and tumour growth in hepatocellular carcinoma (HCC).
  
  
  METHODS
  Hepatocellular carcinoma cell lines were infected with adenoviruses expressing small-hairpin RNA (shRNA) specific for HIF-1α or IL-8, cultured under hypoxic conditions (1% O2), and examined for their levels of HIF-1α, IL-8, and angiogenesis factors using immunoblot. The effects of adenovirus-mediated shRNA-induced HIF-1α and IL-8 knockdown on tumour growth and angiogenesis were also investigated in a subcutaneous Hep3B-tumour mouse model.
  
  
  RESULTS
  Hypoxia-inducible factor-1α knockdown directly repressed tumour growth, whereas IL-8 knockdown indirectly repressed tumour growth. Combined knockdown of HIF-1α and IL-8 increased survival rates of mice. HIF-1α and IL-8 knockdown also decreased microvessel density and tumour volume in vivo. Similarly, HIF-1α and IL-8 knockdown inhibited the angiogenic effects of HCC cell-conditioned media on tube formation and invasion by endothelial cells in vitro.
  
  
  CONCLUSIONS
  These findings indicate that shRNA-induced HIF-1α and IL-8 knockdown inhibit angiogenesis and tumour growth in HCC. Further development of HIF-1α and IL-8 shRNA technologies could lead to effective therapies for HCC.
authors: Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea; Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.
authors: Sung Hoon
authors: SH
authors: Choi
authors: Oh-Joon
authors: OJ
authors: Kwon
authors: Jun Yong
authors: JY
authors: Park
authors: Do Young
authors: DY
authors: Kim
authors: Sang Hoon
authors: SH
authors: Ahn
authors: Seung Up
authors: SU
authors: Kim
authors: Simon Weonsang
authors: SW
authors: Ro
authors: Kyung Sik
authors: KS
authors: Kim
authors: Jeon Han
authors: JH
authors: Park
authors: Seungtaek
authors: S
authors: Kim
authors: Chae-Ok
authors: CO
authors: Yun
authors: Kwang-Hyub
authors: KH
authors: Han
mesh_terms: D000256:Adenoviridae; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000628:therapy*; D055785:Gene Knockdown Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D015151:Immunoblotting; D016209:Interleukin-8 / Q000235:genetics*; D008113:Liver Neoplasms / Q000235:genetics / Q000628:therapy*; D051379:Mice; D009361:Neoplasm Invasiveness / Q000503:physiopathology; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000503:physiopathology*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016209:Interleukin-8
keywords: angiogenesis; hepatocellular carcinoma; hypoxia inducible factor-1 alpha; interleukin-8; tumour xenograft