title: Insufficient radiofrequency ablation promotes angiogenesis of residual hepatocellular carcinoma via HIF-1α/VEGFA.
abstract: BACKGROUND
  The mechanism of rapid growth of the residual tumor after radiofrequency (RF) ablation is poorly understood. In this study, we investigated the effect of hyperthermia on HepG2 cells and generated a subline with enhanced viability and dys-regulated angiogenesis in vivo, which was used as a model to further determine the molecular mechanism of the rapid growth of residual HCC after RF ablation.
  
  
  RESULTS
  Heat treatment was used to establish sublines of HepG2 cells. A subline (HepG2 k) with a relatively higher viability and significant heat tolerance was selected. The cellular protein levels of VEGFA, HIF-1α and p-Akt, VEGFA mRNA and secreted VEGFA were measured, and all of these were up-regulated in this subline compared to parental HepG2 cells. HIF-1α inhibitor YC-1 and VEGFA siRNA inhibited the high viability of the subline. The conditioned media from the subline exerted stronger pro-angiogenic effects. Bevacizumab, VEGFA siRNA and YC-1 inhibited proangiogenic effects of the conditioned media of HepG2 k cells and abolished the difference between parental HepG2 cells and HepG2 k cells. For in vivo studies, a nude mouse model was used, and the efficacy of bavacizumab was determined. HepG2 k tumor had stronger pro-angiogenic effects than parental HepG2 tumor. Bevacizumab could inhibit the tumor growth and angiogenesis, and also eliminate the difference in tumor growth and angiogenesis between parental HepG2 tumor and HepG2 k tumor in vivo.
  
  
  CONCLUSIONS
  The angiogenesis induced by HIF1α/VEGFA produced by altered cells after hyperthermia treatment may play an important role in the rapid growth of residual HCC after RF ablation. Bevacizumab may be a good candidate drug for preventing and treating the process.
authors.affiliation: Department of Hepatobiliary Surgery, West Campus, Capital Medical University, Beijing Chao-yang Hospital, Beijing, People's Republic of China.
authors.forename: Jian
authors.initials: J
authors.lastname: Kong
authors.forename: Jinge
authors.initials: J
authors.lastname: Kong
authors.forename: Bing
authors.initials: B
authors.lastname: Pan
authors.forename: Shan
authors.initials: S
authors.lastname: Ke
authors.forename: Shuying
authors.initials: S
authors.lastname: Dong
authors.forename: Xiuli
authors.initials: X
authors.lastname: Li
authors.forename: Aimin
authors.initials: A
authors.lastname: Zhou
authors.forename: Lemin
authors.initials: L
authors.lastname: Zheng
authors.forename: Wen-bing
authors.initials: WB
authors.lastname: Sun
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D000068258:Bevacizumab; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D017115:Catheter Ablation / Q000009:adverse effects*; D002470:Cell Survival / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000494:pharmacology; D056945:Hep G2 Cells; D006358:Hot Temperature; D006801:Humans; D006979:Hyperthermia, Induced / Q000009:adverse effects*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology; D007191:Indazoles / Q000494:pharmacology; D008113:Liver Neoplasms / Q000473:pathology*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000139:chemically induced*; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D017211:Treatment Failure; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D017077:Culture Media, Conditioned; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007191:Indazoles; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D000068258:Bevacizumab