title: p53 inhibits vascular endothelial growth factor expression in solid tumor.
abstract: BACKGROUND
  The p53 tumor-suppressor gene is one of the most frequently mutated genes in cancers, and its mutations affect various biological actions, such as tumor growth, apoptosis, and so on. During hypoxia, p53 is stabilized by interaction with hypoxia-inducible factor-1 (HIF-1). This interaction raised the possibility for regulating HIF-1 activity by p53, which is still to be elucidated.
  
  
  METHODS
  First, we introduced various types of the p53 mutant gene into Hep3B and evaluated the role of p53 in hypoxic responses, including vascular endothelial growth factor (VEGF) production and HIF-1 activation. Second, Hep3B-vector cells and Hep3B-p53 cells were subcutaneously injected into BALB/c (nu/nu) mice, and tumor progression and the hypoxic responses were analyzed. Finally, we investigated the role of the p53 mutant genes in the level of vascularity in human pancreatic neoplasia.
  
  
  RESULTS
  Here, we showed that expression of wild-type p53, but not null or mutated p53, significantly suppressed HIF-1 activity and production of VEGF, which mostly depends on the HIF-1β protein level. In a tumor xenograft model, we consistently found that loss of p53 promotes VEGF production, neovascularization, and tumor progression via accumulation of HIF-1β protein. Furthermore, in clinical pancreatic neoplasia, tumors with mutated p53 have significantly higher levels of vascularity than those with wild-type p53.
  
  
  CONCLUSIONS
  These results indicate that loss of p53 contributes to neovascularization through regulation of HIF-1.
authors.affiliation: The Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Yoshioka
authors.forename: Shigeomi
authors.initials: S
authors.lastname: Shimizu
authors.forename: Toshinori
authors.initials: T
authors.lastname: Ito
authors.forename: Masahiko
authors.initials: M
authors.lastname: Taniguchi
authors.forename: Masaya
authors.initials: M
authors.lastname: Nomura
authors.forename: Toshirou
authors.initials: T
authors.lastname: Nishida
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Sawa
mesh_terms: D000368:Aged; D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D017354:Point Mutation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: C497397:Arnt protein, mouse; D051793:Hypoxia-Inducible Factor 1; D016159:Tumor Suppressor Protein p53; D042461:Vascular Endothelial Growth Factor A; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator