title: Roles of arrest-defective protein 1(225) and hypoxia-inducible factor 1alpha in tumor growth and metastasis.
abstract: BACKGROUND
  Vascular endothelial growth factor A (VEGFA), a critical mediator of tumor angiogenesis, is a well-characterized target of hypoxia-inducible factor 1 (HIF-1). Murine arrest-defective protein 1A (mARD1A(225)) acetylates HIF-1alpha, triggering its degradation, and thus may play a role in decreased expression of VEGFA.
  
  
  METHODS
  We generated Apc(Min/+)/mARD1A(225) transgenic mice and quantified growth of intestinal polyps. Human gastric MKN74 and murine melanoma B16F10 cells overexpressing mARD1A(225) were injected into mice, and tumor growth and metastasis were measured. VEGFA expression and microvessel density in tumors were assessed using immunohistochemistry. To evaluate the role of mARD1A(225) acetylation of Lys532 in HIF-1alpha, we injected B16F10-mARD1A(225) cell lines stably expressing mutant HIF-1alpha/K532R into mice and measured metastasis. All statistical tests were two-sided, and P values less than .05 were considered statistically significant.
  
  
  RESULTS
  Apc(Min/+)/mARD1A(225) transgenic mice (n = 25) had statistically significantly fewer intestinal polyps than Apc(Min/+) mice (n = 21) (number of intestinal polyps per mouse: Apc(Min/+) mice vs Apc(Min/+)/mARD1A(225) transgenic mice, mean = 83.4 vs 38.0 polyps, difference = 45.4 polyps, 95% confidence interval [CI] = 41.8 to 48.6; P < .001). The growth and metastases of transplanted tumors were also statistically significantly reduced in mice injected with mARD1A(225)-overexpressing cells than in mice injected with control cells (P < .01). Moreover, overexpression of mARD1A(225) decreased VEGFA expression and microvessel density in tumor xenografts (P < .04) and Apc(Min/+) intestinal polyps (P = .001). Mutation of lysine 532 of HIF-1alpha in B16F10-mARD1A(225) cells prevented HIF-1alpha degradation and inhibited the antimetastatic effect of mARD1A(225) (P < .001).
  
  
  CONCLUSIONS
  mARD1A(225) may be a novel upstream target that blocks VEGFA expression and tumor-related angiogenesis.
authors.affiliation: Division of Life and Pharmaceutical Sciences, Ewha Women's University, Seoul, Korea.
authors.forename: Mi-Ni
authors.initials: MN
authors.lastname: Lee
authors.forename: Shi-Nai
authors.initials: SN
authors.lastname: Lee
authors.forename: Se-Hee
authors.initials: SH
authors.lastname: Kim
authors.forename: Bora
authors.initials: B
authors.lastname: Kim
authors.forename: Bo-Kyung
authors.initials: BK
authors.lastname: Jung
authors.forename: Ji Hae
authors.initials: JH
authors.lastname: Seo
authors.forename: Ji-Hyeon
authors.initials: JH
authors.lastname: Park
authors.forename: Jae-Hoon
authors.initials: JH
authors.lastname: Choi
authors.forename: Sun Hee
authors.initials: SH
authors.lastname: Yim
authors.forename: Mi-Ran
authors.initials: MR
authors.lastname: Lee
authors.forename: Jong-Gil
authors.initials: JG
authors.lastname: Park
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Yoo
authors.forename: Jeong Hun
authors.initials: JH
authors.lastname: Kim
authors.forename: Seung-Taek
authors.initials: ST
authors.lastname: Lee
authors.forename: Hwan-Mook
authors.initials: HM
authors.lastname: Kim
authors.forename: Sandra
authors.initials: S
authors.lastname: Ryeom
authors.forename: Kyu-Won
authors.initials: KW
authors.lastname: Kim
authors.forename: Goo Taeg
authors.initials: GT
authors.lastname: Oh
mesh_terms: D000107:Acetylation; D000123:Acetyltransferases / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D007417:Intestinal Polyps / Q000378:metabolism* / Q000473:pathology*; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary; D008239:Lysine; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D008833:Microcirculation; D009154:Mutation; D063209:N-Terminal Acetyltransferase A; D063213:N-Terminal Acetyltransferase E; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000517:prevention & control*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D000123:Acetyltransferases; D063209:N-Terminal Acetyltransferase A; C508558:Naa10 protein, mouse; D063213:N-Terminal Acetyltransferase E; D008239:Lysine