Roles of arrest-defective protein 1225 and hypoxia-inducible factor 1α in tumor growth and metastasis

Mi Ni Lee, Shi Nai Lee, Se Hee Kim, Bora Kim, Bo Kyung Jung, Ji Hae Seo, Ji Hyeon Park, Jae Hoon Choi, Sun Hee Yim, Mi Ran Lee, Jong Gil Park, Ji Young Yoo, Jeong Hun Kim, Seung Taek Lee, Hwan Mook Kim, Sandra Ryeom, Kyu Won Kim, Goo Taeg Oh

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)

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 (mARD1A225) acetylates HIF-1α, triggering its degradation, and thus may play a role in decreased expression of VEGFA.Methods We generated ApcMin/+/mARD1A225 transgenic mice and quantified growth of intestinal polyps. Human gastric MKN74 and murine melanoma B16F10 cells overexpressing mARD1A225 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-1α, we injected B16F10-mARD1A225 cell lines stably expressing mutant HIF-1α/K532R into mice and measured metastasis. All statistical tests were two-sided, and P values less than. 05 were considered statistically significant.Results ApcMin/+/mARD1A225 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 ApcMin/+/mARD1A225 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 mARD1A225-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 ApcMin/+ intestinal polyps (P =. 001). Mutation of lysine 532 of HIF-1α in B16F10-mARD1A225 cells prevented HIF-1α degradation and inhibited the antimetastatic effect of mARD1A225 (P <. 001).Conclusion mARD1A225 may be a novel upstream target that blocks VEGFA expression and tumor-related angiogenesis.

Original languageEnglish
Pages (from-to)426-442
Number of pages17
JournalJournal of the National Cancer Institute
Volume102
Issue number6
DOIs
Publication statusPublished - 2010 Mar

Bibliographical note

Funding Information:
21st Century Frontier Functional Human Genome Project (FG06-2-9); National Research Foundation of Korea (NRF) grant funded by the Ministry of Education, Science & Technology (MEST) through the Creative Research Initiative Program (R16-2004-001010010 to K.-W.K., 2009); Research program for New Drug Target Discovery (M108KB010014-08K0201-01420) grant from MEST.

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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