Decorin antagonizes the angiogenic network: concurrent inhibition of Met, hypoxia inducible factor 1α, vascular endothelial growth factor A, and induction of thrombospondin-1 and TIMP3

J Biol Chem. 2012 Feb 17;287(8):5492-506. doi: 10.1074/jbc.M111.283499. Epub 2011 Dec 22.


Decorin, a small leucine-rich proteoglycan, inhibits tumor growth by antagonizing multiple receptor tyrosine kinases including EGFR and Met. Here, we investigated decorin during normoxic angiogenic signaling. An angiogenic PCR array revealed a profound decorin-evoked transcriptional inhibition of pro-angiogenic genes, such as HIF1A. Decorin evoked a reduction of hypoxia inducible factor (HIF)-1α and vascular endothelial growth factor A (VEGFA) in MDA-231 breast carcinoma cells expressing constitutively-active HIF-1α. Suppression of Met with decorin or siRNA evoked a similar reduction of VEGFA by attenuating downstream β-catenin signaling. These data establish a noncanonical role for β-catenin in regulating VEGFA expression. We found that exogenous decorin induced expression of thrombospondin-1 and TIMP3, two powerful angiostatic agents. In contrast, decorin suppressed both the expression and enzymatic activity of matrix metalloprotease (MMP)-9 and MMP-2, two pro-angiogenic proteases. Our data establish a novel duality for decorin as a suppressor of tumor angiogenesis under normoxia by simultaneously down-regulating potent pro-angiogenic factors and inducing endogenous anti-angiogenic agents.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Decorin / pharmacology*
  • Decorin / therapeutic use
  • Down-Regulation / drug effects*
  • Enzyme Induction / drug effects
  • Female
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Matrix Metalloproteinases / biosynthesis
  • Mice
  • Neovascularization, Pathologic / drug therapy*
  • Neovascularization, Pathologic / genetics*
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Pathologic / pathology
  • Proto-Oncogene Proteins c-met / genetics
  • Signal Transduction / drug effects
  • Thrombospondin 1 / genetics
  • Thrombospondin 1 / metabolism
  • Tissue Inhibitor of Metalloproteinase-3 / genetics
  • Tissue Inhibitor of Metalloproteinase-3 / metabolism
  • Transcription, Genetic / drug effects
  • Transcriptional Activation / drug effects*
  • Up-Regulation / drug effects
  • Vascular Endothelial Growth Factor A / genetics
  • Xenograft Model Antitumor Assays


  • Decorin
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Thrombospondin 1
  • Tissue Inhibitor of Metalloproteinase-3
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Proto-Oncogene Proteins c-met
  • Matrix Metalloproteinases