miR-296 regulates growth factor receptor overexpression in angiogenic endothelial cells

Cancer Cell. 2008 Nov 4;14(5):382-93. doi: 10.1016/j.ccr.2008.10.005.

Abstract

A key step in angiogenesis is the upregulation of growth factor receptors on endothelial cells. Here, we demonstrate that a small regulatory microRNA, miR-296, has a major role in this process. Glioma cells and angiogenic growth factors elevate the level of miR-296 in primary human brain microvascular endothelial cells in culture. The miR-296 level is also elevated in primary tumor endothelial cells isolated from human brain tumors compared to normal brain endothelial cells. Growth factor-induced miR-296 contributes significantly to angiogenesis by directly targeting the hepatocyte growth factor-regulated tyrosine kinase substrate (HGS) mRNA, leading to decreased levels of HGS and thereby reducing HGS-mediated degradation of the growth factor receptors VEGFR2 and PDGFRbeta. Furthermore, inhibition of miR-296 with antagomirs reduces angiogenesis in tumor xenografts in vivo.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / pharmacology
  • Animals
  • Base Sequence
  • Blotting, Western
  • Brain Neoplasms / blood supply*
  • Brain Neoplasms / metabolism*
  • Brain Neoplasms / therapy
  • Cell Movement
  • Cells, Cultured
  • Endosomal Sorting Complexes Required for Transport
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / metabolism*
  • Fluorescent Antibody Technique
  • Glioma / blood supply
  • Glioma / metabolism
  • Glioma / therapy
  • Hepatocyte Growth Factor / metabolism
  • Humans
  • Kidney / cytology
  • Kidney / metabolism
  • Luciferases / metabolism
  • Magnetic Resonance Imaging
  • Mice
  • MicroRNAs / antagonists & inhibitors
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Molecular Sequence Data
  • Neovascularization, Pathologic
  • Oligonucleotides / pharmacology
  • Phosphoproteins / antagonists & inhibitors
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • RNA, Messenger / antagonists & inhibitors
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / pharmacology
  • Receptor, Platelet-Derived Growth Factor beta / antagonists & inhibitors
  • Receptor, Platelet-Derived Growth Factor beta / genetics
  • Receptor, Platelet-Derived Growth Factor beta / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sequence Homology, Nucleic Acid
  • Signal Transduction
  • Umbilical Veins / cytology
  • Umbilical Veins / metabolism
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors
  • Vascular Endothelial Growth Factor Receptor-2 / genetics
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism*
  • Xenograft Model Antitumor Assays

Substances

  • Angiogenesis Inhibitors
  • Endosomal Sorting Complexes Required for Transport
  • MicroRNAs
  • Oligonucleotides
  • Phosphoproteins
  • RNA, Messenger
  • RNA, Small Interfering
  • hepatocyte growth factor-regulated tyrosine kinase substrate
  • Hepatocyte Growth Factor
  • Luciferases
  • Receptor, Platelet-Derived Growth Factor beta
  • Vascular Endothelial Growth Factor Receptor-2

Associated data

  • GEO/GSE13091