miR-296 regulates growth factor receptor overexpression in angiogenic endothelial cells.
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.
Würdinger
Thomas
T
Department of Neurology, Massachusetts General Hospital and Neuroscience Program, Harvard Medical School, Boston, MA 02115, USA.
Tannous
Bakhos A
BA
Saydam
Okay
O
Skog
Johan
J
Grau
Stephan
S
Soutschek
Jürgen
J
Weissleder
Ralph
R
Breakefield
Xandra O
XO
Krichevsky
Anna M
AM
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000098:blood supply* / Q000378:metabolism* / Q000628:therapy; D002465:Cell Movement; D002478:Cells, Cultured; D056827:Endosomal Sorting Complexes Required for Transport; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D005910:Glioma / Q000098:blood supply / Q000378:metabolism / Q000628:therapy; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D051379:Mice; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009389:Neovascularization, Pathologic; D009841:Oligonucleotides / Q000494:pharmacology; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012689:Sequence Homology, Nucleic Acid; D015398:Signal Transduction; D014471:Umbilical Veins / Q000166:cytology / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D056827:Endosomal Sorting Complexes Required for Transport; D035683:MicroRNAs; D009841:Oligonucleotides; D010750:Phosphoproteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C096164:hepatocyte growth factor-regulated tyrosine kinase substrate; D017228:Hepatocyte Growth Factor; D008156:Luciferases; D020797:Receptor, Platelet-Derived Growth Factor beta; D040301:Vascular Endothelial Growth Factor Receptor-2