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