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 PDGFRβ. Furthermore, inhibition of miR-296 with antagomirs reduces angiogenesis in tumor xenografts in vivo.
Bibliographical noteFunding Information:
We would like to acknowledge the Steve Kaplan Fellowship from the American Brain Tumor Association (T.W.); NIH grants NCI P50 CA86355-04 (R.W. and X.O.B.), NCI P01 CA69246 (X.O.B.), and NINDS P30NS045776 (X.O.B.); and the Brain Tumor Society (A.M.K.). We thank E. Erkan, L. Wedekind, and P. Waterman for technical assistance and G.S. Mack for critical reading of the manuscript.