miR-296 Regulates Growth Factor Receptor Overexpression in Angiogenic Endothelial Cells

Thomas Würdinger, Bakhos A. Tannous, Okay Saydam, Johan Skog, Stephan Grau, Jürgen Soutschek, Ralph Weissleder, Xandra O. Breakefield, Anna M. Krichevsky

Research output: Contribution to journalArticlepeer-review

340 Scopus citations

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 PDGFRβ. Furthermore, inhibition of miR-296 with antagomirs reduces angiogenesis in tumor xenografts in vivo.

Original languageEnglish (US)
Pages (from-to)382-393
Number of pages12
JournalCancer Cell
Volume14
Issue number5
DOIs
StatePublished - Nov 4 2008

Bibliographical note

Funding 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.

Keywords

  • CELLCYCLE

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