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

Abstract

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

The regulatory role of microRNAs in angiogenesis‐related diseases

“…The expression of miR‐296 induces angiogenesis in vascular disease and cancer 95, 96. A study showed that glioma or growth factor‐mediated miR‐296 in ECs leads to enhanced levels of pro‐angiogenic growth factor receptors.…”

“…A study showed that glioma or growth factor‐mediated miR‐296 in ECs leads to enhanced levels of pro‐angiogenic growth factor receptors. Growth factor‐induced miR‐296 significantly enhances angiogenesis directly via reducing hepatocyte growth factor‐regulated tyrosine kinase substrate (HGS), thereby increasing VEGFR2 and platelet‐derived growth factor receptor‐β (PDGFR‐β) and inhibiting DLL4 and Notch1 95, 96. Additionally, the results have an effect on improving the expression of VEGF.…”

Time-Course Imaging of Therapeutic Functional Tumor Vascular Normalization by Antiangiogenic Agents

“…2A, i-iii; Â2), suggesting increased intratumor pressure, possibly caused by high permeability of the tumor vessels (Fig. 1B) and poor lymphatic drainage (26,27).…”

MicroRNAs in glioblastoma multiforme pathogenesis and therapeutics

“…miR‐296 is an angiomiR that has been found to be upregulated in endothelial cells with the presence of glioma cells or angiogenic growth factors such as VEGF. Augmented expression of miR‐296 is associated with increased endothelial cell tube formation and enhanced vascularization of tumors, while knockdown of miR‐296 results in reduced tumor angiogenesis 79.…”