Article

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

Department of Neurology, Massachusetts General Hospital and Neuroscience Program, Harvard Medical School, Boston, MA 02115, USA.
Cancer cell (Impact Factor: 23.89). 12/2008; 14(5):382-93. DOI: 10.1016/j.ccr.2008.10.005
Source: PubMed

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.

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Available from: Okay Saydam, Feb 08, 2014
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    • "Similarly, increased miR-296 expression activates angiogenesis in cultured ECs due to the suppression of HGS (hepatocyte growth factor-regulated tyrosine kinase substrate) which mediates VEGFR-2 and PDGFR-β (platelet derived growth factor receptor beta) degradation, whereas miR-296 inhibition reduces angiogenesis in tumour xenografts [120]. In contrast, He et al. identified another two miRNAs, miR-199a and miR-125b, which were downregulated in ovarian cancer tissues and cell lines, and overexpression of these miRNAs inhibits tumour-induced angiogenesis and is associated with a decrease in VEGF mRNA and protein expression [121]. "
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    • "MiR-126, an endothelial-specific miRNA, can modulate VEGF levels and endothelial cell proliferation, whereas knockout of miR-126 leads to loss of vascular integrity and neoangiogenesis [54, 55]. MiR-296 can modulate the expression of VEGF receptor 2 and platelet-derived growth factor (PDGF) receptor β by directly targeting the hepatocyte growth factor-regulated tyrosine kinase substrate (HGS), which mediates degradation of the growth factor receptors [112]. The miR-17-92 cluster, which contains miR-17, miR-18, miR-19a, miR-19b-1, 20a, and miR-92-1, is the first oncogenic miRNAs identified in human [113]. "
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    • "Though this method is suitable for analyzing the expression and cellular localization of microRNAs and target proteins, this method can only be applied for small cell subsets. On the other hand, Würdinger et al. demonstrated that the therapeutic effect of anti-miR-296 inhibiting tumor angiogenesis could be monitored by fluorescence imaging in tumor-xenografted mice 33. The tumor size was reduced and the vasculature changed, however, miR-296 expression level was not directly visualized in living animals. "
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