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: 23.52). 12/2008; 14(5):382-93. DOI: 10.1016/j.ccr.2008.10.005
Source: PubMed


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.

Download full-text


Available from: Okay Saydam, Feb 08, 2014
1 Follower
22 Reads
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: MicroRNAs are one class of small, endogenous, non-coding RNAs that are approximately 22 nucleotides in length; they are very numerous, have been phylogenetically conserved, and involved in biological processes such as development, differentiation, cell proliferation, and apoptosis. MicroRNAs contribute to modulating the expression levels of specific proteins based on sequence complementarity with their target mRNA molecules and so they play a key role in both health and disease. Angiogenesis is the process of new blood vessel formation from preexisting ones, which is particularly relevant to cancer and its progression. Over the last few years, microRNAs have emerged as critical regulators of signalling pathways in multiple cell types including endothelial and perivascular cells. This review summarises the role of miRNAs in tumour angiogenesis and their potential implications as therapeutic targets in cancer.
    BioMed Research International 08/2014; 2014:878450. DOI:10.1155/2014/878450 · 3.17 Impact Factor
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Hepatocellular carcinoma (HCC) is the third leading cause of death from cancer, with dismal outcomes and an increasing incidence worldwide. Hepatocarcinogenesis is a multistep process that progresses from chronic hepatitis through cirrhosis and/or dysplastic nodule to HCC. However, the detailed molecular pathogenesis remains unclear. MicroRNAs (miRNAs), small noncoding RNAs that regulate the translation of many genes, have emerged as key factors involved in several biological processes, including development, differentiation, and cell proliferation. Recent studies have uncovered the contribution of miRNAs to the cancer pathogenesis, as they can behave as oncogenes or tumor suppressor genes. In addition, other studies have demonstrated their potential values in the clinical management of HCC patients as some miRNAs may be used as prognostic or diagnostic markers. In this review, we summarize current knowledge about the roles of miRNAs in carcinogenesis and progression of HCC. We also discuss the potential application of miRNAs as diagnostic biomarkers and their potential roles in the intervention of HCC.
    04/2014; 2014:486407. DOI:10.1155/2014/486407
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: MicroRNAs are small noncoding RNAs regulating gene expression, through base paring with their target mRNAs, which have been actively investigated as key regulators in a wide range of biological processes. Conventional methods such as Northern blot are generally time-consuming, non-repeatable, and cannot be applied in vivo due to the requirement for cell fixation. Therefore, a noninvasive imaging system is required for the monitoring of microRNA biogenesis to understand the versatile functions of microRNAs in vivo as well as in vitro and to accelerate the clinical application of microRNA-based therapy. In this paper, we reviewed noninvasive molecular imaging systems for the monitoring of the biogenesis of microRNAs and post-transcriptional regulation of genes by microRNAs and the roles of microRNAs in various biological processes.
    Theranostics 12/2013; 3(12):1004-1011. DOI:10.7150/thno.4580 · 8.02 Impact Factor
Show more

Similar Publications