Members of the microRNA-17-92 cluster exhibit a cell-intrinsic antiangiogenic function in endothelial cells

• Published in: Blood 2010-06, Vol.115 (23), p.4944-4950
• Main Authors: Doebele, Carmen, Bonauer, Angelika, Fischer, Ariane, Scholz, Alexander, Reiss, Yvonne, Urbich, Carmen, Hofmann, Wolf-Karsten, Zeiher, Andreas M., Dimmeler, Stefanie
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cell Line, Tumor; Endothelial Cells - metabolism; Endothelial Cells - pathology; Hematologic and hematopoietic diseases; Humans; Medical sciences; Mice; MicroRNAs - biosynthesis; MicroRNAs - genetics; Multigene Family; Neoplasms - blood supply; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - pathology; Spheroids, Cellular - metabolism; Spheroids, Cellular - pathology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2010-01-264812

MicroRNAs are endogenously expressed small noncoding RNAs that regulate gene expression on the posttranscriptional level. The miR-17-92 cluster (encoding miR-17, -18a, -19a/b, -20a, and miR-92a) is highly expressed in tumor cells and is up-regulated by ischemia. Whereas miR-92a was recently identified as negative regulator of angiogenesis, the specific functions of the other members of the cluster are less clear. Here we demonstrate that overexpression of miR-17, -18a, -19a, and -20a significantly inhibited 3-dimensional spheroid sprouting in vitro, whereas inhibition of miR-17, -18a, and -20a augmented endothelial cell sprout formation. Inhibition of miR-17 and miR-20a in vivo using antagomirs significantly increased the number of perfused vessels in Matrigel plugs, whereas antagomirs that specifically target miR-18a and miR-19a were less effective. However, systemic inhibition of miR-17/20 did not affect tumor angiogenesis. Further mechanistic studies showed that miR-17/20 targets several proangiogenic genes. Specifically, Janus kinase 1 was shown to be a direct target of miR-17. In summary, we show that miR-17/20 exhibit a cell-intrinsic antiangiogenic activity in endothelial cells. Inhibition of miR-17/20 specifically augmented neovascularization of Matrigel plugs but did not affect tumor angiogenesis indicating a context-dependent regulation of angiogenesis by miR-17/20 in vivo.