Autoregulation of glypican-1 by intronic microRNA-149 fine tunes the angiogenic response to FGF2 in human endothelial cells.
MicroRNA-149 (miR-149) is located within the first intron of the glypican-1 (GPC1) gene. GPC1 is a low affinity receptor for fibroblast growth factor (FGF2) that enhances FGF2 binding to its receptor (FGFR1), subsequently promoting FGF2-FGFR1 activation and signaling. Using bioinformatic approaches, both GPC1 and FGFR1 were identified and subsequently validated as targets for miR-149 (both the mature strand, miR-149, and the passenger strand, miR-149*) in endothelial cells (ECs). As a consequence of their targeting activity towards GPC1 and FGFR1, both miR-149 and miR-149* regulated FGF2 signaling and FGF2-induced responses in ECs, namely proliferation, migration and cord formation. Moreover, lentiviral overexpression of miR-149 reduced in vivo tumor-induced neovascularization. Importantly, FGF2 transcriptionally stimulated the expression of miR-149 independently of its host gene, therefore assuring the steady state of FGF2-induced responses through the regulation of the GPC1-FGFR1 binary complex in ECs.
Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Department of Pathology and the Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520, USA.
Aránzazu
A
Chamorro-Jorganes
Elisa
E
Araldi
Noemi
N
Rotllan
Daniel
D
Cirera-Salinas
Yajaira
Y
Suárez
D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000098:blood supply / Q000378:metabolism; D002478:Cells, Cultured; D016222:Fibroblast Growth Factor 2 / Q000502:physiology*; D015870:Gene Expression; D053673:Glypicans / Q000235:genetics* / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000502:physiology*; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D018919:Neovascularization, Physiologic; D034622:RNA Interference; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
D053673:Glypicans; C551557:MIRN149 microRNA, human; D035683:MicroRNAs; D016222:Fibroblast Growth Factor 2; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1
Angiogenesis; Endothelial cell; FGF2; Glypican-1; miR-149; microRNA