Autoregulation of glypican-1 by intronic microRNA-149 fine tunes the angiogenic response to FGF2 in human endothelial cells
Autoregulation of glypican-1 by intronic microRNA-149 fine tunes the angiogenic response to FGF2 in human endothelial cells
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DOI：
10.1242/jcs.130518
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发表时间：
2014-03-15
影响因子：
4
通讯作者：
Suarez, Yajaira
中科院分区：
文献类型：
--
作者：
Chamorro-Jorganes, Aranzazu;Araldi, Elisa;Suarez, Yajaira
MicroRNA-149(miR-149)位于GPC1基因的第一内含子内。GPC1是成纤维细胞生长因子(FGF2)的低亲和力受体，可增强FGF2与其受体(FGFR1)的结合，进而促进FGF2-FGFR1的激活和信号转导。利用生物信息学方法，GPC1和FGFR1都被鉴定为内皮细胞(ECs)中miR-149(成熟链miR-149和客体链miR-149*)的靶标。由于它们对GPC1和FGFR1的靶向活性，miR-149和miR-149*都调节内皮细胞中的FGF2信号和FGF2诱导的反应，即增殖、迁移和脐带形成。此外，慢病毒过表达miR-149减少了体内肿瘤诱导的新生血管。重要的是，FGF2在转录水平上独立于宿主基因刺激miR-149的表达，从而通过调节内皮细胞中的GPC1-FGFR1二元复合体来确保FGF2诱导的反应的稳定状态。
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.