Somatostatin (SRIF) acts as antiangiogenic factor, but its role in the regulation of microRNAs (miRNAs) targeting proangiogenic factors is unknown. We used human umbilical vein endothelial cells (HUVEC) to investigate whether i. miRNAs targeting proangiogenic factors are influenced by hypoxia, ii. their expression is regulated by SRIF and iii. SRIF-regulated miRNAs affect HUVEC angiogenic phenotype. The involvement of signal transducer and activator of transcription (STAT) 3 and hypoxia inducible factor (HIF)-1 in miRNA effects was studied. Quantitative real-time PCR, Western blot, cell proliferation assays and ELISA were used. Using specific algorithms, three miRNAS (miR-17, miR-18b and miR-361) were predicted to bind angiogenesis-associated factors including STAT3, HIF-1α and vascular endothelial growth factor (VEGF). Hypoxia downregulated miR-17 and miR-361 without affecting miR-18b. SRIF restored decreased levels of miR-361 acting at the SRIF receptor sst1. Downregulated miR-361 was also restored by HIF-1α inhibition with YC-1. Combined application of SRIF did not influence YC-1-induced miR-361 downregulation suggesting that YC-1 and SRIF modulate miR-361 through a common mechanism involving HIF-1α. This possibility was confirmed by the result that HIF-1α activation in normoxia downregulated miR-361 and that this downregulation was prevented by SRIF. miR-361 overexpression reduced hypoxia-induced cell proliferation and VEGF release indicating miR-361 involvement in the acquisition of an angiogenic phenotype by HUVEC. miR-361 effects on VEGF were enhanced by the co-administration of SRIF. Our results suggest that i. SRIF regulates miR-361 expression through a control on HIF-1, ii. miR-361 affects HUVEC angiogenic phenotype and iii. SRIF and miR-361 act cooperatively in limiting hypoxia-induced VEGF release.
|Autori:||DAL MONTE M; LANDI D; MARTINI D; BAGNOLI P|
|Titolo:||Antiangiogenic role of miR-361 in human umbilical vein endothelial cells: functional interaction with the peptide somatostatin|
|Anno del prodotto:||2013|
|Digital Object Identifier (DOI):||10.1007/s00210-012-0808-1|
|Appare nelle tipologie:||1.1 Articolo in rivista|