title: Hypoxia-responsive miRNAs target argonaute 1 to promote angiogenesis.
abstract: Despite a general repression of translation under hypoxia, cells selectively upregulate a set of hypoxia-inducible genes. Results from deep sequencing revealed that Let-7 and miR-103/107 are hypoxia-responsive microRNAs (HRMs) that are strongly induced in vascular endothelial cells. In silico bioinformatics and in vitro validation showed that these HRMs are induced by HIF1α and target argonaute 1 (AGO1), which anchors the microRNA-induced silencing complex (miRISC). HRM targeting of AGO1 resulted in the translational desuppression of VEGF mRNA. Inhibition of HRM or overexpression of AGO1 without the 3' untranslated region decreased hypoxia-induced angiogenesis. Conversely, AGO1 knockdown increased angiogenesis under normoxia in vivo. In addition, data from tumor xenografts and human cancer specimens indicate that AGO1-mediated translational desuppression of VEGF may be associated with tumor angiogenesis and poor prognosis. These findings provide evidence for an angiogenic pathway involving HRMs that target AGO1 and suggest that this pathway may be a suitable target for anti- or proangiogenesis strategies.
authors: Division of Biomedical Sciences, University of California, Riverside, California, USA.
authors: Zhen
authors: Z
authors: Chen
authors: Tsung-Ching
authors: TC
authors: Lai
authors: Yi-Hua
authors: YH
authors: Jan
authors: Feng-Mao
authors: FM
authors: Lin
authors: Wei-Chi
authors: WC
authors: Wang
authors: Han
authors: H
authors: Xiao
authors: Yun-Ting
authors: YT
authors: Wang
authors: Wei
authors: W
authors: Sun
authors: Xiaopei
authors: X
authors: Cui
authors: Ying-Shiuan
authors: YS
authors: Li
authors: Tzan
authors: T
authors: Fang
authors: Hongwei
authors: H
authors: Zhao
authors: Chellappan
authors: C
authors: Padmanabhan
authors: Ruobai
authors: R
authors: Sun
authors: Danny Ling
authors: DL
authors: Wang
authors: Hailing
authors: H
authors: Jin
authors: Gar-Yang
authors: GY
authors: Chau
authors: Hsien-Da
authors: HD
authors: Huang
authors: Michael
authors: M
authors: Hsiao
authors: John Y-J
authors: JY
authors: Shyy
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D060565:Argonaute Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D001483:Base Sequence; D001665:Binding Sites; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000401:mortality; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D039642:Eukaryotic Initiation Factors / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000401:mortality; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D009928:Organ Specificity; D034622:RNA Interference; D015533:Transcriptional Activation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; C115848:AGO1 protein, human; D060565:Argonaute Proteins; D039642:Eukaryotic Initiation Factors; C544749:MIRN103 microRNA, human; C549045:MIRN107 microRNA, human; D035683:MicroRNAs; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C487931:mirnlet7 microRNA, human