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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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3' Untranslated Regions
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Animals
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Argonaute Proteins / genetics*
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Argonaute Proteins / metabolism
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Argonaute Proteins / physiology
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Base Sequence
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Binding Sites
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Carcinoma, Hepatocellular / metabolism
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Carcinoma, Hepatocellular / mortality
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Cell Hypoxia
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Cell Line, Tumor
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Eukaryotic Initiation Factors / genetics*
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Eukaryotic Initiation Factors / metabolism
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Eukaryotic Initiation Factors / physiology
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Female
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High-Throughput Nucleotide Sequencing
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Human Umbilical Vein Endothelial Cells / metabolism
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Humans
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Liver Neoplasms / metabolism
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Liver Neoplasms / mortality
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Male
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Mammary Neoplasms, Experimental / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, SCID
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MicroRNAs / genetics*
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MicroRNAs / metabolism
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Neoplasm Transplantation
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Neovascularization, Pathologic / metabolism*
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Organ Specificity
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RNA Interference
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Transcriptional Activation
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Vascular Endothelial Growth Factor A / genetics
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Vascular Endothelial Growth Factor A / metabolism
Substances
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3' Untranslated Regions
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AGO1 protein, human
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Argonaute Proteins
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Eukaryotic Initiation Factors
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MIRN103 microRNA, human
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MIRN107 microRNA, human
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MicroRNAs
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VEGFA protein, human
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Vascular Endothelial Growth Factor A
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mirnlet7 microRNA, human