Hypoxia-responsive miRNAs target argonaute 1 to promote angiogenesis
Copyright policy )Hypoxia-responsive miRNAs target argonaute 1 to promote angiogenesis
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.
- Taipei Veterans General Hospital Taiwan
- University of California System United States
- Institute of Biomedical Science United Kingdom
- Institute of Bioinformatics and Systems Biology Germany
- University of California, Riverside United States
Male, Binding Sites, Carcinoma, Hepatocellular, Base Sequence, Liver Neoplasms, High-Throughput Nucleotide Sequencing, Mammary Neoplasms, Experimental, Mice, SCID, Cell Hypoxia, Mice, Inbred C57BL, Mice, MicroRNAs, Cell Line, Tumor, Argonaute Proteins, Human Umbilical Vein Endothelial Cells, Animals, Humans, Female, Eukaryotic Initiation Factors, 3' Untranslated Regions
Male, Binding Sites, Carcinoma, Hepatocellular, Base Sequence, Liver Neoplasms, High-Throughput Nucleotide Sequencing, Mammary Neoplasms, Experimental, Mice, SCID, Cell Hypoxia, Mice, Inbred C57BL, Mice, MicroRNAs, Cell Line, Tumor, Argonaute Proteins, Human Umbilical Vein Endothelial Cells, Animals, Humans, Female, Eukaryotic Initiation Factors, 3' Untranslated Regions
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