Hypoxia-responsive miRNAs target argonaute 1 to promote angiogenesis

Zhen Chen, Tsung Ching Lai, Yi-Hua Jan, Feng Mao Lin, Wei-Chi Wang, Han Xiao, Yun-Ting Wang, Wei Sun, Xiaopei Cui, Ying-Shiuan Li, Tzan Fang, Hongwei Zhao, Chellappan Padmanabhan, Ruobai Sun, Danny Ling Wang, Hailing Jin, Gar-Yang Chau, Hsien-Da Huang, Michael Hsiao, Shyy John Y. -J.

Research output: Contribution to journalArticlepeer-review

130 Scopus citations

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 HIF1 alpha 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 fmdings 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.
Original languageEnglish
Pages (from-to)1057-1067
Number of pages11
JournalJournal of Clinical Investigation
Volume123
Issue number3
DOIs
StatePublished - Mar 2013

Keywords

  • ENDOTHELIAL GROWTH-FACTOR; INTERNAL RIBOSOME ENTRY; MESSENGER-RNA; GENE-EXPRESSION; INDUCIBLE FACTOR-1; LET-7 MICRORNA; HUMAN-CELLS; FACTOR-I; CANCER; TRANSLATION

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