Hypoxia-responsive miRNAs target argonaute 1 to promote angiogenesis
Zhen Chen, … , Michael Hsiao, John Y-J. Shyy
Zhen Chen, … , Michael Hsiao, John Y-J. Shyy
Published February 15, 2013
Citation Information: J Clin Invest. 2013;123(3):1057-1067. https://doi.org/10.1172/JCI65344.
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Research Article Oncology

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

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, John Y-J. Shyy

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Figure 1

Hypoxia induces Let-7 and miR-103/107 in ECs.

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Hypoxia induces Let-7 and miR-103/107 in ECs. (A and B) HUVECs were kept...
(A and B) HUVECs were kept under normoxia (21% O2) or were subjected to hypoxia (2% O2) for 24 hours. (A) Northern blotting analysis of Let-7 and miR-103/107 expression. 18S rRNA was detected as loading control. (B) The indicated miRNAs were detected by TaqMan qPCR. The relative expression was normalized to that of U6 RNA, with that of normoxia set as 1. (C) HUVECs were infected with Ad-HIF1α for 72 hours, and miRNAs were quantified by TaqMan qPCR. The relative level of miRNA expression was compared with that of the mock-infected group (0 MOI), set as 1. Bar graphs represent mean ± SD from 3 independent experiments. *P < 0.05 compared with normoxia in B or mock-infected controls in C.