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, John Y-J. Shyy
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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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 5

HRM/AGO1 pathway mediates hypoxia-induced angiogenesis in vitro and responds to hypoxia in vivo.

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HRM/AGO1 pathway mediates hypoxia-induced angiogenesis in vitro and resp...
(A–C) HUVECs were prepared as described in Figure 4, F–H, and underwent in vitro angiogenesis assays. The tube/joint numbers were counted, with normoxia/control RNA group (A), normoxia/control plasmid group (B), or control RNA group (C) set to 1. Scale bar: 100 μm. (D and E) C57BL/6 mice were subjected to hypoxia (10% O2) or normoxia (21% O2) for 5 days. Let-7 and miR-103/107 expression in multi-organs/tissues was detected by TaqMan miRNA qPCR (D) and AGO1 protein level by Western blot analysis (E). The levels of miRNAs in normoxia were set to 1. (F and G) Control RNA or antagomirs (antmiR) were delivered with pluronic gel to hind-limb muscles of C57BL/6 mice and then kept under normoxia or hypoxia for 5 days. The miRNAs in the hind limbs were quantified by qPCR (F) and VEGF by Western blot analysis (G). (D–G) Data represent results from at least 6 animals per group. *P < 0.05 compared with controls or between indicated groups.