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
View: Text | PDF
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

×

Figure 7

Implication of HRM-mediated VEGF desuppression in tumorigenesis.

Options: View larger image (or click on image) Download as PowerPoint
Implication of HRM-mediated VEGF desuppression in tumorigenesis. (A–C) M...
(A–C) Mammary fat pads of SCID mice were implanted with 5 × 105 MDA-MB-231 human breast cancer cells. After 4 weeks, mice were killed and tumors were harvested. Core regions of necrotic tumors and distal areas shown in A were collected for detection of miRNAs (B) and AGO1 protein (C). Scale bar: 2 mm. (B) Specimens collected from 10 animals were pooled into 4 samples (each containing 2 or 3 specimens as indicated) for miRNA qPCR. Bars represent the ratio of miRNA level in the core relative to that in the distal region. (C) Representative images of Western blot analysis with samples from individual mice. (D) Levels of Let-7e and miR-103 was detected in paired normal (N) and tumor (T) tissues, and the T/N expression ratio was calculated. (E and F) Representative IHC staining of AGO1, VEGF, CD31, and ISH of Let-7e and miR-103 in serial sections from patients with AGO1 high/VEGF low (E) and AGO1 low/VEGF high expression patterns (F). Scale bar: 200 μm (×100); 100 μm (×400). Yellow arrowheads indicate the location of microvessels. (G and H) Kaplan-Meier analysis of disease-free (G) and overall survival (H) for 173 HCC patients, stratified by AGO1 and VEGF expression.