Hypoxia-responsive miRNAs target argonaute 1 to promote angiogenesis

被引：163

作者：

Chen, Zhen ^{[1
,2
]}

Lai, Tsung-Ching ^{[3
]}

Jan, Yi-Hua ^{[3
]}

Lin, Feng-Mao ^{[4
]}

Wang, Wei-Chi ^{[4
]}

Xiao, Han ^{[1
]}

Wang, Yun-Ting ^{[5
]}

Sun, Wei ^{[1
]}

Cui, Xiaopei ^{[1
]}

Li, Ying-Shiuan ^{[1
]}

Fang, Tzan ^{[4
]}

Zhao, Hongwei ^{[6
]}

Padmanabhan, Chellappan ^{[6
]}

Sun, Ruobai ^{[1
]}

Wang, Danny Ling ^{[5
]}

Jin, Hailing ^{[6
]}

Chau, Gar-Yang ^{[7
]}

Huang, Hsien-Da ^{[4
]}

Hsiao, Michael ^{[3
]}

Shyy, John Y-J. ^{[1
,2
]}

机构：

[1] Univ Calif Riverside, Div Biomed Sci, Riverside, CA 92521 USA

[2] Univ Calif San Diego, Sch Med, Dept Med, San Diego, CA USA

[3] Acad Sinica, Genom Res Ctr, Taipei 115, Taiwan

[4] Natl Chiao Tung Univ, Inst Bioinformat & Syst Biol, Hsinchu, Taiwan

[5] Acad Sinica, Inst Biomed Sci, Taipei, Taiwan

[6] Univ Calif Riverside, Dept Plant Pathol & Microbiol, Riverside, CA 92521 USA

[7] Taipei Vet Gen Hosp, Dept Surg, Div Gen Surg, Taipei, Taiwan

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2013年 / 123卷 / 03期

关键词：

ENDOTHELIAL GROWTH-FACTOR; INTERNAL RIBOSOME ENTRY; MESSENGER-RNA; GENE-EXPRESSION; LET-7; MICRORNA; TRANSLATION; CANCER; DICER; IDENTIFICATION; TRANSCRIPTION;

D O I：

10.1172/JCI65344

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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.

引用

页码：1057 / 1067

页数：11

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