Hypoxia-responsive miRNAs target argonaute 1 to promote angiogenesis
Hypoxia-responsive miRNAs target argonaute 1 to promote angiogenesis
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DOI：
10.1172/jci65344
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发表时间：
2013-03-01
影响因子：
15.9
通讯作者：
Shyy, John Y-J.
中科院分区：
文献类型：
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作者：
Chen, Zhen;Lai, Tsung-Ching;Shyy, John Y-J.
尽管在缺氧条件下一般抑制翻译，细胞选择性上调一组缺氧诱导基因。深度测序的结果显示Let-7和miR-103/107是在血管内皮细胞中强烈诱导的低氧响应性microRNA（HRM）。计算机生物信息学和体外验证表明，这些HRM由HIF 1 α和靶Argonaute 1（AGO 1）诱导，AGO 1锚定microRNA诱导的沉默复合物（miRISC）。HRM靶向AGO 1导致VEGF mRNA的翻译去抑制。抑制HRM或在没有3'非翻译区的情况下过表达AGO 1可以减少缺氧诱导的血管生成。相反，AGO 1敲低增加体内常氧下的血管生成。此外，来自肿瘤异种移植物和人类癌症标本的数据表明，AGO 1介导的VEGF翻译抑制可能与肿瘤血管生成和预后不良有关。这些发现为涉及靶向AGO 1的HRM的血管生成途径提供了证据，并表明该途径可能是抗血管生成或促血管生成策略的合适靶点。
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.