Repression of VEGFA by CA-rich element-binding microRNAs is modulated by hnRNP L
Repression of VEGFA by CA-rich element-binding microRNAs is modulated by hnRNP L
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DOI：
10.1038/emboj.2011.38
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发表时间：
2011-04-06
期刊：
影响因子：
11.4
通讯作者：
Fox, Paul L.
中科院分区：
文献类型：
--
作者：
Jafarifar, Faegheh;Yao, Peng;Fox, Paul L.
肿瘤相关巨噬细胞表达血管内皮生长因子-A（VEGFA）对肿瘤进展和转移至关重要。缺氧是肿瘤微环境的共同特征，通过增加转录、翻译和mRNA稳定性诱导VEGFA表达。在这里，我们报告了一个新的机制，VEGFA调节缺氧，涉及逆转microRNA（miRNA）介导的沉默VEGFA的表达。我们发现人VEGFA 3 '-UTR中的CA富集元件（CARE）被至少四种miRNA靶向。在这些miRNA中，miR-297和-299在单核细胞中内源性表达，并负调节VEGFA表达。出乎意料的是，缺氧完全逆转了miRNA介导的VEGFA表达抑制。我们发现，异质核核糖核蛋白L（hnRNP L），也结合VEGFA 3 '-UTR CARE，阻止miRNA沉默活性。缺氧诱导核hnRNP L易位到细胞质，这显著增加hnRNP L与VEGFA mRNA的结合，从而抑制miRNA活性。总之，我们描述了一种新的调节机制，其中miRNA和RNA结合蛋白之间的相互作用影响了一个关键的缺氧诱导血管生成蛋白的表达。这些研究可能有助于提供基于miRNA的抗癌治疗工具。The EMBO Journal（2011）30，1324-1334. doi：10.1038/daj.2011.38; 2011年2月22日在线发布
Expression of vascular endothelial growth factor-A (VEGFA) by tumour-associated macrophages is critical for tumour progression and metastasis. Hypoxia, a common feature of the neoplastic microenvironment, induces VEGFA expression by increased transcription, translation, and mRNA stabilization. Here, we report a new mechanism of VEGFA regulation by hypoxia that involves reversal of microRNA (miRNA)-mediated silencing of VEGFA expression. We show that the CA-rich element (CARE) in the human VEGFA 3'-UTR is targeted by at least four miRNAs. Among these miRNAs, miR-297 and -299 are endogenously expressed in monocytic cells and negatively regulate VEGFA expression. Unexpectedly, hypoxia completely reverses miRNA-mediated repression of VEGFA expression. We show that heterogeneous nuclear ribonucleoprotein L (hnRNP L), which also binds the VEGFA 3'-UTR CARE, prevents miRNA silencing activity. Hypoxia induces translocation of nuclear hnRNP L to the cytoplasm, which markedly increases hnRNP L binding to VEGFA mRNA thereby inhibiting miRNA activity. In summary, we describe a novel regulatory mechanism in which the interplay between miRNAs and RNA-binding proteins influences expression of a critical hypoxia-inducible angiogenic protein. These studies may contribute to provide miRNA-based anticancer therapeutic tools. The EMBO Journal (2011) 30, 1324-1334. doi: 10.1038/emboj.2011.38; Published online 22 February 2011