Premium
Repression of VEGFA by CA‐rich element‐binding microRNAs is modulated by hnRNP L
Author(s) -
Jafarifar Faegheh,
Yao Peng,
Eswarappa Sandeepa M,
Fox Paul L
Publication year - 2011
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2011.38
Subject(s) - vascular endothelial growth factor a , microrna , biology , three prime untranslated region , gene silencing , microbiology and biotechnology , psychological repression , rna binding protein , rna interference , messenger rna , untranslated region , cancer research , rna , gene expression , vascular endothelial growth factor , genetics , gene , vegf receptors
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.