title: Repression of VEGFA by CA-rich element-binding microRNAs is modulated by hnRNP L.
abstract: 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.
authors.affiliation: Department of Cell Biology, The Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Faegheh
authors.initials: F
authors.lastname: Jafarifar
authors.forename: Peng
authors.initials: P
authors.lastname: Yao
authors.forename: Sandeepa M
authors.initials: SM
authors.lastname: Eswarappa
authors.forename: Paul L
authors.initials: PL
authors.lastname: Fox
mesh_terms: D020413:3' Untranslated Regions; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D034664:Heterogeneous-Nuclear Ribonucleoprotein L / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia; D035683:MicroRNAs / Q000378:metabolism*; D008954:Models, Biological; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*
chemical_list: D020413:3' Untranslated Regions; D034664:Heterogeneous-Nuclear Ribonucleoprotein L; D035683:MicroRNAs; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A