title: Regulation of proinflammatory genes by the circulating microRNA hsa-miR-939.
abstract: Circulating microRNAs are beneficial biomarkers because of their stability and dysregulation in diseases. Here we sought to determine the role of miR-939, a miRNA downregulated in patients with complex regional pain syndrome (CRPS). Hsa-miR-939 is predicted to target several proinflammatory genes, including IL-6, VEGFA, TNFα, NFκB2, and nitric oxide synthase 2 (NOS2A). Binding of miR-939 to the 3' untranslated region of these genes was confirmed by reporter assay. Overexpression of miR-939 in vitro resulted in reduction of IL-6, NOS2A and NFκB2 mRNAs, IL-6, VEGFA, and NOS2 proteins and NFκB activation. We observed a significant decrease in the NOS substrate l-arginine in plasma from CRPS patients, suggesting reduced miR-939 levels may contribute to an increase in endogenous NOS2A levels and NO, and thereby to pain and inflammation. Pathway analysis showed that miR-939 represents a critical regulatory node in a network of inflammatory mediators. Collectively, our data suggest that miR-939 may regulate multiple proinflammatory genes and that downregulation of miR-939 in CRPS patients may increase expression of these genes, resulting in amplification of the inflammatory pain signal transduction cascade. Circulating miRNAs may function as crucial signaling nodes, and small changes in miRNA levels may influence target gene expression and thus disease.
authors: Pharmacology &Physiology, Drexel University College of Medicine, 245 North 15th Street, Philadelphia, PA 19102, USA.|Gene Therapy Program, Perelman School of Medicine, University of Pennsylvania, Suite 2000, Translational Research Laboratories (TRL), 125 S. 31st Street, Philadelphia, PA 19104-3403, USA.
authors: Marguerite K
authors: MK
authors: McDonald
authors: Pharmacology &Physiology, Drexel University College of Medicine, 245 North 15th Street, Philadelphia, PA 19102, USA.
authors: Sujay
authors: S
authors: Ramanathan
authors: Pharmacology &Physiology, Drexel University College of Medicine, 245 North 15th Street, Philadelphia, PA 19102, USA.
authors: Andrew
authors: A
authors: Touati
authors: School of Biomedical Engineering, Science &Health Systems, Drexel University, 3141 Chestnut Street, Philadelphia, PA 19104, USA.
authors: Yiqian
authors: Y
authors: Zhou
authors: Pharmacology &Physiology, Drexel University College of Medicine, 245 North 15th Street, Philadelphia, PA 19102, USA.
authors: Rushi U
authors: RU
authors: Thanawala
authors: Neurology, Drexel University College of Medicine, 245 North 15th Street, Philadelphia, PA 19102, USA.
authors: Guillermo M
authors: GM
authors: Alexander
authors: School of Biomedical Engineering, Science &Health Systems, Drexel University, 3141 Chestnut Street, Philadelphia, PA 19104, USA.
authors: Ahmet
authors: A
authors: Sacan
authors: Pharmacology &Physiology, Drexel University College of Medicine, 245 North 15th Street, Philadelphia, PA 19102, USA.
authors: Seena K
authors: SK
authors: Ajit
mesh_terms: D002478:Cells, Cultured; D000074166:Circulating MicroRNA / Q000378:metabolism*; D020918:Complex Regional Pain Syndromes / Q000473:pathology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D007155:Immunologic Factors / Q000096:biosynthesis*; D007249:Inflammation / Q000473:pathology*; D035683:MicroRNAs / Q000378:metabolism*
chemical_list: D000074166:Circulating MicroRNA; D007155:Immunologic Factors; C000604729:MIRN939 microRNA, human; D035683:MicroRNAs