title: MicroRNA-132 and microRNA-223 control positive feedback circuit by regulating FOXO3a in inflammatory bowel disease.
abstract: OBJECTIVE
  Although many progresses have been achieved for inflammatory bowel disease (IBD), it is still remained as idiopathic disease to be completely controlled. MicroRNAs (miRNAs) have been identified as key players in many human diseases through degradation or translational inhibition of target genes. Because role of miRNAs in IBD is not completely understood yet, we need to identify miRNAs as novel targets for treatment of IBD.
  
  
  METHODS
  Microarray analysis for miRNAs was performed using dextran sulfate sodium-induced colitis samples and selected differentially regulated miRNAs. Candidate genes were validated using in vitro system and IBD patient samples. Molecular mechanism for regulation of inflammatory signaling was identified using gene modulation system of miRNAs.
  
  
  RESULTS
  We selected 14 upregulated and 15 downregulated miRNAs through microarray analysis. Among candidate miRNAs, significant upregulation of miR-132 and miR-223 was confirmed in inflamed mouse tissues as well as human IBD patient tissues. Through bioinformatics analysis, we identified FOXO3a as direct target of miRNAs and confirmed regulatory mechanism using luciferase assay. Expression of miRNAs clearly suppressed the level of IκBα through downregulation of FOXO3a, leading to enhanced NF-κB signaling to promote the production of pro-inflammatory cytokines. The downregulation of FOXO3a concurrent with upregulation of cytokines was significantly reversed by sequestration of miRNAs with miRNA sponges.
  
  
  CONCLUSIONS
  Our findings provided the evidences that miR-132 and 223 are critical mediators in positive circuit for pathogenesis of IBD by negatively regulating FOXO3a to enhance the expression of inflammatory cytokines and can be a good therapeutic target for IBD treatment.
authors.affiliation: Department of Molecular Medicine, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Korea.
authors.forename: Hye-Youn
authors.initials: HY
authors.lastname: Kim
authors.affiliation: Department of Molecular Medicine, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Korea.|Department of Anatomy, College of Medicine, Seoul National University, Seoul, Korea.
authors.forename: Hyeok Yi
authors.initials: HY
authors.lastname: Kwon
authors.affiliation: Department of Molecular Medicine, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Korea.
authors.forename: Huyen Trang
authors.initials: HT
authors.lastname: Ha Thi
authors.affiliation: Department of Molecular Medicine, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Korea.
authors.forename: Ho Jae
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Department of Pathology, CHA Bundang Medical Center, Seongnam, Korea.
authors.forename: Gwang Il
authors.initials: GI
authors.lastname: Kim
authors.affiliation: CHA Cancer Prevention Research Center, CHA University, Seongnam, Korea.
authors.forename: Ki-Baek
authors.initials: KB
authors.lastname: Hahm
authors.affiliation: Department of Molecular Medicine, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Korea. sthong@gachon.ac.kr.
authors.forename: Suntaek
authors.initials: S
authors.lastname: Hong
mesh_terms: D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003106:Colon / Q000378:metabolism / Q000473:pathology; D019295:Computational Biology / Q000379:methods; D016207:Cytokines / Q000378:metabolism; D025461:Feedback, Physiological; D000071316:Forkhead Box Protein O3 / Q000096:biosynthesis / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics; D055785:Gene Knockdown Techniques; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D015212:Inflammatory Bowel Diseases / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*
chemical_list: D016207:Cytokines; D000071316:Forkhead Box Protein O3; D018836:Inflammation Mediators; D035683:MicroRNAs; C499517:FOXO3 protein, human; C547077:MIRN132 microRNA, human; C525067:MIR223, human
keywords: FOXO3a; inflammatory bowel disease; miR-132; miR-223