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MicroRNA‐132 and microRNA‐223 control positive feedback circuit by regulating FOXO3a in inflammatory bowel disease
Author(s) -
Kim HyeYoun,
Kwon Hyeok Yi,
Ha Thi Huyen Trang,
Lee Ho Jae,
Kim Gwang Il,
Hahm KiBaek,
Hong Suntaek
Publication year - 2016
Publication title -
journal of gastroenterology and hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.214
H-Index - 130
eISSN - 1440-1746
pISSN - 0815-9319
DOI - 10.1111/jgh.13321
Subject(s) - downregulation and upregulation , microrna , inflammatory bowel disease , microarray analysis techniques , microarray , medicine , pathogenesis , proinflammatory cytokine , mir 155 , cancer research , gene expression , immunology , inflammation , biology , disease , gene , genetics
Background and Aim 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.