Hye-Youn Kim1, Hyeok Yi Kwon1,2, Huyen Trang Ha Thi1, Ho Jae Lee1, Gwang Il Kim3, Ki-Baek Hahm4, Suntaek Hong5. 1. Department of Molecular Medicine, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Korea. 2. Department of Anatomy, College of Medicine, Seoul National University, Seoul, Korea. 3. Department of Pathology, CHA Bundang Medical Center, Seongnam, Korea. 4. CHA Cancer Prevention Research Center, CHA University, Seongnam, Korea. 5. Department of Molecular Medicine, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Korea. sthong@gachon.ac.kr.
Abstract
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.
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.
Authors: Yu Zheng Wu; Kathy Yuen Yee Chan; Kam Tong Leung; Hugh Simon Lam; Yuk Him Tam; Kim Hung Lee; Karen Li; Pak Cheung Ng Journal: FEBS Open Bio Date: 2021-06-01 Impact factor: 2.693
Authors: HyunTaek Jung; Jae Seok Kim; Keum Hwa Lee; Kalthoum Tizaoui; Salvatore Terrazzino; Sarah Cargnin; Lee Smith; Ai Koyanagi; Louis Jacob; Han Li; Sung Hwi Hong; Dong Keon Yon; Seung Won Lee; Min Seo Kim; Paul Wasuwanich; Wikrom Karnsakul; Jae Il Shin; Andreas Kronbichler Journal: Int J Biol Sci Date: 2021-05-17 Impact factor: 6.580