MicroRNA-132 and microRNA-223 control positive feedback circuit by regulating FOXO3a in inflammatory bowel disease
MicroRNA-132 and microRNA-223 control positive feedback circuit by regulating FOXO3a in inflammatory bowel disease
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DOI：
10.1111/jgh.13321
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发表时间：
2016-10-01
影响因子：
4.1
通讯作者：
Hong, Suntaek
中科院分区：
文献类型：
--
作者：
Kim, Hye-Youn;Kwon, Hyeok Yi;Hong, Suntaek
背景与目的：虽然炎症性肠病（IBD）的治疗取得了许多进展，但它仍然是一种特发性疾病，需要完全控制。通过靶基因的降解或翻译抑制，MicroRNAs （miRNAs）已被确定为许多人类疾病的关键角色。由于mirna在IBD中的作用尚不完全清楚，我们需要确定mirna作为治疗IBD的新靶点。方法：使用葡聚糖硫酸钠诱导的结肠炎样本和选择的差异调节的mirna进行mirna微阵列分析。候选基因通过体外系统和IBD患者样本进行验证。利用mirna基因调控系统，确定了炎症信号调控的分子机制。结果：通过微阵列分析，我们筛选出14个上调mirna和15个下调mirna。在候选mirna中，miR-132和miR-223在炎症小鼠组织和人类IBD患者组织中被证实显著上调。通过生物信息学分析，我们确定FOXO3a是miRNAs的直接靶点，并通过荧光素酶测定证实了其调控机制。miRNAs的表达通过下调FOXO3a明显抑制I kappa B α水平，导致NF-kappa B信号增强，促进促炎细胞因子的产生。通过miRNA海绵隔离miRNA， FOXO3a的下调与细胞因子的上调被显著逆转。结论：我们的研究结果证明miR-132和223是IBD发病正通路中的关键介质，通过负调控FOXO3a增强炎症因子的表达，可以成为IBD治疗的良好靶点。
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 I kappa B alpha through downregulation of FOXO3a, leading to enhanced NF-kappa B 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.