MicroRNAs Are Differentially Expressed in Ulcerative Colitis and Alter Expression of Macrophage Inflammatory Peptide-2α
MicroRNAs Are Differentially Expressed in Ulcerative Colitis and Alter Expression of Macrophage Inflammatory Peptide-2α
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DOI：
10.1053/j.gastro.2008.07.068
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发表时间：
2008-11-01
期刊：
影响因子：
29.4
通讯作者：
Kwon, John H.
中科院分区：
文献类型：
--
作者：
Wu, Feng;Zikusoka, Michelle;Kwon, John H.
背景与目的：慢性炎症性肠病，如溃疡性结肠炎（UC），与参与炎症和组织重塑的基因差异表达有关。微小RNA（miRNA）可引导mRNA降解和抑制翻译，影响多种疾病进程。我们研究了miRNA在UC组织中是否差异表达，以及是否与调节炎症的基因表达相关。
方法：通过微阵列、定量逆转录 - 聚合酶链反应和原位杂交分析，评估活动性UC、非活动性UC、克罗恩病、肠易激综合征、感染性结肠炎和显微镜下结肠炎患者以及健康受试者的miRNA表达。评估结肠上皮细胞（HT29）中miRNA的表达。通过荧光素酶报告基因构建体测定和特异性miRNA模拟物转染评估miRNA对基因表达的调节。
结果：活动性UC与11种miRNA的差异表达有关；在UC组织中，3种显著降低，8种显著升高。原位杂交分析表明，在活动性UC中表达降低的miR - 192主要定位于结肠上皮细胞。巨噬细胞炎性肽（MIP）-2α是一种由上皮细胞表达的趋化因子，被确定为miR - 192的靶标。在结肠上皮细胞中，肿瘤坏死因子 - α诱导MIP - 2α表达的同时伴随着miR - 192表达的降低，并且观察到miR - 192可调节MIP - 2α的表达。
结论：这些发现扩展了对miRNA已知的作用，表明UC患者（可能还有其他慢性炎症性疾病患者）的组织具有改变的miRNA表达模式。这些发现还表明miRNA可调节结肠上皮细胞衍生的趋化因子表达。
Background & Aims: Chronic inflammatory bowel diseases such as ulcerative colitis (UC) are associated with differential expression of genes involved in inflammation and tissue remodeling. MicroRNAs (miRNAs), which direct mRNA degradation and translational inhibition, influence a number of disease processes. We examined whether miRNAs are differentially expressed in UC tissues and are associated with expression of genes that regulate inflammation. Methods: miRNA expression was assessed in patients with active UC, inactive UC, Crohn's disease, irritable bowel syndrome, infectious colitis, and microscopic colitis, as well as in healthy subjects by microarray, quantitative reverse transcription-polymerase chain reaction and in situ hybridization analyses. Colonic epithelial cell (HT29) expression of miRNAs was assessed. Regulation of gene expression by miRNAs was assessed by luciferase reporter construct assays and transfection of specific miRNA mimics. Results: Active UC was associated with the differential expression of 11 miRNAs; 3 were siginificantly decreased and 8 were significantly increased in UC tissues. In situ hybridization analysis indicated that miR-192, an miRNA with decreased expression in active UC, was predominantly localized to colonic epithelial cells. Macrophage inflammatory peptide (MIP)-2 alpha, a chemokine expressed by epithelial cells, was identified as a target of miR-192. In colon epithelial cells, induction of MIP-2 alpha expression by tumor necrosis factor-a was accompanied by a concomitant reduction in miR-192 expression and miR-192 was observed to regulate the expression of MIP-2a. Conclusions: These findings expand the known roles of miRNAs, indicating that tissues from patients with UC, and possibly other chronic inflammatory diseases, have altered miRNA expression patterns. These findings also demonstrate that miRNAs regulate colonic epithelial cell-derived chemokine expression.