Department of Gastroenterology, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Cell Death Dis. 2013 Mar 14;4(3):e541. doi: 10.1038/cddis.2013.22.
Inflammatory bowel disease (IBD), which consists of Crohn's disease (CD) and ulcerative colitis (UC), is a chronic, inflammatory disorder of the gastro-intestinal tract with unknown etiology. Current evidence suggests that intestinal epithelial cells (IECs) is prominently linked to the pathogenesis of IBD. Therefore, maintaining the intact of epithelium has potential roles in improving pathophysiology and clinical outcomes of IBD. MicroRNAs (miRNAs) act as post-transcriptional gene regulators and regulate many biological processes, including embryonal development, cell differentiation, apoptosis and proliferation. In this study, we found that miR-200b decreased significantly in inflamed mucosa of IBD, especially for UC, when compared with their adjacent normal tissue. Simultaneously, we also found that the genes of E-cadherin and cyclin D1 were reduced significantly and correlated positively to the miR-200b. In addition, the upregulation of transforming growth factor-beta 1 (TGF-β1) was inversely correlated to the miR-200b in IBD. To investigate the possible roles of miR-200b in IECs maintaining, we used TGF-β1 to induce epithelial-mesenchymal transition (EMT) in IEC-6 initially. After sustained over-expressing miR-200b in IEC-6, the EMT was inhibited significantly that was characterized by downregulation of vimentin and upregulation of E-cadherin. Furthermore, we found that miR-200b enhanced E-cadherin expression through targeting of ZEB1, which encode transcriptional repressors of E-cadherin. SMAD2 was found to act as a target of miR-200b with direct evidence that miR-200b binding to the 3' UTR of SAMD2 and the ability of miR-200b to repress SMAD2 protein expression. With SMAD2 depletion, the expression of vimentin decreased correspondingly, which suggested miR-200b might reduce vimentin through regulating the SMAD2. With endogenous over-expression of miR-200b, the proliferation of IEC-6 cells increased significantly by increasing S-phase entry and promoting expression of the protein cyclin D1. Summarily, our study suggested a potential role for mir-200b in maintaining intact of intestinal epithelium through inhibiting EMT and promoting proliferation of IECs.
炎症性肠病（IBD）包括克罗恩病（CD）和溃疡性结肠炎（UC），是一种病因不明的慢性炎症性胃肠疾病。目前的证据表明，肠上皮细胞（IECs）与 IBD 的发病机制密切相关。因此，维持上皮的完整在改善 IBD 的病理生理学和临床结局方面具有潜在作用。微小 RNA（miRNA）作为转录后基因调节剂，调节包括胚胎发育、细胞分化、凋亡和增殖在内的许多生物学过程。在这项研究中，我们发现 miR-200b 在 IBD 的炎症黏膜中显著减少，尤其是在 UC 中，与相邻的正常组织相比。同时，我们还发现 E-钙粘蛋白和细胞周期蛋白 D1 的基因显著减少，并与 miR-200b 呈正相关。此外，TGF-β1 在 IBD 中与 miR-200b 呈负相关。为了研究 miR-200b 在 IECs 维持中的可能作用，我们最初使用 TGF-β1 诱导 IEC-6 上皮-间充质转化（EMT）。在 IEC-6 中持续过表达 miR-200b 后，EMT 显著抑制，特征是波形蛋白下调和 E-钙粘蛋白上调。此外，我们发现 miR-200b 通过靶向 ZEB1 增强 E-钙粘蛋白的表达，ZEB1 编码 E-钙粘蛋白的转录抑制因子。SMAD2 被发现是 miR-200b 的靶标，有直接证据表明 miR-200b 结合到 SMAD2 的 3'UTR 上，以及 miR-200b 抑制 SMAD2 蛋白表达的能力。随着 SMAD2 的耗竭，波形蛋白的表达相应减少，这表明 miR-200b 可能通过调节 SMAD2 减少波形蛋白。通过内源性过表达 miR-200b，显著增加 IEC-6 细胞的 S 期进入，促进 cyclin D1 蛋白的表达，从而显著增加 IEC-6 细胞的增殖。总之，我们的研究表明，miR-200b 通过抑制 EMT 和促进 IECs 增殖，在维持肠道上皮完整方面发挥了潜在作用。
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