MicroRNA-182-5p aggravates ulcerative colitis by inactivating the Wnt/β-catenin signaling pathway through DNMT3A-mediated SMARCA5 methylation.
MicroRNA-182-5p aggravates ulcerative colitis by inactivating the Wnt/β-catenin signaling pathway through DNMT3A-mediated SMARCA5 methylation.
复制标题
MicroRNA-182-5p 通过 DNMT3A 介导的 SMARCA5 甲基化灭活 Wnt/β-catenin 信号通路，从而加重溃疡性结肠炎。
DOI：
10.1016/j.ygeno.2022.110360
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发表时间：
2022
期刊：
影响因子：
4.4
通讯作者：
M. Ouyang
中科院分区：
文献类型：
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作者：
Yan Xu;Junwen Yang;Xiaoli Chen;J. Deng;H. Gong;Fujun Li;M. Ouyang
本研究旨在探讨microRNA(MiR)-182-5p在溃疡性结肠炎(UC)发病机制中的作用。取UC患者的结肠组织，建立葡萄糖硫酸钠诱导的小鼠模型和白细胞介素1β(IL-1β)诱导的Caco-2细胞模型。然后，在IL-1β刺激的Caco-2细胞和DSS处理的小鼠中，改变miR182-5p、SMARCA5和Wnt/β-catenin信号通路以评估它们的功能。在UC患者、IL-1β刺激的Caco-2细胞和DSS处理的小鼠中，MIR182-5p和SMARCA5表达上调，DNMT3A、β-连环蛋白和细胞周期蛋白D1表达下调。在机制上，miR-182-5p靶向DNMT3A上调SMARCA5，从而阻断Wnt/β-catenin信号通路。此外，SMARCA5沉默或Wnt/β-catenin信号通路激活抑制了IL-1β刺激的Caco-2细胞的凋亡，增强了细胞的增殖和上皮屏障功能。SMARCA5沉默可阻断miR-182-5p过表达对IL-1β刺激的Caco-2细胞的影响。SMARCA5沉默或miR-182-5p抑制可改善DSS处理小鼠的肠屏障功能障碍。总的来说，miR-182-5p通过DNMT3A介导的SMARCA5甲基化使Wnt/β-catenin信号通路失活，从而加重UC。
This research focused on novel molecular mechanisms underlying microRNA (miR)-182-5p in ulcerative colitis (UC). Colon tissues were obtained from UC patients, and dextrose sodium sulfate (DSS)-induced mouse and interleukin-1β (IL-1β)-induced Caco-2 cell models were generated. Then, miR-182-5p, SMARCA5, and the Wnt/β-catenin signaling pathway were altered in IL-1β-stimulated Caco-2 cells and DSS-treated mice to assess their function. MiR-182-5p and SMARCA5 were upregulated and DNMT3A, β-catenin, and Cyclin D1 were downregulated in UC patients, IL-1β-stimulated Caco-2 cells, and DSS-treated mice. Mechanistically, miR-182-5p targeted DNMT3A to upregulate SMARCA5, thus blocking the Wnt/β-catenin signaling pathway. Moreover, SMARCA5 silencing or Wnt/β-catenin signaling pathway activation repressed apoptosis and augmented proliferation and epithelial barrier function of IL-1β-stimulated Caco-2 cells. SMARCA5 silencing annulled the impacts of miR-182-5p overexpression on IL-1β-stimulated Caco-2 cells. SMARCA5 silencing or miR-182-5p inhibition ameliorated intestinal barrier dysfunction in DSS-treated mice. Collectively, miR-182-5p aggravates UC by inactivating the Wnt/β-catenin signaling pathway through DNMT3A-mediated SMARCA5 methylation.