Xu Yan, Yang Junwen, Chen Xiaoli, Deng Jiawen, Gong Hui, Li Fujun, Ouyang Miao
Department of Health Management Center, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China.
Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China.
Genomics. 2022 May;114(3):110360. doi: 10.1016/j.ygeno.2022.110360. Epub 2022 Apr 1.
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.
本研究聚焦于溃疡性结肠炎（UC）中微小RNA（miR）-182-5p的新型分子机制。从UC患者获取结肠组织，并构建葡聚糖硫酸钠（DSS）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miR-182-5p、SMARCA5和Wnt/β-连环蛋白信号通路，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，miR-182-5p和SMARCA5上调，而DNMT3A、β-连环蛋白和细胞周期蛋白D1下调。机制上，miR-182-5p靶向DNMT3A以上调SMARCA5，从而阻断Wnt/β-连环蛋白信号通路。此外，SMARCA5沉默或Wnt/β-连环蛋白信号通路激活可抑制IL-1β刺激的Caco-2细胞的凋亡，并增强其增殖和上皮屏障功能。SMARCA5沉默消除了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抑制改善了DSS处理小鼠的肠道屏障功能障碍。总体而言，miR-182-5p通过DNMT3A介导的SMARCA5甲基化使Wnt/β-连环蛋白信号通路失活，从而加重UC。
