Jiang Zhifeng, Yang Feiyu, Qie Jingbo, Jin Chaoyuan, Zhang Feng, Shen Jie, Zhang Lin
Department of Emergency and Critical Care Medicine, Jinshan Hospital, Fudan University, Shanghai, China.
Department of Emergency and Critical Care Medicine, Jinshan Hospital, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
Front Pharmacol. 2021 Aug 12;12:722283. doi: 10.3389/fphar.2021.722283. eCollection 2021.
Intestinal barrier dysfunction is characterized by increased intestinal permeability to lumen endotoxin, showing remarkable predisposition to immune enteropathy, and colorectal cancer tumor necrosis factor (TNF)-α is associated with this pathological process, while the mechanism remains unknown. In this study, different doses of TNF-α were used for Caco-2 cell treatment. We discovered that miR-21-3p expression was obviously increased by TNF-α in a dose-dependent manner. Further study demonstrated that TNF-α could upregulate miR-21-3p expression through the NF-κB signaling pathway. Then, TargetScan and miRWalk miRNA-mRNA interaction prediction online tools were introduced, and metadherin (MTDH) was screened out as a potential target of miR-21-3p. We subsequently found that miR-21-3p could directly target the 3'-untranslated region (UTR) of MTDH mRNA and inhibit its expression. Furthermore, it was demonstrated that miR-21-3p could regulate the Wnt signaling pathway by targeting MTDH mRNA, suggesting the effect of miR-21-3p/MTDH/Wnt axis on intestinal barrier dysfunction. Our findings provide a novel potential biomarker and therapeutic target for intestinal barrier dysfunction and related diseases.
肠道屏障功能障碍的特征是肠道对肠腔内毒素的通透性增加，显著易患免疫性肠病，且结肠直肠癌肿瘤坏死因子（TNF）-α与这一病理过程相关，但其机制尚不清楚。在本研究中，使用不同剂量的TNF-α处理Caco-2细胞。我们发现TNF-α以剂量依赖性方式显著增加miR-21-3p的表达。进一步研究表明，TNF-α可通过NF-κB信号通路上调miR-21-3p的表达。随后，引入TargetScan和miRWalk miRNA-mRNA相互作用预测在线工具，筛选出metadherin（MTDH）作为miR-21-3p的潜在靶标。我们随后发现，miR-21-3p可直接靶向MTDH mRNA的3'-非翻译区（UTR）并抑制其表达。此外，证明miR-21-3p可通过靶向MTDH mRNA调节Wnt信号通路，提示miR-21-3p/MTDH/Wnt轴对肠道屏障功能障碍的影响。我们的研究结果为肠道屏障功能障碍及相关疾病提供了一种新的潜在生物标志物和治疗靶点。
