TNF-α-Induced miR-21-3p Promotes Intestinal Barrier Dysfunction by Inhibiting MTDH Expression.

Zhifeng Jiang,Feiyu Yang,Jie Shen,Lin Zhang,Chaoyuan Jin,Feng Zhang,Jingbo Qie

doi:10.3389/fphar.2021.722283

Zhifeng Jiang, Feiyu Yang + Show 5 more

Open Access

https://doi.org/10.3389/fphar.2021.722283

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Abstract

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.

Highlights

As one of the most important barriers of the body, normal intestinal epithelial tissue forms a selectively permeable barrier that regulates the absorption of nutrients and resistance of toxins, antigens, and foreign microorganisms (Turner, 2009; Du et al, 2015)
MiR-21-3p expression was identified to be regulated by the tumor necrosis factor (TNF)-α/NF-κB signaling pathway, resulting in the downregulation of metadherin (MTDH) expression, which was a key mediator of the Wnt signaling pathway. These findings suggest that the miR-21-3p/MTDH/Wnt axis participates in intestinal barrier dysfunction and provide a better understanding of the pathological process of intestinal barrier dysfunction
It was illustrated that the miR-21-3p expression level remained at a relatively low level when the TNF-α concentration was less than 50 ng/ml

Summary

Introduction

As one of the most important barriers of the body, normal intestinal epithelial tissue forms a selectively permeable barrier that regulates the absorption of nutrients and resistance of toxins, antigens, and foreign microorganisms (Turner, 2009; Du et al, 2015). The maintenance of intestinal barrier function partly relies on the tight junctions (TJs) between adjacent epithelial cells (Farquhar and Palade, 1963; Li et al, 2021). The decreased number of TJ chains or broken TJ chains obviously occur along with the alteration of the expression levels of occludin and claudins in intestinal tissues from patients with IBD (Hering, Fromm, and Schulzke, 2012). These changes lead to the damage of the intestinal barrier system, resulting in increased permeability of the intestinal wall and the risk of pathogen invasion

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