Journal
JOURNAL OF CROHNS & COLITIS
Volume 15, Issue 9, Pages 1542-1557Publisher
OXFORD UNIV PRESS
DOI: 10.1093/ecco-jcc/jjab040
Keywords
Crohn's disease; MALAT1; intestinal mucosal homeostasis; intestinal mucosal barrier; miR-146b-5p
Categories
Funding
- National Natural Science Foundation of China [81870374, 81630018, 82070538]
- Guangzhou Science and Technology Department [202002030041]
- Guangdong Science and Technology Department [2017A030306021]
- Fundamental Research Funds for the Central Universities [19ykzd11]
Ask authors/readers for more resources
The study found that MALAT1 was significantly downregulated in CD patients and experimental colitis mice, and MALAT1 knockout mice were hypersensitive to colitis. MALAT1 restored intestinal homeostasis by regulating miR-146b-5p and the expression of AJC proteins NUMB and CLDN11.
Background and Aims: Intestinal homeostasis disorder is critical for developing Crohn's disease [CD]. Maintaining mucosal barrier integrity is essential for intestinal homeostasis, preventing intestinal injury and complications. Among the remarkably altered long non-coding RNAs [lncRNAs] in CD, we aimed to investigate whether metastasis-associated lung adenocarcinoma transcript 1 [MALAT1] modulated CD and consequent disruption of intestinal homeostasis. Methods: Microarray analyses on intestinal mucosa of CD patients and controls were performed to identify dysregulated lncRNAs. MALAT1 expression was investigated via qRT-PCR and its distribution in intestinal tissues was detected using BaseScope. Intestines from MALAT1 knockout mice with colitis were investigated using histological, molecular, and biochemical approaches. Effects of intestinal epithelial cells, transfected with MALAT1 lentiviruses and Smart Silencer, on monolayer permeability and apical junction complex [AJC] proteins were analysed. MiR-146b-5p was confirmed as a critical MALAT1 mediator in cells transfected with miR-146b-5p mimic/inhibitor and in colitis mice administered agomir-146b-5p/antagomir-146b-5p. Interaction between MALAT1 and miR-146b-5p was predicted via bioinformatics and validated using Dual-luciferase reporter assay and Ago2-RIP. Results: MALAT1 was aberrantly downregulated in the intestine mucosa of CD patients and mice with experimental colitis. MALAT1 knockout mice were hypersensitive to DSS-induced experimental colitis. MALAT1 regulated the intestinal mucosal barrier and regained intestinal homeostasis by sequestering miR-146b-5p and maintaining the expression of the AJC proteins NUMB and CLDN11. Conclusions: Downregulation of MALAT1 contributed to the pathogenesis of CD by disrupting AJC. Thus, a specific MALAT1-miR-146b-5p-NUMB/CLDN11 pathway that plays a vital role in maintaining intestinal mucosal homeostasis may serve as a novel target for CD treatment.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available