Epithelial-to-mesenchymal transition in a fistula-associated anal adenocarcinoma in a patient with long-standing Crohn’s disease

The pathogenesis of Crohn’s disease-associated fibrostenosis and fistulas imply the epithelial-to-mesenchymal transition (EMT) process. As succinate and its receptor (SUCNR1) are involved in intestinal inflammation and fibrosis, we investigated their relevance in EMT and Crohn’s disease (CD) fistulas. Succinate levels and SUCNR1-expression were analyzed in intestinal resections from non-Inflammatory Bowel Disease (non-IBD) subjects and CD patients with stenosing-B2 or penetrating-B3 complications and in a murine heterotopic-transplant model of intestinal fibrosis. EMT, as increased expression of Snail1, Snail2 and vimentin and reduction in E-cadherin, was analyzed in tissues and succinate-treated HT29 cells. The role played by SUCNR1 was studied by silencing its gene. Succinate levels and SUCNR1 expression are increased in B3-CD patients and correlate with EMT markers. SUCNR1 is detected in transitional cells lining the fistula tract and in surrounding mesenchymal cells. Grafts from wild type (WT) mice present increased succinate levels, SUCNR1 up-regulation and EMT activation, effects not observed in SUCNR1−/− tissues. SUCNR1 activation induces the expression of Wnt ligands, activates WNT signaling and induces a WNT-mediated EMT in HT29 cells. In conclusion, succinate and its receptor are up-regulated around CD-fistulas and activate Wnt signaling and EMT in intestinal epithelial cells. These results point to SUCNR1 as a novel pharmacological target for fistula prevention.

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Epithelial–mesenchymal transition in Crohn’s disease

Mucosal Immunology ◽

10.1038/mi.2017.107 ◽

2017 ◽

Vol 11 (2) ◽

pp. 294-303 ◽

Cited By ~ 12

Author(s):

H Jiang ◽

J Shen ◽

Z Ran

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Epithelial Mesenchymal Transition ◽

Mesenchymal Transition

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Proteomics Highlights Common and Distinct Pathophysiological Processes Associated with Ileal and Colonic Ulcers in Crohn’s Disease

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz130 ◽

2019 ◽

Vol 14 (2) ◽

pp. 205-215 ◽

Cited By ~ 2

Author(s):

Nicolas Pierre ◽

Catherine Salée ◽

Charlotte Massot ◽

Noëlla Blétard ◽

Gabriel Mazzucchelli ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Epithelial Mesenchymal Transition ◽

Colonic Disease ◽

Differential Proteomics ◽

Tissue Samples ◽

Mesenchymal Transition ◽

Colonic Ulcer ◽

Endoplasmic Reticulum Protein

Abstract Background and Aims Based on genetics and natural history, Crohn’s disease can be separated into two entities, an ileal and a colonic disease. Protein-based approaches are needed to elucidate whether such subphenotypes are related to distinct pathophysiological processes. Methods The proteome of ulcer edges was compared with that of paired control tissue samples [n = 32 biopsies] by differential proteomics in the ileum and the colon of Crohn’s disease patients [n = 16]. The results were analysed using a hypothesis-driven approach [based on the literature] and a hypothesis-free approach [pathway enrichment analyses] to determine common and segment-specific pathophysiological processes associated with ileal and colonic CD ulcer edges. To confirm the involvement of a key pathway highlighted by proteomics, two proteins were also studied by immunochemistry. Results In the ileum and the colon, 4428 and 5204 proteins, respectively, were identified and quantified. Ileal and colonic ulcer edges differed in having a distinct distribution of proteins associated with epithelial–mesenchymal transition, neutrophil degranulation, and ribosomes. Ileal and colonic ulcer edges were similarly characterized by an increase in the proteins implicated in the endoplasmic reticulum protein-processing pathway and a decrease in mitochondrial proteins. Immunochemistry confirmed the presence of endoplasmic reticulum stress in the mucosa of ileal and colonic ulcer edges. Conclusion This study provides protein-based evidence for partially distinct pathophysiological processes being associated with ileal and colonic ulcer edges in Crohn’s disease patients. This could constitute a first step toward the development of gut segment–specific diagnostic markers and therapeutics.

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Herbs-Partitioned Moxibustion Combined with Acupuncture Inhibits TGF-β1-Smad-Snail-Induced Intestinal Epithelial Mesenchymal Transition in Crohn’s Disease Model Rats

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2019/8320250 ◽

2019 ◽

Vol 2019 ◽

pp. 1-9

Author(s):

Yin Shi ◽

Tao Li ◽

Jing Zhou ◽

Yuwei Li ◽

Liu Chen ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Epithelial Cells ◽

Epithelial Mesenchymal Transition ◽

Intestinal Epithelial Cells ◽

Mrna Levels ◽

Intestinal Epithelial ◽

Cell Marker ◽

Mesenchymal Transition ◽

Intestinal Fibrosis

Crohn’s disease may cause excessive damage and repair in the intestinal epithelium due to its chronic relapsing intestinal inflammation. These factors may initiate the TGF-β 1-Smad pathway to activate the transcription factor of Snail, and the Snail-mediated pathway promotes the transformation of intestinal epithelial cells to mesenchymal cells, leading to intestinal fibrosis. Acupuncture and moxibustion have been demonstrated to prevent intestinal fibrosis in Crohn’s disease. However, it is not clear whether acupuncture and moxibustion can inhibit intestinal epithelial mesenchymal transformation in Crohn’s disease by affecting the TGF-β 1-Smad-Snail pathway. This study indicated that abnormal increased expressions of TGFβ1, TβR2, Smad3, and Snail were significantly downregulated by herbs-partitioned moxibustion at Tianshu (ST25) and Qihai (RN6) and acupuncture at Zusanli (ST36) and Shangjuxu (ST37). In addition, protein and mRNA levels of E-cadherin, the epithelial cell marker, were significantly increased. Protein and mRNA levels of fibronectin, the mesenchymal cell marker, were decreased in the intestinal tissue. Moreover, the number of mesenchymal cells in the intestinal mucosa can be reversely transformed to intestinal epithelial cells. Therefore, herbs-partitioned moxibustion combined with acupuncture can prevent intestinal epithelial mesenchymal transition by inhibiting abnormal expression of TGFβ1, TβR2, Smad3, and Snail in the TGF-β1-Smad-Snail pathway in Crohn’s disease.

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LINC01272 Activates Epithelial-Mesenchymal Transition Through miR-153-5p in Crohn’s Disease

10.21203/rs.3.rs-746920/v1 ◽

2021 ◽

Author(s):

Lin Fang ◽

Mengcheng Hu ◽

Fei Xia ◽

wenxia Bai

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Rna Binding ◽

Epithelial Mesenchymal Transition ◽

Luciferase Reporter ◽

Rna Seq ◽

Mesenchymal Transition ◽

Reporter Assays ◽

Tgf Β1

Abstract Background: Long non-coding RNAs (lncRNAs) have different functions in different diseases. There is seldom research on the functions of lncRNAs in Crohn’s disease (CD). By RNA-seq technology, we identify a lncRNA associated with Crohn's disease. However, the mechanism of lncRNA regulation remains unknown. This study aimed to determine the association of LINC01272 with epithelial cell-mesenchymal transition and the underlined mechanism in CD.Methods: RNA is detected by qRT-PCR. Interaction of protein and RNA was determined by RNA binding protein immunoprecipitation. Luciferase reporter assays were used to detect the targeted miRNA of LINC01272. Tissue fibrosis was observed by Masson and HE staining. The protein expression is determined by western blot and immunofluorescence. Results: LINC01272 was highly expressed in patients with CD. Knockdown of LINC01272 inhibited TGF-β1-induced epithelial-mesenchymal transition (EMT). Additionally, LINC01272 regulated TGF-β1 induced EMT by miR-153-5p axis and knockdown of LINC01272 inhibited EMT in the CD mice in vivo. Conclusion: LINC01272 activated epithelial-mesenchymal transition through miR-153-5p in CD.

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