Abstract
Background and aims: Recent evidences reveal the occurrence of a close relationship among epithelial to mesenchymal transition (EMT), chronic inflammation and fibrosis. ZNF281 is an EMT-inducing transcription factor (EMT-TF) involved in the regulation of pluripotency, stemness, and cancer. The aim of this study was to investigate in vitro, in vivo, and ex vivo a possible role of ZNF281 in the onset and progression of intestinal inflammation. A conceivable contribution of the protein to the development of intestinal fibrosis was also explored.Methods: Human colorectal adenocarcinoma cell line, HT29, and C57BL/6 mice were used for in vitro and in vivo studies. Mucosal biopsy specimens were taken during endoscopy from 29 pediatric patients with Crohn's disease (CD), 24 with ulcerative colitis (UC) and 16 controls. ZNF281 was knocked down by transfecting HT29 cells with 20 nM small interference RNA (siRNA) targeting ZNF281 (siZNF281).Results: We show for the first time that ZNF281 is induced upon treatment with inflammatory agents in HT29 cells, in cultured uninflamed colonic samples from CD patients and in DSS-treated mice. ZNF281 expression correlates with the disease severity degree of CD and UC patients. Silencing of ZNF281 strongly reduces both inflammatory (IL-8, IL-1beta, IL-17, IL-23) and EMT/fibrotic (SNAIL, Slug, TIMP-1, vimentin, fibronectin, and α-SMA) gene expression; besides, it abolishes the increase of extracellular-collagen level as well as the morphological modifications induced by inflammation.Conclusions: The identification of transcription factor ZNF281 as a novel player of intestinal inflammation and fibrosis allows a deeper comprehension of the pathogenetic mechanisms underlying inflammatory bowel disease (IBD) and provide a new target for their cure.
Highlights
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal (GI) tract including two main phenotypes: Crohn’s disease (CD) and ulcerative colitis (UC)
We showed that ZNF281 is induced by inflammatory agent exposure in intestinal cells, in murine colonic tissues and in cultured mucosal samples taken from uninflamed colonic areas of CD patients
We demonstrated that ZNF281 and SNAIL are significantly increased, while Ecadherin decreased, in the inflamed colon of CD and UC patients, and ZNF281 expression levels correlate with the disease severity
Summary
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal (GI) tract including two main phenotypes: Crohn’s disease (CD) and ulcerative colitis (UC). Afterward, activated fibroblasts are recruited to the sites of inflammation to induce wound healing and, fibrosis results due to excessive deposition of extracellular matrix (ECM) [2, 3]. Recent studies propose that epithelial to mesenchymal transition (EMT), typically defined by the acquisition of a spindle cell morphology in combination with loss of E-cadherin, is involved in intestinal fibrosis following chronic inflammation [4,5,6,7]. Recent evidences reveal the occurrence of a close relationship among epithelial to mesenchymal transition (EMT), chronic inflammation and fibrosis. The aim of this study was to investigate in vitro, in vivo, and ex vivo a possible role of ZNF281 in the onset and progression of intestinal inflammation. A conceivable contribution of the protein to the development of intestinal fibrosis was explored
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