Abstract
BackgroundEpithelial-to-mesenchymal transition (EMT) is a phenomenon that allows the conversion of adherent epithelial cells to a mesenchymal cell phenotype, which enhances migratory capacity and invasiveness. Recent studies have suggested that EMT contributes to the pathogenesis of ulcerative colitis (UC). We investigated the promoter DNA methylation status of EMT-related genes in the colonic mucosa in UC.MethodsColonic biopsies were obtained from the rectal inflammatory mucosa of 86 UC patients and the non-inflammatory proximal colonic mucosa of 10 paired patients. Bisulfite pyrosequencing was used to quantify the methylation of 5 candidate CpG island promoters (NEUROG1, CDX1, miR-1247, CDH1, and CDH13) and LINE1.ResultsUsing an unsupervised hierarchical clustering analysis, inflamed rectal mucosa was well separated from mucosa that appeared normal. The CDH1 and CDH13 promoters were significantly associated with patient age (p = 0.04, 0.03, respectively). A similar trend was found between those genes and the duration of disease (CDH1: p = 0.07, CDH13: p = 0.0002, mean of both: p<0.00001). Several positive associations were found between hypermethylation and severe clinical phenotypes (CDX1 and miR-1247 and a refractory phenotype: p = 0.04 and 0.006, respectively. miR-1247 and CDH1 hyper methylation and a more severe Mayo endoscopic subscore: miR-1247: p = 0.0008, CDH1: p = 0.03, mean of both: p = 0.003). When the severe clinical phenotype was defined as having any of five phenotypes (hospitalized more than twice, highest Mayo endoscopic subscore, steroid dependence, refractory, or a history of surgery) miR-1247 hypermethylation was associated with the same phenotype (p = 0.008).ConclusionsOur data suggest that variability in the methylation status of EMT-related genes is associated with more severe clinical phenotypes in UC.
Highlights
Ulcerative colitis (UC) affects the colon and rectum and involves the innermost lining mucosa, manifesting as continuous areas of inflammation, with no segments of normal mucosa [1]
Statistical analysis For the paired inflammatory and non-inflammatory colonic mucosa derived from ten patients, an unsupervised hierarchical clustering analysis was used to identify distinct subgroups based on the methylation status of 5 CpG island promoters
We observed that methylation of CDX1 was considerably higher compared to other genes (NEUROG1, miR-1247, CDH1, and CDH13) across all the samples, possibly due to the difference of methylation susceptibility in colonic tissue or ulcerative colitis (UC)
Summary
Ulcerative colitis (UC) affects the colon and rectum and involves the innermost lining mucosa, manifesting as continuous areas of inflammation, with no segments of normal mucosa [1]. It is characterized by chronic and relapsing colonic inflammation of unknown etiology. DNA methylation, promoter CpG island hypermethylation, contributes to carcinogenesis [3]. A high degree of CpG island hypermethylation is observed in both inflamed colonic tissues and dysplastic lesions, suggesting the potential usefulness of DNA methylation as a biomarker for predicting disease severity and cancer risk [6,7,8]. We investigated the promoter DNA methylation status of EMT-related genes in the colonic mucosa in UC
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