Aberrant methylation of DAPK in long-standing ulcerative colitis and ulcerative colitis-associated carcinoma

Kuester, Doerthe and Guenther, Thomas and Biesold, Susanne and Hartmann, Arndt and Bataille, Frauke and Ruemmele, Petra and Peters, Brigitte and Meyer, Frank and Schubert, Daniel and Bohr, Ulrich R. and Malfertheiner, Peter and Lippert, Hans and Silver, Andrew R. J. and Roessner, Albert and Schneider-Stock, Regine (2010) Aberrant methylation of DAPK in long-standing ulcerative colitis and ulcerative colitis-associated carcinoma. PATHOLOGY RESEARCH AND PRACTICE, 206 (9). pp. 616-624. ISSN 0344-0338,

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Abstract

Death-associated protein kinase (DAPK) has pro-apoptotic functions and participates in various apoptotic systems. DAPK acts as a tumor suppressor, and its inactivation by promoter hypermethylation has been frequently observed in various human cancers. As alterations of pro-apoptotic genes might cause instability in the balance of cell-turnover during chronic inflammatory processes, epigenetic silencing of DAPK might be involved in the carcinogenesis of ulcerative colitis-associated carcinoma (UCC). To evaluate the role of DAPK in the inflammation-driven carcinogenesis of ulcerative colitis (UC), we analyzed promoter hypermethylation and protein expression of DAPK using methylation-specific PCR and immunohistochemistry in 43 UCCs and paired UC-background mucosa, as well as in UC-background mucosa of 50 patients without UCC. The frequency of methylation of DAPK in UCCs was low (27.6%) compared to overall non-neoplastic UC-background mucosa (48.3%; p = 0.02) and sporadic colorectal carcinoma (57.4%, p = 0.019). The difference in the methylation frequency in UC-background mucosa in patients without UCC (54.2%), compared to those with UCC (40.0%), was not significant (p = 0.141). Promoter methylation correlated significantly with decreased DAPK protein expression (p < 0.001) and severity of inflammatory activity (p = 0.024). In unmethylated UC-background mucosa, DAPK protein expression increased with activity of UC-associated inflammation, suggesting a protective role of the pro-apoptotic DAPK during the chronic inflammatory process of UC. Thus, inactivation of DAPK by promoter hypermethylation might be crucial for accumulation of DNA damage in inflamed mucosa of UC, and might therefore contribute to the initiation of the neoplastic process and development of UC-associated carcinoma. (C) 2010 Elsevier GmbH. All rights reserved.

Item Type: Article
Uncontrolled Keywords: INFLAMMATORY-BOWEL-DISEASE; CPG ISLAND METHYLATION; COLORECTAL-CANCER; PROTEIN-KINASE; MICROSATELLITE INSTABILITY; PROMOTER METHYLATION; OXIDATIVE STRESS; ESOPHAGEAL ADENOCARCINOMA; BARRETTS-ESOPHAGUS; GASTRIC-CARCINOMA; Ulcerative colitis; Colorectal carcinoma; DAPK; Inflammation; Epigenetic
Subjects: 600 Technology > 610 Medical sciences Medicine
Divisions: Medicine > Lehrstuhl für Pathologie
Depositing User: Dr. Gernot Deinzer
Date Deposited: 24 Aug 2020 07:47
Last Modified: 24 Aug 2020 07:47
URI: https://pred.uni-regensburg.de/id/eprint/25583

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