Aberrant methylation of DAPK in long-standing ulcerative colitis and ulcerative colitis-associated carcinoma.
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.
Kuester
Doerthe
D
Department of Pathology, Hepatology and Infectious Diseases, Otto-von-Guericke-University, 39120 Magdeburg, Germany. doerthe.kuester@med.ovgu.de
Guenther
Thomas
T
Biesold
Susanne
S
Hartmann
Arndt
A
Bataille
Frauke
F
Ruemmele
Petra
P
Peters
Brigitte
B
Meyer
Frank
F
Schubert
Daniel
D
Bohr
Ulrich R
UR
Malfertheiner
Peter
P
Lippert
Hans
H
Silver
Andrew R J
AR
Roessner
Albert
A
Schneider-Stock
Regine
R
D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D003093:Colitis, Ulcerative / Q000150:complications / Q000235:genetics* / Q000473:pathology; D003110:Colonic Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation; D064550:Death-Associated Protein Kinases; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000235:genetics; D046888:Tissue Array Analysis; D055815:Young Adult
D051017:Apoptosis Regulatory Proteins; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases