Aberrant methylation of DAPK in long-standing ulcerative colitis and ulcerative colitis-associated carcinoma
Aberrant methylation of DAPK in long-standing ulcerative colitis and ulcerative colitis-associated carcinoma
复制标题
DOI：
10.1016/j.prp.2010.05.004
复制
发表时间：
2010-01-01
影响因子：
2.8
通讯作者：
Schneider-Stock, Regine
中科院分区：
文献类型：
--
作者：
Kuester, Doerthe;Guenther, Thomas;Schneider-Stock, Regine
死亡相关蛋白激酶(DAPK)具有促凋亡功能，参与多种细胞凋亡系统。DAPK是一种肿瘤抑制因子，其启动子高甲基化使其失活的现象在多种人类癌症中经常被观察到。由于促凋亡基因的改变可能导致慢性炎症过程中细胞周转平衡的不稳定，DAPK的表观遗传沉默可能参与了溃疡性结肠炎相关癌(UCC)的发生。为探讨DAPK在溃疡性结肠炎(UC)炎症致癌过程中的作用，我们用甲基化特异性聚合酶链式反应和免疫组织化学方法检测了43例UCC和配对UC背景粘膜以及50例非UCC患者UC背景粘膜中DAPK基因启动子的甲基化和蛋白表达。与非肿瘤性UC背景粘膜(48.3%；p=0.02)和散发性结直肠癌(57.4%，p=0.019)相比，UCC中DAPK甲基化频率较低(27.6%)。非UCC患者UC背景黏膜甲基化频率(54.2%)与UCC患者(40.0%)相比差异无统计学意义(p=0.141)。启动子甲基化与DAPK蛋白表达降低(p<；0.001)和炎症活动的严重程度(p=0.024)显著相关。在未甲基化的UC背景粘膜中，DAPK蛋白的表达随着UC相关炎症活动的增加而增加，提示促凋亡的DAPK在UC慢性炎症过程中具有保护作用。因此，启动子高甲基化导致的DAPK失活可能是UC炎症黏膜DNA损伤积累的关键，从而可能有助于UC相关肿瘤的发生和发展。(C)2010年爱思唯尔股份有限公司。版权所有。
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.