DNA hypermethylation on multiple CpG islands associated with increased DNA methyltransferase DNMT1 protein expression during multistage urothelial carcinogenesis
DNA hypermethylation on multiple CpG islands associated with increased DNA methyltransferase DNMT1 protein expression during multistage urothelial carcinogenesis
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DOI：
10.1097/01.ju.0000154632.11824.4d
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发表时间：
2005-05-01
影响因子：
6.6
通讯作者：
Hirohashi, S
中科院分区：
文献类型：
--
作者：
Nakagawa, T;Kanai, Y;Hirohashi, S
目的：我们阐明了在尿路上皮癌发生过程中多个CpG岛上异常DNA甲基化的意义及其与DNA甲基转移酶DNMT 1蛋白表达的相关性。我们采用甲基化特异性聚合酶链反应结合亚硫酸氢盐限制性内切酶分析，检测了12例正常尿路上皮组织中多个CpG岛的DNA甲基化状态，无明显组织学改变的非癌性尿路上皮23例，膀胱癌70例。p16基因CpG岛的DNA甲基化（0%、17%和21%）和死亡相关蛋白激酶（13%，33%和29%）基因，并且在肿瘤-2中甲基化在正常尿路上皮、NBCs和TCC中分别检测到12个（0%、6%和30%）、25个（25%、27%和35%）和31个（45%、56%和79%）克隆。NBCs中3个或更多个CpG岛上同时发生DNA高甲基化的发生率（38%）显著高于正常尿路上皮（0%，p = 0.0455），在TCC中甚至更高（59%，p = 0.0043）。非乳头状癌（结节浸润性癌及其前体，即扁平原位癌，71%）中CpG岛甲基化表型的发生率显著高于乳头状癌（40%，p = 0.0143）。在所有检查的标本中，3个或更多CpG岛上的同时DNA超甲基化与化学评价的DNMT 1蛋白过度表达显著相关（p = 0.0167）。多个CpG岛上的DNA高甲基化与DNMT 1蛋白的过度表达相关，可能参与多阶段尿路上皮癌的发生，甚至在癌前阶段，特别是在尿路上皮结节性浸润癌的发展中。膀胱
Purpose: We elucidated the significance of aberrant DNA methylation on multiple CpG islands and its correlation with DNA methyltransferase DNMT1 protein expression during urothelial carcinogenesis.Materials and Methods: We examined the DNA methylation status on multiple CpG islands by methylation specific polymerase chain reaction and combined bisulfite restriction enzyme analysis in 12 specimens of normal urothelium, 23 of noncancerous urothelium showing no remarkable histological changes obtained from patients with bladder cancer (NBC) and 70 of transitional cell carcinoma (TCC).Results: DNA methylation on CpG islands of the p16 (0%, 17% and 21%) and death-associated protein kinase (13%, 33% and 29%) genes, and methylated in tumor-2 (56%, 60% and 76%), 12 (0%, 6% and 30%), 25 (25%, 27% and 35%) and 31 (45%, 56% and 79%) clones was detected in normal urothelium, NBCs and TCCs, respectively. The incidence of concurrent DNA hypermethylation on 3 or more CpG islands in NBCs (38%) was significantly higher than that in normal urothelium (0%, p = 0.0455) and even higher in TCCs (59%, p = 0.0043). The incidence of the CpG island methylator phenotype in nonpapillary carcinomas (nodular invasive carcinomas and their precursors, ie flat carcinoma in situ, 71%) was significantly higher than in papillary carcinomas (40%, p = 0.0143). In all specimens examined concurrent DNA hypermethylation on 3 or more CpG islands significantly correlated with immunohistochemically evaluated DNMT1 protein over expression (p = 0.0167).Conclusions: DNA hypermethylation on multiple CpG islands in association with DNMT1 protein over expression may participate in multistage urothelial carcinogenesis even at the precancerous stage and particularly in the development of nodular invasive carcinomas of the bladder.