Urothelial carcinomas arising in arsenic-contaminated areas are associated with hypermethylation of the gene promoter of the death-associated protein kinase
Urothelial carcinomas arising in arsenic-contaminated areas are associated with hypermethylation of the gene promoter of the death-associated protein kinase
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DOI：
10.1111/j.1365-2559.2007.02871.x
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发表时间：
2007-12-01
期刊：
影响因子：
6.4
通讯作者：
Chai, C-Y
中科院分区：
文献类型：
--
作者：
Chen, W-T;Hung, W-C;Chai, C-Y
目的：高砷污染地区尿路上皮癌的发生机制尚不清楚。目的：探讨死亡相关蛋白激酶(DAPK)基因高甲基化与慢性砷暴露的关系。方法与结果：采用甲基化特异性聚合酶链式反应检测17例砷污染地区尿路上皮癌和21例非砷污染地区尿路上皮癌中DAPK基因启动子甲基化频率。发生在砷污染地区的尿路上皮癌的DAPK高甲基化状态显著高于来自非污染地区的患者(P=0.018)。在被砷污染的生活环境中的患者中，DAPK高甲基化与患者的年龄、肿瘤侵袭性、组织学分级和复发有统计学意义的相关性。在来自非污染地区的尿路上皮癌患者中没有发现这种情况。免疫组织化学检测发现DAPK启动子甲基化与低强度DAPK表达密切相关(P=0.037)。结论：砷暴露可诱导尿路上皮癌DAPK启动子甲基化，使其功能失活。这可能被证明是导致砷污染环境中患者肿瘤恶性表型的关键分子事件。
Aims: The mechanisms of urothelial carcinogenesis in areas highly contaminated with arsenic remain unclear. The aim was to determine whether hypermethylation of death-associated protein kinase (DAPK) gene is associated with chronic arsenic exposure.Methods and results: The frequency of aberrant promoter methylation of DAPK in 17 urothelial carcinomas from an arsenic-contaminated area and 21 urothelial carcinomas from a non-arsenic-contaminated area was determined by methylation-specific polymerase chain reaction. DAPK hypermethylation status was significantly higher in urothelial cancers arising in arsenic-contaminated areas when compared with tumours from patients from non-contaminated areas (P = 0.018). In the subset of patients from living environments which were contaminated with arsenic, there was a statistically significant association between DAPK hypermethylation and patient's age, tumour invasiveness, histological grade and recurrence. This was not seen for urothelial carcinoma from patients from non-contaminated areas. A close correlation was also found between DAPK promoter methylation and low-intensity DAPK expression, as detected by immunohistochemistry (P = 0.037).Conclusions: Exposure to arsenic may induce DAPK promoter hypermethylation and inactivate the function of DAPK in urothelial carcinoma. This could prove to be a key molecular event contributing to the malignant phenotype of tumour arising in patients from arsenic-contaminated environments.