Arsenic is a known human urinary bladder carcinogen. While arsenic is known to cause aberrant DNA methylation, the mechanism of arsenic-triggered bladder carcinogenesis is not fully understood. The goal of this study was to identify aberrant DNA methylation in rat bladder urothelial carcinoma (UC) induced by dimethylarsinic acid (DMAV), a major organic metabolite of arsenic. We performed genome-wide DNA methylation and microarray gene expression analyses of DMAV-induced rat UCs and the urothelium of rats treated for 4 weeks with DMAV. We identified 40 genes that were both hypermethylated and downregulated in DMAV-induced rat UCs. Notably, four genes (CPXM1, OPCML, TBX20, and KCND3) also showed reduced expression in the bladder urothelium after 4 weeks of exposure to DMAV. We also found that CPXM1 is aberrantly methylated and downregulated in human bladder cancers and human bladder cancer cells. Genes with aberrant DNA methylation and downregulated expression in DMAV-exposed bladder urothelium and in DMAV-induced UCs in rats, suggest that these alterations occurred in the early stages of arsenic-induced bladder carcinogenesis. Further study to evaluate the functions of these genes will advance our understanding of the role of aberrant DNA methylation in arsenic bladder carcinogenesis, and will also facilitate the identification of new therapeutic targets for arsenic-related bladder cancers.
砷是已知的人类膀胱致癌物。虽然砷可导致DNA异常甲基化，但其诱发膀胱癌变的具体机制尚未完全阐明。本研究旨在鉴定由砷的主要有机代谢产物二甲基胂酸（DMAV）诱导的大鼠膀胱尿路上皮癌（UC）中的异常DNA甲基化模式。通过对DMAV诱导的大鼠UC及经DMAV处理4周的大鼠尿路上皮组织进行全基因组DNA甲基化分析与微阵列基因表达分析，我们鉴定出40个在DMAV诱导的大鼠UC中同时呈现高甲基化与表达下调的基因。值得注意的是，其中四个基因（CPXM1、OPCML、TBX20和KCND3）在暴露于DMAV四周后的膀胱尿路上皮中也呈现表达降低现象。此外，我们发现CPXM1基因在人类膀胱癌组织及膀胱癌细胞系中同样存在异常甲基化与表达下调。这些在DMAV暴露的膀胱尿路上皮及DMAV诱导的大鼠UC中均出现DNA异常甲基化与表达下调的基因，提示这些改变可能发生于砷诱导膀胱癌变的早期阶段。对这些基因功能的深入研究将深化我们对异常DNA甲基化在砷致膀胱癌变中作用机制的理解，并为开发砷相关膀胱癌的新治疗靶点提供重要线索。
DNA Methylation Aberrations in Dimethylarsinic Acid-Induced Bladder Carcinogenesis
肿瘤(癌症)患者之家