Hypermethylation and loss of expression of glutathione peroxidase-3 in Barrett's tumorigenesis
Hypermethylation and loss of expression of glutathione peroxidase-3 in Barrett's tumorigenesis
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DOI：
10.1593/neo.05328
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发表时间：
2005-09-01
期刊：
影响因子：
4.8
通讯作者：
El-Rifai, W
中科院分区：
文献类型：
--
作者：
Lee, OJ;Schneider-Stock, R;El-Rifai, W
慢性胃食管反流病是巴雷特食管 (BE) 的已知危险因素，会引起氧化性粘膜损伤。谷胱甘肽过氧化物酶-3 (GPx3) 是一种具有有效细胞外抗氧化活性的分泌蛋白。在此，我们研究了 GPx3 的 mRNA 和蛋白表达，并探讨了启动子高甲基化作为 Barrett 癌发生过程中 GPx3 基因失活的表观遗传机制。对 42 例巴雷特腺癌 (BA) 进行的定量实时逆转录聚合酶链反应显示，91% 的肿瘤样本中 GPx3 mRNA 水平持续降低。在 62% 的 Barrett 化生样品、82% 的不典型增生样品和 88% 的 BA 样品中检测到 GPx3 启动子高甲基化。 GPx3 的两个等位基因的高甲基化在 BA 中最常见 (P = .001)。对匹配组织切片（正常、BE、Barrett 不典型增生和 BA）中 GPx3 进行免疫组织化学染色显示，Barrett 不典型增生和腺癌样本中 GPx3 染色较弱甚至不存在，其中启动子高度甲基化。免疫组织化学丧失的程度与高甲基化模式相关（单等位基因与双等位基因）。在 BA 及其相关病变中观察到的启动子高甲基化频率和 GPx3 表达逐渐丧失，以及其作为有效抗氧化剂的已知功能，表明表观遗传失活和谷胱甘肽途径的调节可能在 BE 的发生和进展中至关重要。
Chronic gastroesophageal reflux disease is a known risk factor for Barrett's esophagus (BE), that induces oxidative mucosal damage. Glutathione peroxidase-3 (GPx3) is a secretory protein with potent extracellular antioxidant activity. Herein, we have investigated the mRNA and protein expression of GPx3, and explored promoter hypermethylation as an epigenetic mechanism for GPx3 gene inactivation during Barrett's carcinogenesis. Quantitative real-time reverse transcription polymerase chain reaction on 42 Barrett's adenocarcinomas (BAs) revealed consistently reduced levels of GPx3 mRNA in 91% of tumor samples. GPx3 promoter hypermethylation was detected in 62% of Barrett's metaplasia, 82% of dysplasia, and 88% of BA samples. Hypermethylation of both alleles of GPx3 was most frequently seen in BA (P = .001). Immunohistochemical staining of GPx3 in matching tissue sections (normal, BE, Barrett's dysplasia, and BA) revealed a weak-to-absent GPx3 staining in Barrett's dysplasia and adenocarcinoma samples where the promoter was hypermethylated. The degree of loss of immunohistochemistry correlated with the hypermethylation pattern (monoallelic versus biallelic). The observed high frequency of promoter hypermethylation and progressive loss of GPx3 expression in BA and its associated lesions, together with its known function as a potent antioxidant, suggest that epigenetic inactivation and regulation of glutathione pathway may be critical in the development and progression of BE.