Silencing of DUOX NADPH oxidases by promoter hypermethylation in lung cancer
Silencing of DUOX NADPH oxidases by promoter hypermethylation in lung cancer
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DOI：
10.1158/0008-5472.can-07-5782
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发表时间：
2008-02-15
期刊：
影响因子：
11.2
通讯作者：
Knaus, Ulla G.
中科院分区：
文献类型：
--
作者：
Luxen, Sylvia;Belinsky, Steven A.;Knaus, Ulla G.
肺癌的发生与异常的启动子甲基化相关，从而导致许多肿瘤抑制基因或对细胞维持至关重要的基因的转录沉默。在这里，我们报告说，NADPH氧化酶DUOX 1和DUOX 2，这是在气道中的活性氧产生的主要来源之一，经常在人类肺癌沉默。肺癌细胞系的筛选揭示了DUOX 1和DUOX 2表达的丧失，其在用5-氮杂2 '-脱氧胞苷处理后恢复。与DUOX在转录和功能上相关的两个基因DUOXA 1和DUOXA 2在肺癌细胞和肺癌标本中也显示出协同下调。亚硫酸氢盐测序和甲基化特异性PCR显示，两个DUOX基因中富含CpG的启动子区域是高甲基化的。在50%的原发性腺癌中检测到至少一个DUOX基因的表观遗传修饰。来自癌组织和匹配的健康组织的气道切片的免疫组织化学分析证实了Duox在呼吸道纤毛上皮细胞中的下调。将功能性Duox 1重新引入肺癌细胞系增加了细胞迁移和伤口修复，而不影响细胞生长。我们的研究结果表明，15号染色体上的一个区域，包括DUOX 1，DUOX 2，和他们的成熟因子是肺癌表观遗传沉默的常见目标。
The development of lung cancer is associated with aberrant promoter methylation and thus transcriptional silencing of many tumor suppressor genes or genes critical for cellular maintenance. Here we report that the NADPH oxidases DUOX1 and DUOX2, which are one of the main sources for reactive oxygen species production in the airway, are frequently silenced in human lung cancer. Screening of lung cancer cell lines revealed loss of DUOX1 and DUOX2 expression, which was restored after treatment with 5-aza 2'-deoxycytidine. Two genes, DUOXA1 and DUOXA2, which are transcriptionally and functionally linked to DUOX, also showed coordinated down-regulation in lung cancer cells and lung cancer specimen. Bisulfite sequencing and methylation-specific PCR revealed that CpG-rich promoter regions in both DUOX genes are hypermethylated. Epigenctic modification of at least one DUOX gene was detected in 50% of primary adenocarcinomas. Immunohistochemical analysis of airway sections derived from cancerous and matched healthy tissues confirmed down-regulation of Duox in the ciliated epithelial cells lining the respiratory tract. Reintroduction of functional Duox1 into lung cancer cell lines increased cell migration and wound repair without affecting cell growth. Our results suggest that an area on chromosome 15 that includes DUOX1, DUOX2, and their maturation factors is a frequent target for epigenetic silencing in lung cancer.