Epigenetic alteration of Wnt pathway antagonists in progressive glandular neoplasia of the lung
Epigenetic alteration of Wnt pathway antagonists in progressive glandular neoplasia of the lung
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DOI：
10.1093/carcin/bgn017
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发表时间：
2008-05-01
期刊：
影响因子：
4.7
通讯作者：
Herman, James G.
中科院分区：
文献类型：
--
作者：
Licchesi, Julien D. F.;Westra, William H.;Herman, James G.
背景资料：非典型腺瘤样增生（AAH）是肺腺癌发生的前体病变，因此是研究与肺肿瘤发生相关的早期遗传和表观遗传改变（如Wnt通路改变）的理想靶点。研究方法：我们通过测定活性β-连环蛋白的水平来评估肺癌细胞系中Wnt信号传导活性的水平，并使用逆转录聚合酶链反应测定Wnt拮抗剂APC、DKK 1、DKK 3、LKB 1、SFRP 1、2、4、5、WIF 1和RUNX 3的表达水平。使用多重巢式甲基化特异性聚合酶链反应，我们分析了这些基因的启动子区域甲基化在切除的肺组织中的组织病理学序列的腺肿瘤（正常肺实质，低级别和高级别AAH，腺癌）。结果如下：大多数非小细胞肺癌细胞系（16个中的11个，69%）具有与启动子高甲基化相关的活性Wnt信号传导和Wnt拮抗剂沉默的证据。Wnt拮抗剂启动子区甲基化在原发性肺腺癌中是常见的，并且随着肿瘤发生的每个阶段，Wnt拮抗剂基因甲基化的频率和甲基化的基因数量显著增加（对Rend P
Background: Atypical adenomatous hyperplasia (AAH) is now recognized as a precursor lesion from which lung adenocarcinomas arise and thus represents an ideal target for studying the early genetic and epigenetic alterations associated with lung tumorigenesis such as alterations of the Wnt pathway. Methods: We assessed the level of Wnt signaling activity in lung cancer cell lines by determining the level of active beta-catenin and determined the level of expression of Wnt antagonists APC, DKK1, DKK3, LKB1, SFRP1, 2, 4, 5, WIF1 and RUNX3 using reverse transcription polymerase chain reaction. Using multiplex nested methylation-specific polymerase chain reaction, we analyzed promoter region methylation of these genes in resected lung tissue in the histopathologic sequence of glandular neoplasia ( normal lung parenchyma, low-grade and high-grade AAH, adenocarcinoma). Results: The majority of non-small cell lung cancer cell lines ( 11 of 16, 69%) have evidence of active Wnt signaling and silencing of Wnt antagonists correlated with promoter hypermethylation. Promoter region methylation of Wnt antagonists was common in primary lung adenocarcinoma and there was a significant increase in the frequency of methylation for Wnt antagonist genes and the number of genes methylated with each stage of tumorigenesis ( test for rend P