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首页> 外文期刊>Oncogene >Xeroderma pigmentosum group C gene expression is predominantly regulated by promoter hypermethylation and contributes to p53 mutation in lung cancers
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Xeroderma pigmentosum group C gene expression is predominantly regulated by promoter hypermethylation and contributes to p53 mutation in lung cancers

机译：色素干色素C组基因表达主要受启动子甲基化调控，并导致肺癌中p53突变

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Reduced DNA repair capability is associated with developing lung cancer, especially in nonsmokers. XPC participates in the initial recognition of DNA damage during the DNA nucleotide excision repair process. We hypothesize that inactivation of XPC by promoter hypermethylation may play an important role in the reduction of DNA repair capability to cause p53 mutation during lung carcinogenesis. In this report we demonstrate that hypermethylation of 17 CpG islands between -175 and -1 of the XPC promoter correlates very well with XPC expression levels in eight lung cancer cell lines. When cells with hypermethylated XPC promoters were treated with the demethylating agent 5-aza-2'-deoxycytidine, XPC expression was de-repressed. Interestingly, XPC hypermethylation was found in 4 of 5 (80%) lung cancer cell lines harbored p53 mutation, but not observed in two lung cancer cells which had a wild-type p53 gene. Among the analysis of the hypermethylation status of 158 lung tumors, XPC hypermethylation is more common in nonsmokers (39 of 94, 41%) than in smokers (14 of 64, 22%; P=0.010). Additionally, XPC hypermethylation is more often with G T or G C mutations in the p53 gene. To verify whether XPC inactivation is involved in the occurrence of p53 mutation, XPC gene of A549 cells was knockdown by a small interference RNA and then XPC-inactivated cells were treated with benzo[a]pynrene for different passages. Surprisingly, G T mutation in p53 gene at codon 215 was indeed detected in XPC-inactivated A549 cells of passages 15 and confirmed by loss of transcription activity of mdm2. These results show that hypermethylation of the XPC promoter may play a crucial role in XPC inactivation, which may partly contribute to the occurrence of p53 mutations during lung tumorigenesis, especially nonsmokers.
机译：DNA修复能力降低与发展中的肺癌有关，尤其是在不吸烟者中。 XPC在DNA核苷酸切除修复过程中参与了DNA损伤的初步识别。我们假设启动子的过度甲基化使XPC失活可能在减少肺癌发生过程中引起p53突变的DNA修复能力的降低中起重要作用。在此报告中，我们证明XPC启动子的-175和-1之间的17个CpG岛的超甲基化与XPC在八个肺癌细胞系中的表达水平非常相关。当用去甲基化剂5-氮杂-2'-脱氧胞苷处理具有高甲基化XPC启动子的细胞时，XPC表达被抑制。有趣的是，在具有p53突变的5个肺癌细胞系中，有4个（80％）发现XPC高甲基化，但在两个具有野生型p53基因的肺癌细胞中未观察到XPC高甲基化。在对158例肺肿瘤的高甲基化状态进行的分析中，与不吸烟者相比，XPCC高甲基化在非吸烟者中更为普遍（94人中占39％，占41％），在吸烟者中占14％，中占22％，P = 0.010。另外，XPC的高甲基化更常见于p53基因中的G T或G C突变。为了验证XPC失活是否与p53突变有关，用小的干扰RNA敲低了A549细胞的XPC基因，然后用苯并[a] re对XPC失活的细胞进行了不同的传代。出人意料的是，确实在第15代XPC灭活的A549细胞中检测到第215位密码子p53基因的G T突变，并通过mdm2转录活性的丧失得以证实。这些结果表明，XPC启动子的高度甲基化可能在XPC失活中起关键作用，这可能部分促成肺肿瘤发生期间p53突变的发生，特别是非吸烟者。

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