Increased cytosine DNA-methyltransferase activity is target-cell-specific and an early event in lung cancer
Increased cytosine DNA-methyltransferase activity is target-cell-specific and an early event in lung cancer
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DOI：
10.1073/pnas.93.9.4045
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发表时间：
1996-04-30
影响因子：
11.1
通讯作者：
Issa, JPJ
中科院分区：
文献类型：
--
作者：
Belinsky, SA;Nikula, KJ;Issa, JPJ
DNA-甲基转移酶（DNA-MTase）活性增加与肿瘤发展之间的关联表明，这种酶在癌症的发生和发展中起着重要作用。如果受起始致癌物影响的靶细胞表现出酶活性的变化，则DNA-MTase在肿瘤形成过程中的真正功能作用将得到进一步证实。这一假设是通过检查DNA-MTase活性肺泡II型（目标）和克拉拉（非目标）细胞A/J和C3 H小鼠表现出高和低的易感性，分别为肺肿瘤形成。增加的DNA-MTase活性仅在易感A/J小鼠的靶肺泡型IT细胞中发现，并引起这些细胞中总体DNA甲基化的显着增加。在致癌物暴露后7天检测到DNA-MTase和DNA甲基化变化，因此是肿瘤演变的早期事件。通过RNA原位杂交在致癌剂处理的A/J小鼠的肥大肺泡II型细胞中也检测到基因表达增加，表明表达水平升高可能是癌前病变的生物标志物。酶活性在肺癌进展过程中逐渐增加，与增生、腺瘤和癌中DNA-MTase基因表达增加一致。因此，这些结果表明，早期DNA-MTase活性的增加与肿瘤的发展密切相关，并构成了癌变的关键步骤。通过增加DNA-MTase表达来检测癌前肺病，以及用特定抑制剂阻断这种变化的有害影响的可能性，将为肺癌提供新的干预策略。
The association between increased DNA-methyltransferase (DNA-MTase) activity and tumor development suggests a fundamental role for this enzyme in the initiation and progression of cancer. A true functional role for DNA-MTase in the neoplastic process would be further substantiated if the target cells affected by the initiating carcinogen exhibit changes in enzyme activity. This hypothesis was addressed by examining DNA-MTase activity in alveolar type II (target) and Clara (nontarget) cells from A/J and C3H mice that exhibit high and low susceptibility, respectively, for lung tumor formation. Increased DNA-MTase activity was found only in the target alveolar type IT cells of the susceptible A/J mouse and caused a marked increase in overall DNA methylation in these cells. Both DNA-MTase and DNA methylation changes were detected 7 days after carcinogen exposure and, thus, were early events in neoplastic evolution. Increased gene expression was also detected by RNA in situ hybridization in hypertrophic alveolar type II cells of carcinogen-treated A/J mice, indicating that elevated levels of expression may be a biomarker for premalignancy. Enzyme activity increased incrementally during lung cancer progression and coincided with increased expression of the DNA-MTase gene in hyperplasias, adenomas, and carcinomas. Thus, these results indicate that early increases in DNA-MTase activity are strongly associated with neoplastic development and constitute a key step in carcinogenesis. The detection of premalignant lung disease through increased DNA-MTase expression and the possibility of blocking the deleterious effects of this change with specific inhibitors will offer new intervention strategies for lung cancer.