Life-span inhalation exposure to mainstream cigarette smoke induces lung cancer in B6C3F1 mice through genetic and epigenetic pathways
Life-span inhalation exposure to mainstream cigarette smoke induces lung cancer in B6C3F1 mice through genetic and epigenetic pathways
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DOI：
10.1093/carcin/bgi150
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发表时间：
2005-11-01
期刊：
影响因子：
4.7
通讯作者：
Belinsky, SA
中科院分区：
文献类型：
--
作者：
Hutt, JA;Vuillemenot, BR;Belinsky, SA
尽管多年来，香烟烟雾在流行病学上与人类肺癌有关，但一直缺乏香烟烟雾诱发肺癌的动物模型。本研究表明，雌性B6C3F1小鼠一生暴露于主流香烟烟雾250 mg总颗粒物/立方米，每周5天，每天6小时，可引起肺泡局灶性增生症、肺腺瘤、乳头状瘤和腺癌的发生率显著增加。香烟烟雾暴露的小鼠(n=330)的增生性病变的发生率是假暴露小鼠的10倍，原发肺癌(腺瘤和乳头状瘤)、腺癌(腺癌)和转移性肺腺癌(n=326)的发生率分别是假暴露小鼠的4.6倍、7.25倍和5倍。在假暴露小鼠(47%)和香烟暴露小鼠(60%)的肿瘤中，发现K-ras基因第12密码子的激活点突变的比率相似。在两组中，颠换和转换突变的百分比相似。在假吸烟和香烟烟雾暴露的小鼠肿瘤中都检测到死亡相关蛋白(DAP)-激酶和维甲酸受体(RAR)-β基因启动子的高甲基化，在香烟烟雾暴露的小鼠肿瘤中RAR-β甲基化的频率有增加的趋势。这些结果强调了K-ras的激活和DAP-激酶和RAR-β的沉默在肺癌发生发展中的重要性，并证实了该小鼠模型在研究肺癌发生中的相关性。
Although cigarette smoke has been epidemiologically associated with lung cancer in humans for many years, animal models of cigarette smoke-induced lung cancer have been lacking. This study demonstrated that life time whole body exposures of female B6C3F1 mice to mainstream cigarette smoke at 250 mg total particulate matter/m(3) for 6 h per day, 5 days a week induces marked increases in the incidence of focal alveolar hyperplasias, pulmonary adenomas, papillomas and adenocarcinomas. Cigarette smoke-exposed mice (n = 330) had a 10-fold increase in the incidence of hyperplastic lesions, and a 4.6-fold (adenomas and papillomas), 7.25-fold (adenocarcinomas) and 5-fold (metastatic pulmonary adenocarcinomas) increase in primary lung neoplasms compared with sham-exposed mice (n = 326). Activating point mutations in codon 12 of the K-ras gene were identified at a similar rate in tumors from sham-exposed mice (47%) and cigarette smoke-exposed mice (60%). The percentages of transversion and transition mutations were similar in both the groups. Hypermethylation of the death associated protein (DAP)-kinase and retinoic acid receptor (RAR)-beta gene promoters was detected in tumors from both sham- and cigarette smoke-exposed mice, with a tendency towards increased frequency of RAR-beta methylation in the tumors from the cigarette smoke-exposed mice. These results emphasize the importance of the activation of K-ras and silencing of DAP-kinase and RAR-beta in lung cancer development, and confirm the relevance of this mouse model for studying lung tumorigenesis.