Jiang Cheng-Lan, He Shui-Wang, Zhang Yun-Dong, Duan He-Xian, Huang Tao, Huang Yun-Chao, Li Gao-Feng, Wang Ping, Ma Li-Ju, Zhou Guang-Biao, Cao Yi
Laboratory of Molecular and Experimental Pathology, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China.
Kunming College of Life Sciences, University of Chinese Academy of Sciences, Kunming 650223, China.
Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
The lung cancer incidence in the Xuanwei and neighboring region, Yunnan, China, is among the highest in China and is attributed to severe air pollution with high benzo(a)pyrene levels. We systematically and comparatively analyzed DNA methylation alterations at genome and gene levels in Xuanwei lung cancer tissues and cell lines, as well as benzo(a)pyrene-treated cells and mouse samples. We obtained a comprehensive dataset of genome-wide cytosine-phosphate-guanine island methylation in air pollution-related lung cancer samples. Benzo(a)pyrene exposure induced multiple alterations in DNA methylation and in mRNA expressions of DNA methyltransferases and ten-11 translocation proteins; these alterations partially occurred in Xuanwei lung cancer. Furthermore, benzo(a)pyrene-induced DKK2 and EN1 promoter hypermethylation and LPAR2 promoter hypomethylation led to down-regulation and up-regulation of the genes, respectively; the down-regulation of DKK2 and EN1 promoted the cellular proliferation. Thus, DNA methylation alterations induced by benzo(a)pyrene contribute partially to abnormal DNA methylation in air pollution-related lung cancer, and these DNA methylation alterations may affect the development and progression of lung cancer. Additionally, vitamin C and B6 can reduce benzo(a)pyrene-induced DNA methylation alterations and may be used as chemopreventive agents for air pollution-related lung cancer.
中国云南宣威及周边地区的肺癌发病率位居全国前列，这归因于苯并(a)芘水平高导致的严重空气污染。我们系统地、比较性地分析了宣威肺癌组织和细胞系、以及经苯并(a)芘处理的细胞和小鼠样本在基因组和基因水平上的DNA甲基化改变。我们获得了空气污染相关肺癌样本中全基因组胞嘧啶-磷酸-鸟嘌呤岛甲基化的综合数据集。苯并(a)芘暴露诱导了DNA甲基化以及DNA甲基转移酶和ten-11易位蛋白mRNA表达的多种改变；这些改变部分发生在宣威肺癌中。此外，苯并(a)芘诱导的DKK2和EN1启动子高甲基化以及LPAR2启动子低甲基化分别导致了这些基因的下调和上调；DKK2和EN1的下调促进了细胞增殖。因此，苯并(a)芘诱导的DNA甲基化改变部分导致了空气污染相关肺癌中异常的DNA甲基化，并且这些DNA甲基化改变可能影响肺癌的发生和发展。此外，维生素C和B6可以减少苯并(a)芘诱导的DNA甲基化改变，并且可能用作空气污染相关肺癌的化学预防剂。
