Abstract
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.
Highlights
Diseases caused by air pollution have become a serious health problem worldwide
The present study used fourteen Xuanwei and Fuyuan lung cancer (XWLC) tissue samples that had been identified as non-small cell lung cancer (NSCLC) and included 11 cases of adenocarcinoma (AD) and three cases of squamous cell carcinoma (SCC); eight out of the 14 patients were the never smoking women; the 14 cases of XWLC were used for whole genome sequencing in a previous study [11]
BaP exposure induced multiple alterations in DNA methylation and in the mRNA expression level of DNA methyltransferases (DNMTs) and ten-11 translocation proteins (TETs); these alterations partially occurred in XWLC
Summary
Diseases caused by air pollution have become a serious health problem worldwide. For example, approximately 350,000–500,000 people in China die prematurely each year as a result of air pollution [1]. Examples of air pollution-related lung cancer exist in Xuanwei City and neighboring region (Fuyuan County), Yunnan Province, China [6,7,8]. In these districts, the lung cancer incidence is four to five times higher than the national average, and non-smoking women suffer from lung cancer more frequently compared to those in other areas. Benzo(a)pyren (BaP) is the most common PAH, and BaP exposure levels are strongly associated with the incidence of XWLC (Supplementary Figure S1) In these highly air-polluted regions, the primary source of BaP exposure could be attributed to burning coal in the home, and smokers had slightly higher BaP exposure than non-smokers [11]. Our previous studies demonstrated that XWLCs showed some distinct characteristics at the molecular level compared with lung cancers in other regions [11,12,13]
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