PM2.5致ErbB-2/ErbB-4基因低甲基化在肺癌发生过程中的作用及其机制研究

肺癌居我国肿瘤发病率和死亡率之首，大气颗粒物可诱发肺癌，已被国际癌症研究机构列为人类确定致癌物。课题组前期研究发现，PM2.5可导致与肺癌密切相关的ErbB基因低甲基化，但其作用机制尚不清楚。本课题采用细胞模型、动物模型和非吸烟人群肺癌样本系统研究PM2.5致ErbB基因低甲基化在肺癌发生过程中的作用及分子机制。体外条件下研究PM2.5致细胞氧化损伤和DNA损伤等毒性表型及细胞异常增殖、细胞恶性转化和迁移浸润能力，分析ErbB基因甲基化对下游信号通路Ras/Raf/MAPK和PI3K/Akt的调控作用，通过甲基化抑制剂和基因沉默技术进行反向验证；动物实验观察恶转细胞成瘤能力及PM2.5亚慢性暴露的致癌作用，分析ErbB基因甲基化对肺癌信号通路的调控作用；采用非吸烟人群肺癌组织和癌旁组织进行ErbB基因甲基化水平、mRNA水平和蛋白水平验证。研究将为我国大气污染治理和肺癌防治提供科学依据。

Lung cancer ranks the first in cancer incidence and mortality in our country. Fine particulate matter has been classified by the International Agency for research on cancer as humans carcinogens that can induce the lung cancer. Our previously study found that PM2.5 can lead to hypomethylation of ErbB gene that closely related to lung cancer. However, the mechanism is not clear. We investigate the function of hypomethylation of ErbB and its mechanism in the progress of lung cancer induced by PM2.5 through cellular models, animal models and samples of lung cancer in non-smokers. In vitro, we study the PM2.5-induced toxicities, such as oxidative damage and DNA damage. We also investigate the abnormal cell proliferation, cell malignant transformation and the capacity of migration infiltration. The regulation of ErbB methylation to downstream signaling pathways of Ras and PI3K/Akt are analyzed through the reverse-verified of inhibitors of methylation and gene silencing technology. We observe the capcity of evil cells into cancer through animal experiments and the carcinogenic effects of subchronic exposure of PM2.5. The regulation of ErbB methylation to the signaling pathways are explored. We evaluate ErbB methylation levels, mRNA and protein levels by adapting lung cancer samples and carcinoma tissues of non-smokers. Our research will provide scientific evidence for air pollution control and lung cancer prevention in China.