SO2暴露诱导肺癌肿瘤转移效应及其上皮间质转化（EMT）调控机制

Lung cancer is the most common cause of cancer-related mortality in the world.Epidemiologic studies show an association between the mortality of lung cancer and SO2 exposure. However, if SO2 exposure will influence the incidence of lung cancer remains disputed, existing experimental studies also lack evidences as to the presence of effects about SO2. Epithelial-mesenchymal transition (EMT) is considered to be a critical event in the pathogenesis of tumor metastasis. In the present project,we will treat human bronchial epithelial cells and lung cancer cells with SO2 derivatives (bisulfite and sulfite, 3:1 M/M), and examine the changes of ROS generation, transcriptional factors activation, DNA methylation and EMT markers expression to explore the effects of SO2 inhalation on the early tumor metastasis and caner development. Following this, we plan to treat tumor model mices with SO2 at various concentrations and determine the changes of above factors to verify the regulation mechanisms of EMT during SO2 inhalation-caused tumor distant metastasis. The work is undertaken to indicate the effects of SO2 exposure on the process of lung cancer development, illuminate regulation mechanism of the EMT, set up effective biomarkers for early detection, provide experimental evidence for effective protection, early diagnosis and targeted therapies for the high risk group in polluted area.

肺癌是全球发病率和死亡率最高的恶性肿瘤疾病。流行病学研究表明，SO2吸入与肺癌病死率增加显著相关，而与肺癌发病风险的相关性研究结果仍存有争议，相关分子机制更是鲜见报道。EMT在肺癌肿瘤转移中发挥重要作用。为此，本研究拟通过分别对人正常支气管上皮细胞和肺癌细胞进行SO2衍生物染毒，考察染毒前后自由基水平，转录因子活化，DNA甲基化及EMT标志因子表达的变化，探讨SO2暴露对肺癌早期肿瘤转移和发展的影响，明确EMT发生作为该肿瘤效应早期诊断的生物学标志的可能性，揭示SO2暴露诱导肺癌肿瘤侵袭转移的调控机制；在此基础上拟对肺癌模型小鼠进行SO2动式吸入染毒，进一步验证SO2吸入暴露对肺癌肿瘤远端转移能力的影响及其调控机制。通过本研究，旨在阐明SO2暴露对肺癌肿瘤发展的影响，建立早期诊断分子生物标志，确定EMT发生的调控机制，为健康人群的日常防护和高危人群的临床诊断、治疗和预后提供理论依据。

肺癌是全球发病率和死亡率最高的恶性肿瘤疾病。流行病学研究表明，室外大气污染物吸入与肺癌病死率增加显著相关，而与肺癌发病风险的相关性研究结果仍存有争议，相关分子机制更是鲜见报道。EMT在肺癌肿瘤转移中发挥重要作用。为此，本研究煤烟性区域性大气污染物暴露对癌细胞转移的影响及其分子调控途径。结果表明，(1) SO2暴露可显著诱导A549 和BEAS2B细胞侵袭转移效应的发生，转录因子snail的介导和启动子区的甲基化调控发挥了重要的作用。 同时，SO2和PM10复合暴露可通过ROS介导的NF-κB的激活可协同诱导肺癌细胞侵袭迁移效应的发生；(2)中国北方城市郊区冬季燃煤型PM2.5和PM10暴露可诱导肺癌细胞A549侵袭迁移，上皮间质转化和胞外基质的降解机制参与该调控过程的发生；(3) PPARγ介导的EMT机制参与煤矸石场周边村庄土壤PAHs污染诱导的肝癌细胞HEPG2的迁移。通过本研究，旨在确定煤烟性区域性污染物暴露对癌细胞转移的影响及其分子调控途径，建立相关生物表观遗传靶标和危险度评价指标，煤烟性区域大气污染物排放标准修订、人群暴露的健康效应及防护治疗提供理论支撑。