Th17/Treg细胞失衡在多环芳烃致肺癌早期效应改变中的作用及机制研究

Polycyclic aromatic hydrocarbons (PAHs) is a major carcinogen for lung cancer. Chronic inflammation has been considered a key factor in tumorigenesis. To date, limited biomarker studies on inflammatory injury induced by PAHs. Based on the evidence of aberrant alterations of CD4 + T cells and T helper 17 (Th17) cytokine in PAHs-exposed population and cells in vitro, we speculate Th17/Treg imbalance is key event in the early adverse effects of lung cancer. We will build PAHs-exposed population cohort and detect changes of Th17 cytokines and pulmonary specific proteins in serum and sputum by multiplex system. We will also assess changes of inflammation and microenvironment in the collected sputum cells, which as the target cells. In co-culture system with bronchial epithelial cells and macrophages, we will develop the malignant transformed cell models induced by PAHs. Combined lung cancer translational study and high-throughput sequencing on microRNA expression and transcriptome, we will find the key microRNA molecules which may be involved in the PAHs induced lung carcinogenesis. From these data, we will elucidate the role and mechanism of inflammatory cytokines and microRNA in the PAHs induced carcinogenesis. Combined population with laboratory study, our project can solve the key issues of early adverse effect induced by occupational and enviromental PAHs exposure. The hypothesis was clear and original. Outcomes of this project will give important evidences for evaluating the lung cancer risk for PAHs and health surveillance in exposed workers.

多环芳烃（PAHs）是导致肺癌的主要致癌物,慢性炎症是肿瘤发生发展的关键因素，但在PAHs的早期效应标志物研究很少涉及。在人群和体外研究中，我们发现PAHs致CD4+T细胞和Th17细胞因子异常改变，推测Th17/Treg失衡在肺癌早期效应中发挥作用。本项目拟建立观察队列，收集痰细胞，评估靶细胞的炎症和微环境改变；采用悬浮芯片技术在血清、痰液中寻找Th17因子和肺部损伤蛋白的改变；创建支气管上皮细胞和巨噬细胞共培养体系，建立PAHs恶性转化模型；结合miroRNA表达谱和转录组测序技术，依靠转化医学研究，寻找肺癌和炎症发生过程中关键microRNA分子，阐明相关炎症因子和microRNA在PAHs致细胞癌变中的作用和机制。人群研究与实验室研究有机结合，解决职业和一般人群PAHs暴露早期健康效应的关键问题。本项目假说清晰、独创性强、为评估PAHs致肺癌的风险和健康监护方案提供重要依据。

多环芳烃（PAHs）是广泛存在的环境致癌物，流行病学研究虽然证实职业PAHs暴露与焦炉工人罹患肺癌间的因果联系，但从暴露到肺癌发生过程中的重要生物学改变和反映早期健康效应的标志物还很有限,也缺少相关机制研究。本研究在前期职业多环芳烃暴露人群队列的基础上，进行了人群队列的跟踪随访，并补充退休焦炉工人群，开展了多环芳烃与呼吸系统炎性损伤标志物和机制学研究。本研究中多批次系统的鉴定了不同岗位人群PAHs和颗粒物的暴露特征和致癌风险，并首次在多人群中发现了职业PAHs暴露与血清CC16等多个肺损伤标志物的剂量-效应关系；首次在焦炉工人群中探讨了PAHs暴露与DNA甲基化转移酶和基因组DNA甲基化的暴露-反应关系，并发现了DNMT3A的中介作用；首次在焦炉工人群中研究了淋巴细胞亚群和免疫细胞因子对PAHs的剂量-效应关系，确定了Th17通路中部分因子在遗传损伤和肿瘤发生中的作用，并在体外细胞中开展了验证。研究中还发现氧化应激和microRNA等标志物在多环芳烃致遗传学损伤中的作用，建立了微量全血法高通量彗星实验方法，并在人群研究中获得有效的应用。本项目多项研究成果在领域内专业期刊发表，其中高水平国际期刊论文5篇，中文核心期刊6篇；团队成员参加国内外学术会议交流20余人次；培养研究生8名。项目的研究成果有助于指导职业多环芳烃暴露人群呼吸性疾病的防治和健康风险评估。

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