以乙醛脱氢酶1（ALDH1）为标志物研究PM2.5暴露对肺癌干细胞生物学功能的影响及其调控机制

Lung cancer is the leading cause of cancer-related deaths worldwide. Aldehyde dehydrogenases 1 (ALDH1) was a functional marker of the lung cancer stem cells (LCSCs). Epidemiologic studies show that inhalation exposure to fine particulate matter (PM2.5) correlates with increased mortality of lung cancer. Nevertheless, studies on the biological effects of lung cancer and its underlying molecular mechanisms induced by PM2.5 exposure were rarely reported. In the present project, fluorescence-activated cell sorting analysis will be used to differentiate between the ALDH-positive and ALDH-negative cancer stem cells in A549 and H1299 lung cancer cell lines. Furthermore, the biological effects of LCSCs induced by PM2.5 and the role of ALDH1 in this progress will be revealed in vitro. On this basis, combining with the specific interventions and xenograft model, the regulating role of Wnt/β-catenin signaling pathway on PM2.5 exposure-induced biological effects will be analysised. The work is undertaken to indicate the effects of PM2.5 exposure on the biological functions of LCSCs and its regulation mechanism, as well as provide a scientific basis for establishing a biological marker for safety assessment of PM2.5 exposure, health hazard effect analysis of smog, and early diagnosis and targeted therapy for high-risk population.

肺癌是全球致死率最高的恶性肿瘤。ALDH1是肺癌干细胞的功能性标志物。流行病学研究显示，PM2.5暴露与肺癌病死率增加相关，而关于PM2.5暴露对肺癌生物学效应及其分子机制的研究还鲜见报道。本项目拟采用流式分选人肺癌ALDH+细胞，建立PM2.5细胞暴露模型，揭示PM2.5暴露诱导肺癌干细胞的生物学效应以及ALDH1在此过程中的作用；在此基础上，结合特异性干扰措施和肺癌小鼠模型，解析Wnt/β-catenin信号通路对PM2.5暴露诱导肺癌干细胞生物学效应的调控作用。通过本研究，旨在阐明PM2.5暴露诱导肺癌干细胞的生物学效应及其调控机制，建立生物学标志物，为PM2.5暴露安全评价、雾霾健康危害解析、高危人群的早期诊断提供科学依据。

PM2.5是一种重要的常见空气污染物，其引发的健康危害问题受到人们更多的关注。流行病学研究表明，PM2.5长期暴露与肺癌相关，但确切的致病分子机制还不清楚。本项目结果显示，PM2.5暴露诱导人肺癌ALDH+细胞的增殖、克隆形成、肿瘤球形成等肿瘤生物学功能改变；发现了PM2.5暴露促进肺癌ALDH+细胞生物学功能改变的肿瘤干细胞标志物；研究了ALDH+和ALDH-细胞生物学功能和肿瘤干细胞标志物表达方面的差异，进一步揭示了ALDH1在PM2.5诱导肺癌干细胞生物学效应中的作用；探讨了PM2.5暴露诱导肺癌干细胞生物学效应的分子调控机理，发现Wnt/β-catenin信号通路参与了PM2.5暴露诱导肺癌干细胞生物学功能变化。此结果有望为PM2.5暴露安全评价、居民健康防护、提供科学的理论依据，同时为高危人群肺癌的早期诊断、治疗和预后提供新的靶点和模式。