Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China; School of Continuing Education, Nanjing Medical University, Nanjing 211166, China.
Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China.
Ecotoxicol Environ Saf. 2019 Jan 15;167:309-316. doi: 10.1016/j.ecoenv.2018.10.033. Epub 2018 Oct 18.
Epidemiological studies have associated ambient fine particulate matter (PM) exposure with lung cancer, in which epithelial-mesenchymal transition (EMT) is an initial process. Thus, it is important to identify the key molecule or pathway involved in the PM induced EMT. Human bronchial epithelial (HBE) cells were exposed to PM (100 or 500 μg/ml) for 30 passages and analyzed by metabolomics to identify the alteration of metabolites related to PM exposure. The expression levels of EMT markers were evaluated by qRT-PCR and Western blot assays in HBE cells and murine lung tissues. Reduced epithelial markers, increased mesenchymal markers expression levels and increased capacity of metastasis were observed in PM-exposed HBE cells. Metabolomics analysis suggested upregulation of citrate acid with fold change (FC) of 2.89 or 4.18 in 100 or 500 μg/ml PM treated HBE cells. For both of the in vitro and in vivo study, the up-regulation of ATP citrate lyase (ACLY) was confirmed following PM exposure. Importantly, ACLY knockdown in HBE cells reversed EMT, migration and invasion capacities in HBE cells induced by PM. Taken together, our data suggest that inhibition of ACLY demonstrates a protection against PM-induced EMT, providing a concern on the molecular mechanisms of PM-associated pulmonary disorders.
流行病学研究表明，环境细颗粒物（PM）暴露与肺癌有关，上皮-间充质转化（EMT）是初始过程。因此，确定 PM 诱导 EMT 中涉及的关键分子或途径非常重要。用 PM（100 或 500μg/ml）处理人支气管上皮（HBE）细胞 30 代，通过代谢组学分析鉴定与 PM 暴露相关的代谢物变化。用 qRT-PCR 和 Western blot 检测 PM 暴露的 HBE 细胞和鼠肺组织中 EMT 标志物的表达水平。PM 暴露的 HBE 细胞中观察到上皮标志物减少、间充质标志物表达水平增加和转移能力增强。代谢组学分析表明，柠檬酸水平上调，在 100 或 500μg/ml PM 处理的 HBE 细胞中分别上调 2.89 或 4.18 倍。在体外和体内研究中，均证实 PM 暴露后 ATP 柠檬酸裂解酶（ACLY）上调。重要的是，在 HBE 细胞中敲低 ACLY 可逆转 PM 诱导的 EMT、迁移和侵袭能力。总之，我们的数据表明，抑制 ACLY 可防止 PM 诱导的 EMT，这为 PM 相关肺部疾病的分子机制提供了关注。
