邻苯二甲酸二(2-乙基)己酯诱导的小细胞外囊泡 miR-26a-5p 促进了附近正常 A549 细胞的转移。
DEHP-elicited small extracellular vesicles miR-26a-5p promoted metastasis in nearby normal A549 cells.
机构信息
Key Lab of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen, 361021, PR China; College of Resources and Environment, University of Chinese Academy of Sciences, Beijing, 100049, PR China.
Key Lab of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen, 361021, PR China; Laboratory of Molecular Biology, Department of Biochemistry, Anhui Medical University, Hefei, 230032, PR China.
出版信息
Environ Pollut. 2021 Mar 1;272:116005. doi: 10.1016/j.envpol.2020.116005. Epub 2020 Nov 6.
Small extracellular vesicles (sEV) are small lipid bilayer particles released by cells. sEV have been shown to play critical roles in intercellular communication. Di (2-ethylhexyl) phthalate (DEHP), widely used as plasticizers, has been detected in the environment and human beings. DEHP was found to exist in the air particles and showed pulmonary toxicity. However, there's little knowledge about the role of sEV in mediating the toxicity of DEHP-induced lung toxicity. We hypothesized that sEV mediated the toxicity of DEHP through their cargo. To validate this, lung epithelial cells (A549) were exposed to various concentrations (0, 0.2, 2 and 20 μM) of DEHP for 48 h. sEV extracted from DEHP-exposed A549 cells were cultured with unexposed A549 cells. Results showed that DEHP induced the epithelial-mesenchymal transition (EMT) and promoted the migration and invasion ability of A549 cells. The number of released sEV significantly increased in the culture media in DEHP-exposed groups compared to unexposed groups. The sEV can enter the unexposed A549 cells and enhance its EMT and the ability of migration and invasion. Treatment with GW4869 in DEHP-exposed A549 cells almost blocked the effects of DEHP-elicited sEV in normal A549 cells. Sequencing and functional analysis showed that the enrichment of significantly differentially expressed sEV miRNAs were related to tumor etiology. MiR-26a-5p was significantly enriched in DEHP-elicited sEV. Inhibition of miR-26a-5p in DEHP-exposed cells led to the downregulation of miR-26a-5p in sEV, and thus abolished the effects of DEHP-elicited sEV in normal A549 cells, whereas overexpression of miR-26a-5p restored the effects. The transcription factors twist is one of the downstream targets in the effects of sEV-miR-26a-5p on EMT process. In all, our results showed that DEHP exposure promoted the secretion of miR-26a-5p in sEV, which subsequently enhanced the EMT, migration and invasion ability in neighboring normal cells via the twist.
小细胞外囊泡 (sEV) 是由细胞释放的小脂质双层颗粒。sEV 已被证明在细胞间通讯中发挥关键作用。邻苯二甲酸二 (2-乙基己基) 酯 (DEHP) 作为增塑剂被广泛应用，已在环境和人类中被检测到。DEHP 存在于空气颗粒中，表现出肺毒性。然而，关于 sEV 在介导 DEHP 诱导的肺毒性中的作用知之甚少。我们假设 sEV 通过其 cargo 介导 DEHP 的毒性。为了验证这一点，用不同浓度 (0、0.2、2 和 20 μM) 的 DEHP 处理肺上皮细胞 (A549) 48 h。用 DEHP 处理过的 A549 细胞提取的 sEV 与未暴露的 A549 细胞共培养。结果表明，DEHP 诱导上皮-间充质转化 (EMT)，并促进 A549 细胞的迁移和侵袭能力。与未暴露组相比，DEHP 暴露组培养物中的 sEV 释放数量明显增加。sEV 可进入未暴露的 A549 细胞，并增强其 EMT 和迁移及侵袭能力。在 DEHP 处理的 A549 细胞中用 GW4869 处理几乎阻断了 DEHP 诱导的 sEV 在正常 A549 细胞中的作用。测序和功能分析表明，明显差异表达的 sEV miRNAs 的富集与肿瘤病因有关。miR-26a-5p 在 DEHP 诱导的 sEV 中显著富集。在 DEHP 处理的细胞中抑制 miR-26a-5p 导致 sEV 中 miR-26a-5p 的下调，并因此消除了 DEHP 诱导的 sEV 在正常 A549 细胞中的作用，而 miR-26a-5p 的过表达则恢复了作用。转录因子 twist 是 sEV-miR-26a-5p 对 EMT 过程影响的下游靶标之一。总之，我们的结果表明，DEHP 暴露促进了 sEV 中 miR-26a-5p 的分泌，随后通过 twist 增强了邻近正常细胞中的 EMT、迁移和侵袭能力。
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