Abstract
Exposure to ambient particulate matter (PM) has been linked to the increasing incidence and mortality of lung cancer, but the principal toxic components and molecular mechanism remain to be further elucidated. In this study, human lung adenocarcinoma A549 cells were treated with serial concentrations of water-extracted PM10 (WE-PM10) collected from Beijing, China. Our results showed that exposure to 25 and 50 μg/ml of WE-PM10 for 48 h significantly suppressed miR-26a to upregulate lin-28 homolog B (LIN28B), and in turn activated interleukin 6 (IL6) and signal transducer and activator of transcription 3 (STAT3) in A549 cells, subsequently contributing to enhanced epithelial–mesenchymal transition and accelerated migration and invasion. In vivo pulmonary colonization assay further indicated that WE-PM10 enhanced the metastatic ability of A549 cells. In addition, luciferase reporter assay demonstrated that 3′ untranslated region of LIN28B was a direct target of miR-26a. Last but not the least, the key toxic contribution of metals in WE-PM10 was confirmed by the finding that removal of metals through chelation significantly rescued WE-PM10-mediated inflammatory, carcinogenic and metastatic responses. Taken together, miR-26a could act as the tumor suppressor in PM10-related lung cancer, and PM10-bound metals promoted lung cancer cell metastasis through downregulation of miR-26a that directly mediated LIN28B expression.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China [41390240, 21677140 and 21477124]; the Youth Innovation Promotion Association, CAS [217349]; the Knowledge Innovation Program of the Chinese Academy of Sciences [IUEQN201301 and IUEQN201506]; the Natural Science Foundation of Fujian, China [2017J01028].
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All of the animal experiments were carried out in accordance with the guidelines of the Xiamen University Institutional Committee for the Care and Use of Laboratory Animals and the Institutional Animal Ethics Committee of Institute of Urban Environment, Chinese Academy of Sciences. The manuscript did not contain clinical studies or patient data.
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Supplementary Method: Apoptosis detection. Table S1. Primers used in the construction of luciferase reporters. Table S2. Primers used in qPCR analyses of mRNA. Table S3. Primers used in qPCR analyses of miRNA. Fig. S1. Expression of miR-26a. Fig. S2. mRNA expression of LIN28B. Fig. S3. WE-PM10 did not induce apoptosis or proliferation in A549 cells. Fig. S4. Quantification of the protein levels in Fig. 2g and the transwell assays in Fig. 2h. Fig. S5. Quantification of protein levels in Fig. 7d (PDF 677 KB)
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Lu, YY., Lin, Y., Ding, DX. et al. MiR-26a functions as a tumor suppressor in ambient particulate matter-bound metal-triggered lung cancer cell metastasis by targeting LIN28B–IL6–STAT3 axis. Arch Toxicol 92, 1023–1035 (2018). https://doi.org/10.1007/s00204-017-2141-4
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DOI: https://doi.org/10.1007/s00204-017-2141-4