Abstract
Exposure to environmental and occupational contaminants leads to lung cancer. 3-Nitrobenzanthrone (3-nitro-7H-benz[de]anthracen-7-one, 3-NBA) is a potential carcinogen in ambient air or diesel particulate matter. Studies have revealed that short-term exposure to 3-NBA induces cell death, reactive oxygen species activation, and DNA adduct formation and damage. However, details of the mechanism by which chronic exposure to 3-NBA influences lung carcinogenesis remain largely unknown. In this study, human lung epithelial BEAS-2B cells were continuously exposed to 0–10-μM 3-NBA for 6 months. NanoString analysis was conducted to evaluate gene expression in the cells, revealing that 3-NBA–mediated transformation results in a distinct gene expression signature including carbon cancer metabolism, metastasis, and angiogenesis. Alterations in tumor-promoting genes such as EREG (epiregulin), SOX9, E-cadherin, TWIST, and IL-6 were involved in epithelial cell aggressiveness. Kaplan–Meier plotter analyses indicated that increased EREG and IL-6 expressions in early-stage lung cancer cells are correlated with poor survival. In vivo xenografts on 3-NBA–transformed cells exhibited prominent tumor formation and metastasis. EREG knockout cells exposed to 3-NBA for a short period exhibited high apoptosis and low colony formation. By contrast, overexpression of EREG in 3-NBA–transformed cells markedly activated the PI3K/AKT and MEK/ERK signaling pathways, resulting in tumorigenicity. Furthermore, elevated IL-6 and EREG expressions synergistically led to STAT3 signaling activation, resulting in clonogenic cell survival and migration. Taken together, chronic exposure of human lung epithelial cells to 3-NBA leads to malignant transformation, in which the EREG signaling pathway plays a pivotal mediating role.
Graphical abstract
• Short-term exposure of lung epithelial cells to 3-NBA can lead to ROS production and cell apoptosis.
• Long-term chronic exposure to 3-NBA upregulates the levels of tumor-promoting genes such as EREG and IL-6.
• Increased EREG expression in 3-NBA–transformed cells markedly contributes to tumorigenesis through PI3K/AKT and MEK/ERK activation and synergistically enhances the IL-6/STAT3 signaling pathway, which promotes tumorigenicity.
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Acknowledgements
We thank the CRISPR Gene Targeting Core Lab at Taipei Medical University for providing technical support. This manuscript was edited by Wallace Academic Editing.
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The datasets used or analyzed are available from the corresponding author upon reasonable request.
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Deregulated KEGG pathways were identified using STRING software (http://string-db.org). Differential genes were analyzed (www.kmplot.com) using Kaplan–Meier plotter with published lung cancer microarray datasets.
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This work was supported by grants from the Ministry of Science and Technology of the Republic of China (MOST: 108-2314-B-038-111-MY3 and 108-2314-B-038-063-MY3), Ministry of Education of the Republic of China (DP2-109-21121-01-T-01), Taipei Medical University and Shuang Ho Hospital (109TMU-SHH-09), Taipei Medical University (TMU107-AE1-B04), and Shuang Ho Hospital (108-FRP-04 and 109-FRP-03).
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KYC and CHT designed the study and wrote the manuscript. PHF and WLS drafted the manuscript and interpreted the data. SCH, CWL, NVH, CSL, and WTL collected the primary data and prepared the figures. TTC and YHT contributed to the literature review and performed statistical analysis. KYL and SMW supervised and reviewed the entire project and manuscript preparation. All authors have read and approved the manuscript.
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Chen, KY., Tseng, CH., Feng, PH. et al. 3-Nitrobenzanthrone promotes malignant transformation in human lung epithelial cells through the epiregulin-signaling pathway. Cell Biol Toxicol 38, 865–887 (2022). https://doi.org/10.1007/s10565-021-09612-1
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DOI: https://doi.org/10.1007/s10565-021-09612-1