1,4‐Dioxane Induces Epithelial‐Mesenchymal Transition and Carcinogenesis in an Nrf2‐Dependent Manner
ABSTRACT The carcinogenic potential of the environmental pollutant 1,4‐dioxane (1,4‐D) in humans is not yet fully understood or recognised. In this study, we provide evidence that 1,4‐D acts as a carcinogen in human epithelial cells. Using the human bronchial epithelial cell line BEAS‐2B, with or wi...
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| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2025-05-01
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| Series: | Journal of Extracellular Vesicles |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/jev2.70072 |
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| Summary: | ABSTRACT The carcinogenic potential of the environmental pollutant 1,4‐dioxane (1,4‐D) in humans is not yet fully understood or recognised. In this study, we provide evidence that 1,4‐D acts as a carcinogen in human epithelial cells. Using the human bronchial epithelial cell line BEAS‐2B, with or without CRISPR‐Cas9‐mediated Nrf2 knockout, we demonstrate that continuous exposure to environmentally relevant concentrations of 1.25–20 ppm 1,4‐D over 2 months induces malignant transformation in an Nrf2‐dependent manner. Transformed cells exhibit enhanced anchorage‐independent growth in soft agar, increased migration and invasion, and tumorigenic potential in a xenograft mouse model. Integrated RNA sequencing and proteomics analyses reveal that 1,4‐D robustly activates Nrf2 signalling, driving extracellular vesicle (EV) biogenesis and cargo loading with syndecan 4 (SDC4) and other proteins, including COL12A1, CAPG and NNMT, which are associated with epithelial‐mesenchymal transition (EMT) and cancer metastasis. Nrf2 knockout reduces SDC4 expression and its incorporation into EVs, leading to decreased EV uptake by recipient cells. Unlike EVs from 1,4‐D‐transformed WT cells, which enhance the proliferation, migration and invasion of recipient cells, EVs from 1,4‐D‐transformed Nrf2 KO cells exhibit a diminished capacity to promote these EMT properties. Furthermore, we demonstrate that the Nrf2 target gene SDC4, induced by 1,4‐D and enriched in EVs, plays a critical role in EV uptake by recipient cells, thereby facilitating EMT propagation. Collectively, our findings suggest that 1,4‐D is a human carcinogen, with its carcinogenicity largely dependent on Nrf2 activation, which orchestrates the biogenesis of EVs with EMT‐promoting functions. |
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| ISSN: | 2001-3078 |