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...
Saved in:
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2025-05-01
|
| Series: | Journal of Extracellular Vesicles |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/jev2.70072 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849325588195573760 |
|---|---|
| author | Ziwei Wang Chitra Thakur Zhuoyue Bi Yiran Qiu Wenxuan Zhang Haoyan Ji Arjun K. Venkatesan Sashank Cherukuri Ke Jian Liu John D. Haley Xinwei Mao Jaymie Meliker Fei Chen |
| author_facet | Ziwei Wang Chitra Thakur Zhuoyue Bi Yiran Qiu Wenxuan Zhang Haoyan Ji Arjun K. Venkatesan Sashank Cherukuri Ke Jian Liu John D. Haley Xinwei Mao Jaymie Meliker Fei Chen |
| author_sort | Ziwei Wang |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-ab89ec3ff5b44e459183852906d9f586 |
| institution | Kabale University |
| issn | 2001-3078 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Extracellular Vesicles |
| spelling | doaj-art-ab89ec3ff5b44e459183852906d9f5862025-08-20T03:48:22ZengWileyJournal of Extracellular Vesicles2001-30782025-05-01145n/an/a10.1002/jev2.700721,4‐Dioxane Induces Epithelial‐Mesenchymal Transition and Carcinogenesis in an Nrf2‐Dependent MannerZiwei Wang0Chitra Thakur1Zhuoyue Bi2Yiran Qiu3Wenxuan Zhang4Haoyan Ji5Arjun K. Venkatesan6Sashank Cherukuri7Ke Jian Liu8John D. Haley9Xinwei Mao10Jaymie Meliker11Fei Chen12Stony Brook Cancer Center, Department of Pathology, Renaissance School of Medicine Stony Brook University Stony Brook New York USAStony Brook Cancer Center, Department of Pathology, Renaissance School of Medicine Stony Brook University Stony Brook New York USAStony Brook Cancer Center, Department of Pathology, Renaissance School of Medicine Stony Brook University Stony Brook New York USAStony Brook Cancer Center, Department of Pathology, Renaissance School of Medicine Stony Brook University Stony Brook New York USAStony Brook Cancer Center, Department of Pathology, Renaissance School of Medicine Stony Brook University Stony Brook New York USAStony Brook Cancer Center, Department of Pathology, Renaissance School of Medicine Stony Brook University Stony Brook New York USACivil Engineering, School of Marine and Atmospheric Sciences Stony Brook University Stony Brook New York USAStony Brook Cancer Center, Department of Pathology, Renaissance School of Medicine Stony Brook University Stony Brook New York USAStony Brook Cancer Center, Department of Pathology, Renaissance School of Medicine Stony Brook University Stony Brook New York USAStony Brook Cancer Center, Department of Pathology, Renaissance School of Medicine Stony Brook University Stony Brook New York USADepartment of Civil Engineering, College of Engineering and Applied Sciences Stony Brook University Stony Brook New York USADepartment of Family, Population and Preventive Medicine, Renaissance School of Medicine Stony Brook University Stony Brook New York USAStony Brook Cancer Center, Department of Pathology, Renaissance School of Medicine Stony Brook University Stony Brook New York USAABSTRACT 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.https://doi.org/10.1002/jev2.700721,4‐dioxaneEMTEV biogenesisNrf2SDC4 |
| spellingShingle | Ziwei Wang Chitra Thakur Zhuoyue Bi Yiran Qiu Wenxuan Zhang Haoyan Ji Arjun K. Venkatesan Sashank Cherukuri Ke Jian Liu John D. Haley Xinwei Mao Jaymie Meliker Fei Chen 1,4‐Dioxane Induces Epithelial‐Mesenchymal Transition and Carcinogenesis in an Nrf2‐Dependent Manner Journal of Extracellular Vesicles 1,4‐dioxane EMT EV biogenesis Nrf2 SDC4 |
| title | 1,4‐Dioxane Induces Epithelial‐Mesenchymal Transition and Carcinogenesis in an Nrf2‐Dependent Manner |
| title_full | 1,4‐Dioxane Induces Epithelial‐Mesenchymal Transition and Carcinogenesis in an Nrf2‐Dependent Manner |
| title_fullStr | 1,4‐Dioxane Induces Epithelial‐Mesenchymal Transition and Carcinogenesis in an Nrf2‐Dependent Manner |
| title_full_unstemmed | 1,4‐Dioxane Induces Epithelial‐Mesenchymal Transition and Carcinogenesis in an Nrf2‐Dependent Manner |
| title_short | 1,4‐Dioxane Induces Epithelial‐Mesenchymal Transition and Carcinogenesis in an Nrf2‐Dependent Manner |
| title_sort | 1 4 dioxane induces epithelial mesenchymal transition and carcinogenesis in an nrf2 dependent manner |
| topic | 1,4‐dioxane EMT EV biogenesis Nrf2 SDC4 |
| url | https://doi.org/10.1002/jev2.70072 |
| work_keys_str_mv | AT ziweiwang 14dioxaneinducesepithelialmesenchymaltransitionandcarcinogenesisinannrf2dependentmanner AT chitrathakur 14dioxaneinducesepithelialmesenchymaltransitionandcarcinogenesisinannrf2dependentmanner AT zhuoyuebi 14dioxaneinducesepithelialmesenchymaltransitionandcarcinogenesisinannrf2dependentmanner AT yiranqiu 14dioxaneinducesepithelialmesenchymaltransitionandcarcinogenesisinannrf2dependentmanner AT wenxuanzhang 14dioxaneinducesepithelialmesenchymaltransitionandcarcinogenesisinannrf2dependentmanner AT haoyanji 14dioxaneinducesepithelialmesenchymaltransitionandcarcinogenesisinannrf2dependentmanner AT arjunkvenkatesan 14dioxaneinducesepithelialmesenchymaltransitionandcarcinogenesisinannrf2dependentmanner AT sashankcherukuri 14dioxaneinducesepithelialmesenchymaltransitionandcarcinogenesisinannrf2dependentmanner AT kejianliu 14dioxaneinducesepithelialmesenchymaltransitionandcarcinogenesisinannrf2dependentmanner AT johndhaley 14dioxaneinducesepithelialmesenchymaltransitionandcarcinogenesisinannrf2dependentmanner AT xinweimao 14dioxaneinducesepithelialmesenchymaltransitionandcarcinogenesisinannrf2dependentmanner AT jaymiemeliker 14dioxaneinducesepithelialmesenchymaltransitionandcarcinogenesisinannrf2dependentmanner AT feichen 14dioxaneinducesepithelialmesenchymaltransitionandcarcinogenesisinannrf2dependentmanner |