1,4-Dioxane Induces Epithelial-Mesenchymal Transition and Carcinogenesis in an Nrf2-Dependent Manner

Area of Science:

• Environmental toxicology
• Cellular and molecular oncology
• Carcinogenesis

Background:

• The carcinogenic potential of 1,4-dioxane (1,4-D) in humans remains unclear.
• 1,4-D is an environmental pollutant with potential health risks.

Purpose of the Study:

• To investigate the carcinogenic effects of 1,4-D on human epithelial cells.
• To elucidate the role of Nrf2 signaling in 1,4-D-induced carcinogenesis.
• To identify molecular mechanisms, including extracellular vesicles (EVs), involved in 1,4-D carcinogenicity.

Main Methods:

• Exposure of human bronchial epithelial cells (BEAS-2B) with and without Nrf2 knockout to 1.25-20 ppm 1,4-D for 2 months.
• Assays for malignant transformation: anchorage-independent growth, migration, invasion, and xenograft tumorigenicity.
• Integrated RNA sequencing and proteomics analyses.
• EV characterization, cargo analysis, and functional assays in recipient cells.

Main Results:

• Continuous 1,4-D exposure induced malignant transformation in an Nrf2-dependent manner.
• Transformed cells showed enhanced tumorigenic potential and metastasis-associated properties.
• 1,4-D activated Nrf2, promoting EV biogenesis and cargo loading with syndecan 4 (SDC4) and other EMT-related proteins.
• Nrf2 knockout reduced SDC4 in EVs, impairing EV uptake and EMT propagation.
• SDC4, enriched in EVs, is critical for EV uptake and EMT facilitation.

Conclusions:

• 1,4-D acts as a human carcinogen, primarily through Nrf2-dependent pathways.
• Nrf2 activation orchestrates EV biogenesis and function, promoting cancer metastasis.
• Targeting Nrf2-mediated EV pathways could offer therapeutic strategies against 1,4-D-induced cancers.