Reactive oxygen species-dependent regulation of hypoxia-inducible factor 1α/C-X-C motif chemokine receptor 4 signaling promotes ozone-induced cancer metastasis.

Air pollutants, including vehicle emissions and photochemical smog such as ozone, have become a significant health concern in most industrialized nations. Inhaling ozone has repeatedly been linked to increased lung inflammation, immune responses, and cancer development, ultimately speeding up lung cancer metastasis and leading to higher death rates. However, the direct connection between ozone exposure and tumor cell migration has not yet been definitively established. This study aims to investigate the effects of ozone exposure on cancer spread and its underlying mechanisms, focusing on the hypoxia-inducible factor 1α (HIF-1α)/C-X-C motif chemokine receptor 4 (CXCR4) pathway, which influences cancer cell migration and epithelial-mesenchymal transition (EMT). Using B16F10 melanoma and LL2 Lewis lung carcinoma cells, we examined how 1 ppm ozone exposure affects reactive oxygen species (ROS) production and its subsequent impact on the HIF-1α/CXCR4 pathway. Our results show a significant increase in HIF-1α/CXCR4 expression and EMT-related proteins after ozone exposure. Additionally, the use of arbutin, a known ROS scavenger, significantly reduced HIF-1α/CXCR4 levels and cell migration, confirming the role of ROS in ozone-induced metastasis. In summary, our research suggests that ozone promotes cancer spread by activating the HIF-1α/CXCR4 signaling pathway, highlighting an environmental factor that could facilitate cancer progression.