Particulate matter 2.5 promotes bladder cancer cell migration and invasion through the crosstalk between integrin-mediated MAPK/ERK and Wnt/β-catenin pathways.

BACKGROUND: Fine particulate matter 2.5 (PM(2.5)), a key indicator of air pollution, is classified as a human carcinogen. However, the link between air pollution and bladder cancer (BC) progression remains unclear. Dysregulation of the Wingless-related integration site (Wnt)/β-catenin and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathways is a key driver of tumorigenesis in multiple cancers, including BC. RESULTS: This study demonstrated that PM(2.5) exposure enhances BC cell migration and invasion. Ribonucleic acid (RNA) sequencing identified the Wnt signaling pathway as a key regulator in PM(2.5)-exposed BC cells. Elevated protein levels of Wnt3A, Wnt5A, and β-catenin, along with the nuclear translocation of β-catenin, further highlighted the role of the PM(2.5)-activated Wnt/β-catenin pathway in promoting BC progression. The interaction between the Wnt/β-catenin and MAPK/ ERK pathways was examined using inhibitors and shRNAs. MEK or ERK inhibition not only suppressed PM(2.5)-induced upregulation of Wnt3A, Wnt5A, and β-catenin nuclear translocation but also significantly reduced the migration and invasion of PM(2.5)-exposed BC cells. Both pathways represent promising therapeutic targets, and several existing pathway-specific inhibitors may be repurposed for the future clinical management of PM(2.5)-induced BC progression. CONCLUSIONS: PM(2.5) promotes BC progression through both the MAPK/ERK and Wnt/β-catenin signaling pathways. MEK/ERK inhibition suppressed PM(2.5)-induced nuclear translocation of β-catenin, suggesting that the MAPK/ERK pathway functions upstream of the Wnt/β-catenin pathway. This study provides mechanistic insights into how PM(2.5) exposure drives BC progression and offers a potential foundation for developing targeted therapies for PM(2.5)-associated BC.