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 (PM2.5), 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 PM2.5 exposure enhances BC cell migration and invasion. Ribonucleic acid (RNA) sequencing identified the Wnt signaling pathway as a key regulator in PM2.5-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 PM2.5-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 PM2.5-induced upregulation of Wnt3A, Wnt5A, and β-catenin nuclear translocation but also significantly reduced the migration and invasion of PM2.5-exposed BC cells. Both pathways represent promising therapeutic targets, and several existing pathway-specific inhibitors may be repurposed for the future clinical management of PM2.5-induced BC progression.

CONCLUSIONS

PM2.5 promotes BC progression through both the MAPK/ERK and Wnt/β-catenin signaling pathways. MEK/ERK inhibition suppressed PM2.5-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 PM2.5 exposure drives BC progression and offers a potential foundation for developing targeted therapies for PM2.5-associated BC.