Work

The epigenetic-modified downregulation of LOXL1 protein mediates EMT in bladder epithelial cells exposed to benzo[a]pyrene and its metabolite BPDE

Year: 2024

Type: article

Abstract: • Exposure to B[a]P and its metabolite BPDE initiates and promotes the EMT process in bladder epithelial cells and rat models. • B[a]P/BPDE exposure initiates and promotes the EMT process through ROS/DNMTs/LOXL1 cascade, thereby contributing to bladder carcinogenesis. • LOXL1 may be a potential biomarker for early diagnosis and a novel target for the precise treatment of bladder cancer. Benzo[a]pyrene (B[a]P) is a well-known polycyclic aromatic hydrocarbon (PAH) pollutant with high carcinogenicity, widespread environmental presence, and significant threat to public health. Epidemiological studies have linked exposure to B[a]P and its metabolite 7,8-dihydroxy-9,10-epoxybenzo[a]pyrene (BPDE) to the development and progression of various cancers, including bladder cancer. However, its underlying mechanism remains unclear. Our study revealed that B[a]P and BPDE induced epithelial-mesenchymal transition (EMT), a critical early event in cell malignant transformation, involving a decrease in E-Cadherin and upregulation of N-Cadherin protein levels, leading to increased cell motility and migration in bladder epithelial cells. Further studies have indicated that LOXL1 DNA undergoes methylation and modification influenced by methyltransferase 3a (DNMT3a) and DNMT3b, resulting in decreased LOXL1 protein levels. The decreased LOXL1 promotes the zinc finger transcription factor SLUG, which then inhibits E-Cadherin protein levels and initiates the EMT process. Moreover, DNMT3a/3b expression appears to be influenced by intracellular oxidative stress levels. These findings suggest that exposure to B[a]P/BPDE promotes the EMT process through the pivotal factor LOXL1, thereby contributing to bladder carcinogenesis. Our study provides a theoretical basis for considering LOXL1 as a potential biomarker for early diagnosis and a novel target for the precise diagnosis and treatment of bladder cancer.

Source: International Immunopharmacology

DOI: 10.1016/j.intimp.2024.113232