Tobacco smoking exposure-mediated ELAVL1 regulates bladder cancer cell senescence via autophagy activation.

Tobacco smoking is a well-established risk factor for bladder cancer, which shows connection to cell senescence in various diseases. However, the regulatory mechanisms linking tobacco smoking exposure to senescence regulation in bladder cancer remain incompletely characterized. In this investigation, we demonstrated that the smoking carcinogen 4-aminobiphenyl (4-ABP) inhibited cell senescence while enhancing proliferative, invasive, and migratory capacities of bladder cancer cells, as evidenced by SA-β-gal staining, western blot and cell malignant phenotype experiments. We further identified 275 cell senescence-related genes specific to bladder cancer based on CellAge database, the Nanjing bladder cancer dataset and public database. Through genome-wide association studies in 580 bladder cancer cases and 1,101 controls, we pinpointed that rs12978895 G>A in ELAVL1 was significantly correlated with decreased bladder cancer risk (odds ratio = 0.79, 95% confidence interval = 0.68-0.92) and interacted with smoking (P = 0.043). In genetic regulation, both experimental and population study showed that the A allele of rs12978895 significantly reduced ELAVL1 expression, while elevated ELAVL1 levels were observed in tumor tissues. Notably, exposed to smoking carcinogen 4-ABP resulted in a markedly increased expression of ELAVL1, which inhibited senescence of bladder cancer cells. Mechanistically, 4-ABP upregulated ELAVL1 suppressed cell senescence through autophagy activation, thus promoting bladder cancer progression. This study elucidated the genetic susceptibility and biological function of ELAVL1 in tobacco smoking exposure cell models, shedding light on the etiology of bladder cancer.