Pu Qiuyi, Gao Fang, Xiao Yanping, Wu Jiajin, Wang Chao, Mo Xiaoxiao, Zhang Zhengdong, Zheng Rui, Wu Dongmei
Departments of Environmental Genomics and Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health; Institute of Clinical Research, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Nanjing, China.
Department of Urology, The Third Affiliated Hospital of Nanjing Medical University (Changzhou Second People's Hospital), Changzhou, China.
Toxicology. 2025 Sep;516:154193. doi: 10.1016/j.tox.2025.154193. Epub 2025 May 14.
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 1101 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.
吸烟是膀胱癌公认的危险因素，在各种疾病中显示出与细胞衰老的关联。然而，吸烟暴露与膀胱癌衰老调节之间的调控机制仍未完全明确。在本研究中，我们证明吸烟致癌物4-氨基联苯（4-ABP）抑制细胞衰老，同时增强膀胱癌细胞的增殖、侵袭和迁移能力，SA-β-半乳糖苷酶染色、蛋白质免疫印迹和细胞恶性表型实验证实了这一点。我们基于CellAge数据库、南京膀胱癌数据集和公共数据库，进一步鉴定出275个膀胱癌特异性细胞衰老相关基因。通过对580例膀胱癌病例和1101例对照进行全基因组关联研究，我们确定ELAVL1基因中的rs12978895 G>A与膀胱癌风险降低显著相关（优势比=0.79，95%置信区间=0.68-0.92），且与吸烟存在相互作用（P=0.043）。在基因调控方面，实验研究和人群研究均表明，rs12978895的A等位基因显著降低ELAVL1表达，而在肿瘤组织中观察到ELAVL1水平升高。值得注意的是，暴露于吸烟致癌物4-ABP会导致ELAVL1表达明显增加，从而抑制膀胱癌细胞衰老。机制上，4-ABP上调的ELAVL1通过激活自噬抑制细胞衰老，从而促进膀胱癌进展。本研究阐明了ELAVL1在吸烟暴露细胞模型中的遗传易感性和生物学功能，为膀胱癌的病因学研究提供了线索。
