Wu Feixiang, Wu Shasha, Huang Yu, Xiao Xiao, Yu Haitao, Bai Xuesong, Zhang Chunlin, Feng Zhenwei, Li Li, Mei Yuhua, Li Xinyuan, Gou Xin
Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Department of Urology, The Third Hospital of Mianyang, Sichuan Mental Health Center, Mianyang, Sichuan, China.
J Transl Med. 2025 Jul 11;23(1):785. doi: 10.1186/s12967-025-06835-2.
Smoking is a well-established risk factor for bladder cancer; however, the molecular mechanisms underlying this association remain unclear. This study aimed to elucidate the link between smoking and bladder cancer and identify the molecular mechanisms by which smoking promotes tumor progression.
The relationships between smoking and bladder cancer were assessed with cross-sectional analyses and Mendelian randomization (MR) analyses. Bioinformatics analyses were conducted to identify the key genes involved in smoking-induced bladder cancer progression. Following treatment of bladder cancer cells with cigarette smoke extract (CSE), the effects of CKAP2L on proliferation and metastasis were evaluated using in vitro proliferation, migration, and invasion assays, as well as an in vivo subcutaneous tumor model. FOXM1 binding to the CKAP2L promoter was determined by chromatin immunoprecipitation (ChIP) assay.
Both cross-sectional and MR analyses confirmed the positive relationship between smoking and bladder cancer. Functional experiments revealed that CSE treatment promoted the proliferation and metastasis of bladder cancer cells. CKAP2L was identified as a key gene by bioinformatics analyses, and its expression was upregulated by CSE treatment. Additionally, CKAP2L knockdown inhibited cell proliferation, migration, and invasion; arrested the cell cycle at the S and G2/M phases; and regulated the expression of related proteins. Overexpression of CKAP2L exhibited the opposite results. The ChIP‒qPCR assay confirmed significant binding of FOXM1 to the CKAP2L promoter.
Smoking promoted bladder cancer progression by upregulating CKAP2L and FOXM1, which drive tumor progression via cell cycle regulation. This identifies the FOXM1/CKAP2L axis as a mechanism by which smoking facilitates bladder cancer progression.
吸烟是膀胱癌公认的危险因素；然而，这种关联背后的分子机制仍不清楚。本研究旨在阐明吸烟与膀胱癌之间的联系，并确定吸烟促进肿瘤进展的分子机制。
采用横断面分析和孟德尔随机化（MR）分析评估吸烟与膀胱癌之间的关系。进行生物信息学分析以确定参与吸烟诱导的膀胱癌进展的关键基因。用香烟烟雾提取物（CSE）处理膀胱癌细胞后，使用体外增殖、迁移和侵袭试验以及体内皮下肿瘤模型评估CKAP2L对增殖和转移的影响。通过染色质免疫沉淀（ChIP）试验确定FOXM1与CKAP2L启动子的结合。
横断面分析和MR分析均证实吸烟与膀胱癌之间存在正相关。功能实验表明，CSE处理促进了膀胱癌细胞的增殖和转移。生物信息学分析确定CKAP2L为关键基因，CSE处理上调了其表达。此外，CKAP2L敲低抑制细胞增殖、迁移和侵袭；使细胞周期停滞在S期和G2/M期；并调节相关蛋白的表达。CKAP2L过表达则表现出相反的结果。ChIP-qPCR试验证实FOXM1与CKAP2L启动子有显著结合。
吸烟通过上调CKAP2L和FOXM1促进膀胱癌进展，它们通过细胞周期调控驱动肿瘤进展。这确定了FOXM1/CKAP2L轴是吸烟促进膀胱癌进展的一种机制。
