Department of Urology, Tangdu Hospital, the Air Force Medical University, 1 Xinsi Road, Baqiao District, Xi'an, 710038, Shannxi Province, China.
Department of Urology, General Hospital of Central Theater Command of Chinese People's Liberation Army, 627 Wuluo Road, Wuchang District, Wuhan, 430070, Hubei Province, China.
Naunyn Schmiedebergs Arch Pharmacol. 2024 Sep;397(9):6889-6901. doi: 10.1007/s00210-024-03061-3. Epub 2024 Apr 4.
Extra spindle-polar body like 1 (ESPL1) is associated with the development of a variety of cancers, including bladder cancer, and is closely related to chemoresistance. In this study, we aimed to reveal the role of ESPL1 in bladder cancer progression and cisplatin (DDP) resistance. First, ESPL1 was found to be highly expressed in tumor tissues and cells of bladder cancer, and more highly expressed in cisplatin resistant tumor tissues or cells. The binding of PAX2 in ESPL1 promoter region was predicted by Jaspar database and verified by Ch-IP analysis and the luciferase reporter gene assay. Next, cisplatin-resistant T24 cells (T24/DDP) were established and transfected with ESPL1 siRNA (si-ESPL1) or overexpression vector (pcDNA-ESPL1) or co-transfected with PAX2 siRNA (si-PAX2) or overexpression vector (pcDNA-PAX2), and then treated with DDP or AG490, an inhibitor of JAK2. The results showed that silencing ESPL1 significantly reduced T24/DDP cell viability, colony formation and invasion, enhanced sensitivity to DDP, and induced cell apoptosis. Silencing PAX2 decreased ESPL1 expression, enhanced sensitivity to DDP, and induced apoptosis of T24/DDP cells, and inhibited activation of JAK2/STAT3 pathway. Overexpressing ESPL1 reversed the effect of PAX2 silencing on T24/DDP cells, while AG490 counteracted the reversal effect of overexpressing ESPL1. Finally, a xenograft tumor model was established and found that silencing ESPL1 or DDP treatment inhibited tumor growth, while silencing ESPL1 combined with DDP treatment had the best effect. In summary, this study suggested that PAX2-mediated ESPL1 transcriptional activation enhanced cisplatin resistance in bladder cancer by activating JAK2/STAT3 pathway.
额外纺锤极体 1 (ESPL1) 与多种癌症的发展有关，包括膀胱癌，并且与化疗耐药密切相关。在这项研究中，我们旨在揭示 ESPL1 在膀胱癌进展和顺铂（DDP）耐药中的作用。首先，发现 ESPL1 在膀胱癌组织和细胞中高度表达，并且在顺铂耐药的肿瘤组织或细胞中表达更高。Jaspar 数据库预测 PAX2 结合在 ESPL1 启动子区域，并通过 Ch-IP 分析和荧光素酶报告基因检测验证。接下来，建立顺铂耐药 T24 细胞（T24/DDP），并转染 ESPL1 siRNA（si-ESPL1）或过表达载体（pcDNA-ESPL1）或共转染 PAX2 siRNA（si-PAX2）或过表达载体（pcDNA-PAX2），然后用 DDP 或 JAK2 抑制剂 AG490 处理。结果表明，沉默 ESPL1 显著降低 T24/DDP 细胞活力、集落形成和侵袭能力，增强 DDP 敏感性，并诱导细胞凋亡。沉默 PAX2 降低 ESPL1 表达，增强 T24/DDP 细胞对 DDP 的敏感性，并诱导细胞凋亡，抑制 JAK2/STAT3 通路的激活。过表达 ESPL1 逆转了 PAX2 沉默对 T24/DDP 细胞的影响，而 AG490 拮抗了过表达 ESPL1 的逆转作用。最后，建立了异种移植肿瘤模型，发现沉默 ESPL1 或 DDP 处理抑制肿瘤生长，而沉默 ESPL1 联合 DDP 处理效果最佳。总之，本研究表明 PAX2 介导的 ESPL1 转录激活通过激活 JAK2/STAT3 通路增强了膀胱癌对顺铂的耐药性。
