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PAX2 mediated upregulation of ESPL1 contributes to cisplatin resistance in bladder cancer through activating the JAK2/STAT3 pathway

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Abstract

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.

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Acknowledgements

We appreciate all the members involved in this study.

Funding

This study was supported by grants from the Hospital National Natural Science Foundation Booster Fund (No. 2021ZTXM027) and National Natural Science Foundation of China (No. 82002687).

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Author notes

  1. Wei Zhang, Yong Wang and Qisheng Tang contributed equally to this work.

Authors and Affiliations

  1. Department of Urology, Tangdu Hospital, the Air Force Medical University, 1 Xinsi Road, Baqiao District, Xi’an, 710038, Shannxi Province, China

    Wei Zhang, Yong Wang, Qisheng Tang, Zhenyu Li, Zhiguang Zhao & Dian Jiao

  2. 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

    Jinbo Sun

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  1. Wei Zhang
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  2. Yong Wang
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  4. Zhenyu Li
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  5. Jinbo Sun
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  6. Zhiguang Zhao
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All authors contributed to data analysis, drafting, and revising the article; gave final approval of the version to be published; and agreed to be accountable for all aspects of the work. All authors contributed to the article and approved the submitted version. The authors declare that all data were generated in-house and that no paper mill was used.

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Correspondence to Jinbo Sun, Zhiguang Zhao or Dian Jiao.

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Zhang, W., Wang, Y., Tang, Q. et al. PAX2 mediated upregulation of ESPL1 contributes to cisplatin resistance in bladder cancer through activating the JAK2/STAT3 pathway. Naunyn-Schmiedeberg's Arch Pharmacol (2024). https://doi.org/10.1007/s00210-024-03061-3

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