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Cellular and Molecular Biology

ITGB4 up-regulated by STAT3 reduces the sensitivity of bladder cancer to cisplatin by suppressing p53

British Journal of Cancer (2026)Cite this article

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Abstract

Background

Cisplatin-based chemotherapy is the first-line treatment for patients with advanced bladder cancer (BC). However, the development of cisplatin resistance limits its antitumor effects. While, the mechanism of cisplatin resistance remains unclear.

Methods

Bioinformatics techniques were used to analyse genes and pathways associated with cisplatin therapy resistance. A variety of biological techniques were used to identify the role of ITGB4 in cisplatin sensitivity in BC and its potential molecular mechanism.

Results

In this study, we demonstrated that ITGB4 plays a key role in regulating the sensitivity of p53 wild-type (WT) BC to cisplatin therapy. Our findings revealed that ITGB4 inhibits the activation of p53 by suppressing the phosphorylation at the p53-S15 site and promotes the degradation of p53 by facilitating the binding of MDM2 to p53, thereby reducing the sensitivity of BC to cisplatin.Additionally, we showed that ITGB4 influences the antitumor effects of MDM2 inhibitors when they are combined with cisplatin therapy. Furthermore, we found that the elevated expression of ITGB4 in cisplatin-resistant BC cells were mediated by STAT3 activation. The combination of STAT3 inhibitors can enhance the antitumor effect of cisplatin in BC.

Conclusions

ITGB4 is a key molecule influencing cisplatin sensitivity in p53 WT BC, and the combination of STAT3 inhibitors can enhance the antitumor effect of cisplatin.

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Fig. 1: ITGB4 plays a key role in regulating the sensitivity of p53 wild-type bladder cancer to cisplatin therapy.
Fig. 2: ITGB4 regulates p53-related pathways and binds to p53.
Fig. 3: ITGB4 regulates bladder cancer sensitivity to cisplatin through p53.
Fig. 4: ITGB4 inhibits the phosphorylation of p53-S15 and promotes the binding of MDM2 to p53.
Fig. 5: ITGB4 regulates the anti-bladder cancer effect of MDM2 inhibitors combined with cisplatin.
Fig. 6: STAT3 up-regulates ITGB4 expression in bladder cancer, and STAT3 inhibitors enhance the sensitivity of bladder cancer to cisplatin.

Data availability

The datasets used and/or analysed during the current study are available from the corresponding authors upon reasonable request.

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Acknowledgements

The authors are grateful for the data provided by TCGA and GEO dataset participants and researchers.

Funding

This study was supported by the Chinese National Natural Science Foundation (Grant No. 82373435 (YL), 82172878 (YL)); The Science and Technology Innovation Program of Hunan Province (Grant No. 2025RC1020 (YL)); Leading Talents Project of Henan Provincial Health Commission (Grant No. YXKC2022007 (TY)), Supporting Project of Henan Cancer Hospital, China National Clinical Key Specialty Construction Project (Grant No. YBW0013 (TY)); Medical Innovation Project of Fujian Province (2025CXB001, WYB); Natural Science Foundation of Fujian Province(2025J01067, WYB).

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Author notes

  1. These authors contributed equally: Zhuo Xing, Haozhe Xu, Pingxia Lin.

Authors and Affiliations

  1. Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, China

    Zhuo Xing, Haozhe Xu, Pingxia Lin, Yulong Hong, Shuai Shao & Yuan Li

  2. The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China

    Tiejun Yang

  3. Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China

    Yongbao Wei

  4. Department of Urology, Fuzhou University Affiliated Provincial Hospital, Fuzhou, China

    Yongbao Wei

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  1. Zhuo Xing
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  4. Yulong Hong
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Contributions

Z Xin: methodology; H Xu: methodology; P Lin: methodology; Y Hong: methodology; S Shao: investigation; T Yang: conceptualisation; Y Li: investigation, project administration; Y Wei: project administration.

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Correspondence to Tiejun Yang, Yuan Li or Yongbao Wei.

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Xing, Z., Xu, H., Lin, P. et al. ITGB4 up-regulated by STAT3 reduces the sensitivity of bladder cancer to cisplatin by suppressing p53. Br J Cancer (2026). https://doi.org/10.1038/s41416-026-03364-7

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