ITGB4 up-regulated by STAT3 reduces the sensitivity of bladder cancer to cisplatin by suppressing p53
Menée à l'aide de lignées cellulaires et de modèles murins de cancer de la vessie, cette étude met en évidence un mécanisme par lequel la surexpression de la sous-unité bêta 4 de l'intégrine, induite par l'activateur de transcription STAT3, réduit la sensibilité des cellules cancéreuses au cisplatine en inhibant l'activation de la protéine p53 et en favorisant sa dégradation
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.
British Journal of Cancer , article en libre accès, 2026