化疗耐药是膀胱癌治疗失败的一个重要原因，识别赋予耐药性的基因是开发新的治疗策略以改善治疗结果的重要一步。在本研究中，我们发现吉西他滨联合顺铂 (GEM/DDP) 疗法可诱导 NF-κB 信号传导，从而促进 p65 介导的 OIP5 转录激活。 OIP5 招募 E3 泛素连接酶 TRIP12 结合并降解磷酸酶 PPP1CB，从而增强 YBX1 的转录因子活性。这反过来又在 YBX1 转录控制下上调耐药相关基因，导致化疗耐药。此外，PPP1CB降解可以增强IKKβ的磷酸化活性，触发NF-κB信号级联，进一步刺激OIP5基因表达，从而形成负反馈调节环。一致地，OIP5 表达升高与膀胱癌患者的化疗耐药和不良预后相关。此外，我们使用基于 CRISPR/Cas9 的工程基因电路，可以实时监测化疗耐药的进展，在检测到 NF-κB 信号传导增加时诱导 OIP5 敲除。该基因回路显着抑制体内肿瘤细胞生长，强调了基因疗法和化疗在癌症治疗中协同作用的潜力。© 2024。作者，获得 Springer Nature Limited 的独家许可。

Chemoresistance is an important cause of treatment failure in bladder cancer, and identifying genes that confer drug resistance is an important step toward developing new therapeutic strategies to improve treatment outcomes. In the present study, we show that gemcitabine plus cisplatin (GEM/DDP) therapy induces NF-κB signaling, which promotes p65-mediated transcriptional activation of OIP5. OIP5 recruits the E3 ubiquitin ligase TRIP12 to bind to and degrade the phosphatase PPP1CB, thereby enhancing the transcription factor activity of YBX1. This in turn upregulates drug-resistance-related genes under the transcriptional control of YBX1, leading to chemoresistance. Moreover, PPP1CB degradation can enhance the phosphorylation activity of IKKβ, triggering the NF-κB signaling cascade, which further stimulates OIP5 gene expression, thus forming a negative feedback regulatory loop. Consistently, elevated OIP5 expression was associated with chemoresistance and poor prognosis in patients with bladder cancer. Furthermore, we used a CRISPR/Cas9-based engineered gene circuit, which can monitor the progression of chemoresistance in real-time, to induce OIP5 knockout upon detection of increased NF-κB signaling. The gene circuit significantly inhibited tumor cell growth in vivo, underscoring the potential for synergy between gene therapy and chemotherapy in the treatment of cancer.© 2024. The Author(s), under exclusive licence to Springer Nature Limited.