State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou, China.
Cell Prolif. 2022 Dec;55(12):e13325. doi: 10.1111/cpr.13325. Epub 2022 Aug 26.
Bladder cancer (BC) is one of the most common malignant cancers, with poor prognosis and high incidence. Cisplatin is the standard chemotherapy for muscle invasive bladder cancer; however, chemotherapy resistance remains a major challenge. Moreover, oncogenic signalling and the specific mechanisms underlying cisplatin resistance in BC remain largely unclear METHODS: In this study, RT-PCR, Western blot, immunofluorescence, and immunohistochemistry were used to measure gene and protein expression. Colony formation assay and flow cytometry were performed to evaluate the proliferation of BC cells. Gene set enrichment analysis was performed to identify the function in which ZBTB11 was involved. Luciferase and chromatin immunoprecipitation experiments were performed to determine the transcriptional regulation mechanism of ZBTB11. The effects of ZBTB11 on the malignant phenotypes of BC cells were examined in vitro and in vivo RESULTS: The results showed that ZBTB11 was remarkably upregulated in BC tissues, which was associated with poor prognosis in patients with BC. Furthermore, we found that knockdown of ZBTB11 remarkably inhibited the proliferation and tumorigenesis of BC cells by inducing apoptosis. Mechanistically, the knockdown of ZBTB11 transcriptionally inhibited DDX1 to suppress R-loop clearance, resulting in DNA damage in BC cells. Importantly, the ZBTB11/DDX1 axis is required for the chemotherapy resistance of BC cells to cisplatin CONCLUSION: Our findings not only reveal an underlying mechanism by which the ZBTB11/DDX1 axis promotes the tumorigenesis of BC but also provide a potential target for a combination strategy of cisplatin-based chemotherapy for BC.
膀胱癌（BC）是最常见的恶性肿瘤之一，预后不良，发病率高。顺铂是肌层浸润性膀胱癌的标准化疗药物；然而，化疗耐药仍然是一个主要挑战。此外，致癌信号和 BC 中顺铂耐药的具体机制在很大程度上仍不清楚。
在这项研究中，使用 RT-PCR、Western blot、免疫荧光和免疫组织化学来测量基因和蛋白表达。通过集落形成实验和流式细胞术评估 BC 细胞的增殖。进行基因集富集分析以确定 ZBTB11 参与的功能。进行荧光素酶和染色质免疫沉淀实验以确定 ZBTB11 的转录调控机制。在体外和体内研究 ZBTB11 对 BC 细胞恶性表型的影响。
结果表明，ZBTB11 在 BC 组织中显著上调，与 BC 患者的预后不良相关。此外，我们发现，通过诱导细胞凋亡，ZBTB11 的敲低显著抑制了 BC 细胞的增殖和肿瘤发生。
从机制上讲，ZBTB11 转录抑制 DDX1 以抑制 R 环清除，导致 BC 细胞中的 DNA 损伤。重要的是，ZBTB11/DDX1 轴是 BC 细胞对顺铂化疗耐药所必需的。
我们的研究结果不仅揭示了 ZBTB11/DDX1 轴促进 BC 肿瘤发生的潜在机制，还为基于顺铂的化疗联合治疗 BC 提供了一个潜在的靶点。
