Department of Urology and Pediatric Urology, University Medical Center Bonn (UKB), Venusberg-Campus 1, 53127, Bonn, Germany.
Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
Sci Rep. 2023 Jan 2;13(1):73. doi: 10.1038/s41598-022-26579-z.
The prognosis of patients with advanced urothelial carcinoma (UC) remains poor and improving treatment continues to be a major medical need. CUB domain containing protein 1 (CDCP1) is a known oncogene in various types of solid cancers and its overexpression is associated with impaired prognosis. However, its role in UC remains undetermined. Here we assessed the clinical relevance of CDCP1 in two cohorts of UC at different stages of the disease. Immunohistochemistry showed that CDCP1 is highly expressed in advanced UC, which significantly correlates with shorter overall survival. Importantly, the basal/squamous UC subtype showed significantly enriched CDCP1 at the mRNA and protein levels. The functional role of CDCP1 overexpression was assessed taking advantage of ex vivo organoids derived from the CDCP1 transgenic mouse model. Furthermore, CDCP1 knockout UC cell lines were generated using CRISPR/Cas9 technology. Interestingly, CDCP1 overexpression significantly induced the activation of MAPK/ERK pathways in ex vivo organoids and increased their proliferation. Similarly, CDCP1 knockout in UC cell lines reduced their proliferation and migration, concomitant with MAPK/ERK pathway activity reduction. Our results highlight the relevance of CDCP1 in advanced UC and demonstrate its oncogenic role, suggesting that targeting CDCP1 could be a rational therapeutic strategy for the treatment of advanced UC.
晚期尿路上皮癌（UC）患者的预后仍然较差，改善治疗方法仍然是一个主要的医学需求。CUB 结构域包含蛋白 1（CDCP1）是各种实体癌中的一种已知癌基因，其过表达与预后不良有关。然而，其在 UC 中的作用仍未确定。在这里，我们在两个不同疾病阶段的 UC 队列中评估了 CDCP1 的临床相关性。免疫组织化学显示 CDCP1 在晚期 UC 中高度表达，与总生存期缩短显著相关。重要的是，基底/鳞状 UC 亚型在 mRNA 和蛋白水平上均显示出 CDCP1 的明显富集。利用源自 CDCP1 转基因小鼠模型的体外类器官评估了 CDCP1 过表达的功能作用。此外，还使用 CRISPR/Cas9 技术生成了 CDCP1 敲除 UC 细胞系。有趣的是，CDCP1 过表达在体外类器官中显著诱导了 MAPK/ERK 通路的激活，增加了它们的增殖。同样，UC 细胞系中 CDCP1 的敲除降低了它们的增殖和迁移，同时降低了 MAPK/ERK 通路的活性。我们的研究结果强调了 CDCP1 在晚期 UC 中的相关性，并证明了其致癌作用，提示靶向 CDCP1 可能是治疗晚期 UC 的一种合理的治疗策略。
