The Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
Department of Urology, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.
Nat Rev Urol. 2018 Jun;15(6):345-357. doi: 10.1038/s41585-018-0005-1.
The Notch pathway has been implicated in both oncogenic and tumour-suppressive roles in cancer depending on the tissue type and cellular context. However, until recently, little was known about the pathway in bladder cancer. Studies have revealed that NOTCH1 copy number and expression are decreased in bladder cancer and NOTCH1 activation in bladder cancer cell lines reduces proliferation, suggesting that NOTCH1 acts as a tumour suppressor. Furthermore, in transgenic models, bladder cancer is promoted by bladder-specific inactivation of a component of the γ-secretase complex, which liberates the intracellular domain of neurogenic locus Notch homologue protein (NOTCH) and starts the signalling cascade. By contrast, further work has demonstrated that NOTCH2 acts as an oncogene that promotes cell proliferation and metastasis through epithelial-to-mesenchymal transition, cell cycle progression, and maintenance of stemness. Studies indicating that NOTCH1 and NOTCH2 have opposite effects on the progression of bladder cancer could give rise to potential therapeutic approaches aimed at blocking or restoring the Notch pathway.
Notch 通路在癌症中具有致癌和肿瘤抑制作用，但其具体作用取决于组织类型和细胞环境。然而，直到最近，人们对膀胱癌中的该通路知之甚少。研究表明，膀胱癌中 Notch1 的拷贝数和表达减少，而 Notch1 在膀胱癌细胞系中的激活可降低增殖，表明 Notch1 起肿瘤抑制因子的作用。此外，在转基因模型中，通过膀胱特异性失活 γ-分泌酶复合物的一个组成部分促进膀胱癌，该复合物释放神经源性基因座 Notch 同源蛋白 (NOTCH) 的细胞内结构域并启动信号级联。相比之下，进一步的研究表明，NOTCH2 作为一种癌基因，通过上皮-间充质转化、细胞周期进程和干细胞特性的维持促进细胞增殖和转移。表明 Notch1 和 Notch2 对膀胱癌进展具有相反影响的研究可能为靶向阻断或恢复 Notch 通路提供潜在的治疗方法。
