Department of Urology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University, Nijmegen, the Netherlands.
Mol Oncol. 2021 Jul;15(7):1882-1900. doi: 10.1002/1878-0261.12957. Epub 2021 May 22.
Bladder urothelial cell carcinoma (UCC) incidence is about three times higher in men compared with women. There are several indications for the involvement of hormonal factors in the aetiology of UCC. Here, we provide evidence of androgen signalling in UCC progression. Microarray and qPCR analysis revealed that the androgen receptor (AR) mRNA level is upregulated in a subset of UCC cases. In an AR-positive UCC-derived cell line model, UM-UC-3-AR, androgen treatment increased clonogenic capacity inducing the formation of big stem cell-like holoclones, while AR knockdown or treatment with the AR antagonist enzalutamide abrogated this clonogenic advantage. Additionally, blockage of AR signalling reduced the cell migration potential of androgen-stimulated UM-UC-3-AR cells. These phenotypic changes were accompanied by a rewiring of the transcriptome with almost 300 genes being differentially regulated by androgens, some of which correlated with AR expression in UCC patients in two independent data sets. Our results demonstrate that AR signals in UCC favouring the development of an aggressive phenotype and highlights its potential as a therapeutic target for bladder cancer.
膀胱癌尿路上皮细胞癌 (UCC) 的发病率男性比女性高约三倍。有几种迹象表明，荷尔蒙因素在 UCC 的发病机制中起作用。在这里，我们提供了雄激素信号在 UCC 进展中的证据。微阵列和 qPCR 分析显示，雄激素受体 (AR) mRNA 水平在一部分 UCC 病例中上调。在 AR 阳性的 UCC 衍生细胞系模型 UM-UC-3-AR 中，雄激素处理增加了集落形成能力，诱导形成大的干细胞样合胞体，而 AR 敲低或用 AR 拮抗剂恩杂鲁胺处理则消除了这种集落形成优势。此外，阻断 AR 信号降低了雄激素刺激的 UM-UC-3-AR 细胞的迁移能力。这些表型变化伴随着转录组的重布线，将近 300 个基因受到雄激素的差异调节，其中一些基因与两个独立数据集的 UCC 患者的 AR 表达相关。我们的研究结果表明，AR 在 UCC 中的信号有利于侵袭性表型的发展，并突出了其作为膀胱癌治疗靶点的潜力。
