Bladder urothelial cell carcinoma (UCC) incidence is about three times higher in men compared to 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.
Molecular oncology. 2021 Apr 02 [Epub ahead of print]
Maria V Luna-Velez, Jelmer J Dijkstra, Marina A Heuschkel, Frank P Smit, Guillaume van de Zande, Dominique Smeets, J P Michiel Sedelaar, Michiel Vermeulen, Gerald W Verhaegh, Jack A Schalken
Department of Urology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, the Netherlands., Department of Molecular Biology, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen, the Netherlands., MDxHealth, Nijmegen, the Netherlands., Department of Genetics, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, the Netherlands.