title: Androgen receptor expands the population of cancer stem cells in upper urinary tract urothelial cell carcinoma cells.
abstract: Androgen receptor (AR) affects the development and progression of upper urinary tract urothelial cell carcinoma (UUTUC). However, the regulatory mechanism exerted by AR to affect UUTUC cells remains unclear. Here we investigated whether AR promotes UUTUC development and progression, possibly by expanding the population of cancer stem cells (CSCs), which are a particular population of cells within cancer cells responsible for tumor initiation, drug resistance and metastasis. We compared UUTUC cells with or without the addition of AR on their CSC population with flow cytometry, colony formation and sphere formation assay to determine the effect of AR on CSC activity, and real-time PCR was used to detect the expression stemness genes and miRNAs. In vivo tumor formation was evaluated with the implantation of cancer cells in nude mice. We found that the addition of AR in UUTUC cells, significantly increased the population of CSC, clonogenicity, sphere formation and the expression of stemness genes (Oct4, Bmi1 and Nanog), altered CSC-related miRNA profile, as well as promoted epithelial mesenchymal transition (EMT). And AR inhibitor, enzalutamide was shown to suppress AR's effect on tumorsphere formation. Furthermore, in an immune-deficient mouse model, the addition of AR in UUTUC cells also increased the tumor formation capacity. This study will help us better understand the extent to which AR contributes to UUTUC progression by expanding their CSC population and capacity. Our findings could explain high incidence of UUTUC observed in males. And targeting AR may lead to novel therapeutic approaches for genetically diversified urothelial carcinomas in precision medicine era.
authors.affiliation: Sex Hormone Research Center, Departments of Urology/Surgery and Medical Laboratory Science and Biotechnology, Graduate Institute of Clinical Medical Science, China Medical University/HospitalTaichung 404, Taiwan; Department of Urology, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical FoundationTaichung 404, Taiwan.
authors.forename: Chi-Cheng
authors.initials: CC
authors.lastname: Chen
authors.affiliation: Sex Hormone Research Center, Departments of Urology/Surgery and Medical Laboratory Science and Biotechnology, Graduate Institute of Clinical Medical Science, China Medical University/HospitalTaichung 404, Taiwan; Department of Urology, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical FoundationTaichung 404, Taiwan.
authors.forename: Teng-Fu
authors.initials: TF
authors.lastname: Hsieh
authors.affiliation: Sex Hormone Research Center, Departments of Urology/Surgery and Medical Laboratory Science and Biotechnology, Graduate Institute of Clinical Medical Science, China Medical University/Hospital Taichung 404, Taiwan.
authors.forename: Chi-Ping
authors.initials: CP
authors.lastname: Huang
authors.affiliation: Sex Hormone Research Center, Departments of Urology/Surgery and Medical Laboratory Science and Biotechnology, Graduate Institute of Clinical Medical Science, China Medical University/Hospital Taichung 404, Taiwan.
authors.forename: Ai-Lin
authors.initials: AL
authors.lastname: Yu
authors.affiliation: Sex Hormone Research Center, Departments of Urology/Surgery and Medical Laboratory Science and Biotechnology, Graduate Institute of Clinical Medical Science, China Medical University/Hospital Taichung 404, Taiwan.
authors.forename: Wen-Lin
authors.initials: WL
authors.lastname: Chang
authors.affiliation: Sex Hormone Research Center, Departments of Urology/Surgery and Medical Laboratory Science and Biotechnology, Graduate Institute of Clinical Medical Science, China Medical University/Hospital Taichung 404, Taiwan.
authors.forename: Chih-Rong
authors.initials: CR
authors.lastname: Shyr
keywords: Androgen receptor; cancer stem cells; tumorsphere; upper urinary tract urothelial cell carcinoma