Androgen receptor expands the population of
Cancer stem cells in upper urinary tract urothelial carcinoma cells
Chi-Cheng Chen1,2, Teng-Fu Hsieh1,2, Chi-Ping Huang1, and Chih-Rong Shyr1
1Sex Hormone Research Center, Departments of Urology/Surgery and Medical
Technology, Graduate Institute of Clinical Medical Science, China Medical
University/Hospital, Taichung, Taiwan
2Department of Urology, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical
Foundation, Taichung, Taiwan
Purpose: Androgen receptor (AR) plays a role in the development and progression of upper
urinary tract urothelial cell carcinoma (UUTUC). Here we investigated whether AR stimulates 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.
Materials and Methods: We compared BFTC 909 cells with or without the addition of AR on their CSC population with flow cytometry, colony formation and sphere formation assay to
determine the effects of AR on CSC activity. To observe the effects of AR on BFTC 909 cells, quantitative real-time PCR was used to detect the expression stemness genes and miRNAs and western blotting was also performed to examine EMT (epithelial-mesenchymal transition) related proteins. In vivo tumor formation was also evaluated with the implantation of cancer cells in nude mice and IHC was used to detect OCT4 and MMP9 expression on the tumor samples.
Results: We found that the addition of AR in UUTUC cells, (BFTC 909 cell line) significantly
increased the population of CSC, clonogenicity, sphere formation and the expression of stemness genes (Oct4, Bmi1 and Nanog) and CSC-related miRNA profile as well as EMT related proteins. Furthermore, in an immune-deficient mouse model, the addition of AR in UUTUC cells also increased the tumor formation.
Conclusions: This study will help us better understand the extent to which AR contributes to
UUTUC by expanding their CSC population and capacity and could explain high incidence of UUTUC observed in males. These findings may lead AR to serve as a potential therapeutic target for urothelial carcinomas in the future.