The Role And Mechanisms Of Androgen Receptor In Invasion And Metastasis Of Bladder Cancer

Objectives: To investigate the role and mechanism of androgen and androgenreceptor in the invasion and metastasis of bladder cancer.Methods: To observe the changes of epithelial-mesenchymal transition (EMT)associated markers and invasive ability of bladder cancer cells which are either ARoverexpressed or AR knockdown. To study the mechanism of EMT induced by AR inbladder cancer cells with Dual luciferase reporter gene assay and confocal microscopy.To detect the expression of AR and EMT associated proteins in human bladder cancertissues. To study the role of androgen and AR on bladder cancer invasion in vivousing nude mouse model with AR overexpressed stable cell line.Results: Androgen induces EMT and promotes the invasive ability in AR positivebladder cancer cell lines, and this effect can be interrupted by flutamide (an antagonistof AR). Androgen upregulates the expression of ETM associated transcriptional factorslug and activates Wnt pathway. Compared to the tumors established with parental5637cells, the tumors established with AR overexpressed stable cell line5637-ARgrow faster and exhibite more tendency of invasion and lymphoid metastasis. Noobvious relation is established between AR and prognosis or tumor grade in humanbladder cancer tissues, however, there is a positive relation between high expressionofAR and low expression of E-cadherin or high expression of slug.Conclusion: AR signal pathway plays an important role in bladder cancer invasionand metastasis. The major mechanism is that AR activates Wnt/β-catenin pathway,leading to upregulation of slug, which in the end promotes EMT of bladder cancercells. These results, for the first time, reveal the important role of AR pathway in the invasion and metastasis of bladder cancer both in vitro and in vivo, and provide newtargets to battle the invasion and metastasis of bladder cancer.