Ectopic WWOX Expression Inhibits Growth of 5637 Bladder Cancer Cell In Vitro and In Vivo.

WW domain-containing oxidoreductase (WWOX) gene located in the common fragile site FRA16D region exhibits loss or reduction of expression in multiple types of carcinomas including bladder cancer. However, the role of WWOX in the tumorigenesis and development of bladder cancer remains elusive. In this study, WWOX overexpression construct was transfected into 5637 bladder cancer cell line in which WWOX expression was compromised. Constitutive expression of ectopic WWOX in 5637 cells suppressed cell proliferation and cell cycle progression, which was associated with downregulation of Cyclin B, D1, and E. Moreover, WWOX overexpression promoted apoptosis in 5637 cells and resulted in upregulation of Bax, downregulation of Bcl-2, and elevated levels of cleaved caspase-3 and cleaved PARP, indicating activation of the intrinsic apoptosis pathway. Furthermore, WWOX overexpression suppressed tumorigenicity of 5637 cells and promoted apoptosis in the xenograft tumors as demonstrated in a xenograft mouse model. In summary, our data indicate that WWOX plays a critical role in the regulation of proliferation, cell cycle, apoptosis, and tumorigenesis of bladder cancer cells, suggesting that WWOX may have potential clinical implications in bladder cancer therapy.