Cytotoxic necrotizing factor 1 promotes bladder cancer angiogenesis through activating RhoC.

Uropathogenic Escherichia coli (UPEC), a leading cause of urinary tract infections, is associated with prostate and bladder cancers. Cytotoxic necrotizing factor 1 (CNF1) is a key UPEC toxin; however, its role in bladder cancer is unknown. In the present study, we found CNF1 induced bladder cancer cells to secrete vascular endothelial growth factor (VEGF) through activating Ras homolog family member C (RhoC), leading to subsequent angiogenesis in the bladder cancer microenvironment. We then investigated that CNF1-mediated RhoC activation modulated the stabilization of hypoxia-inducible factor 1 alpha (HIF1 alpha) to upregulate the VEGF. We demonstrated in vitro that active RhoC increased heat shock factor 1 (HSF1) phosphorylation, which induced the heat shock protein 90 alpha (HSP90 alpha) expression, leading to stabilization of HIF1 alpha. Active RhoC elevated HSP90 alpha, HIF1 alpha, VEGF expression, and angiogenesis in the human bladder cancer xenografts. In addition, HSP90 alpha, HIF1 alpha, and VEGF expression were also found positively correlated with the human bladder cancer development. These results provide a potential mechanism through which UPEC contributes to bladder cancer progression, and may provide potential therapeutic targets for bladder cancer.