Inducible Nitric Oxide Synthase and PPARγ are Involved in Bladder Cancer Progression

Abstract

Purpose: We evaluated the role of inducible nitric oxide synthase and PPARgamma as prognostic factors for bladder cancer. Materials and Methods: Inducible nitric oxide synthase and PPAR were evaluated by Western blot and immunohistochemistry in a mouse bladder cancer model of nonmuscle invasive and invasive MB49-I tumor cells, and in human bladder cancer samples. Results: Inducible nitric oxide synthase expression was negative in mouse normal urothelium and higher in invasive than in noninvasive MB49 tumors. In vitro inducible nitric oxide synthase activity, determined as nitrite, was higher in MB49-I than in MB49 cells (p=0.001). In human samples expression was also associated with tumor invasion. Nuclear PPARgamma expression was negative in normal mouse urothelium but higher in non-muscle invasive MB49 than in MB49-I tumors. Similarly in human tumors low PPARgamma was associated with poor prognosis factors, such as high histological grade (p=0.0160) and invasion status (p=0.0352). A positive correlation was noted between inducible nitric oxide synthase and PPARgamma in low histological grade and nonmuscle invasive tumors (Pearson correlation index 0.6368, p=0.0351, 0.4438 and 0.0168, respectively). As determined by gene reporter assay, PPARgamma activity was induced by nitric oxide only in non-muscle invasive MB49 cells (p=0.001). Conclusions: Results suggest that increased PPARgamma controls inducible nitric oxide synthase expression at early tumor stages. However, regulation is lost at advanced tumor stages, when the increase in inducible nitric oxide synthase and the decrease in PPARgamma seem to be associated with bladder cancer progression.