Expression of Spred2 in the Urothelial Tumorigenesis of the Urinary Bladder

Aberrant activation of the Ras/Raf/ERK-MAPK pathway is involved in the progression of cancer, including urothelial carcinoma; but the negative regulation remains unclear. Here, we investigated pathological expression of Spred2 (Sprouty-related EVH1 domain-containing protein 2), a negative regulator of the Ras/Raf/ERK-MAPK pathway, and the relation to ERK activation and a cell proliferation marker Ki67 index in various categories of 275 urothelial tumors obtained from clinical patients. In situ hybridization demonstrated that Spred2 mRNA was highly expressed in high-grade non-invasive papillary urothelial carcinoma (HGPUC) and carcinoma in situ (CIS), and the expression was decreased in invasive urothelial carcinoma (IUC). Immunohistochemically, membranous Spred2 expression, important to interact with Ras/Raf, was preferentially found in HGPUC. Interestingly, membranous Spred2 expression was decreased in CIS and IUC relative to HGPUC, while ERK activation and Ki67 index were increased. HGPUC with membranous Spred2 expression correlated significantly with lower levels of ERK activation and Ki67 index as compared to those with negative Spred2 expression. Thus, our pathological findings suggest that Spred2 negatively regulates cancer progression in non-invasive papillary carcinoma possibly through inhibiting Ras/Raf/ERK-MAPK pathway, but this regulatory mechanism is lost in CIS and IUC. Spred2 appears to be a key regulator in the progression of non-invasive bladder carcinoma.