The prognostic impact of the ubiquitin ligase subunits Skp2 and Cks1 in colorectal carcinoma

BACKGROUND: Loss of the cell-cycle inhibitory protein p27^Kip1 is associated with poor prognosis in colorectal carcinoma. The decrease in p27^Kip1 levels is the result of increased proteasome-dependent degradation, mediated and rate-limited by its specific ubiquitin ligase subunits S-phase kinase protein (Skp) 2 and cyclin-dependent kinase subunit (Cks) 1. Recently, Skp2 and Cks1 expression were found to be increased in some colorectal carcinomas, but their potential role as prognostic markers for survival is unknown. The present study was undertaken to assess the prognostic value of both Skp2 and Cks1 in colorectal carcinoma. MATERIALS AND METHODS: The expression of Skp2, Cks1, and p27^Kip1 was examined by immunohistochemistry using highly specific antibodies on formalin-fixed, paraffin-embedded tissue sections from 80 patients with colorectal carcinoma. RESULTS: Overexpression of Skp2 and Cks1 strongly correlated with loss of p27^Kip1 and loss of tumor differentiation. A significant decrease in overall survival was observed in patients expressing high Skp2 or Cks1 levels, and in particular, patients with Stage II and III disease. Each protein provided significant additional prognostic information to that given by disease stage, tumor grade, or p27 ^Kip1 expression. CONCLUSIONS: Results suggest that overexpression of Skp2 or Cks1 is strongly associated with poor prognosis and may thus be used as prognostic markers for overall survival in colorectal carcinoma.