The ubiquitin ligase subunits Skp2 and Cks1 are novel independent prognostic markers for survival in colorectal cancer

Abstract

Introduction: Loss of the cell-cycle inhibitory protein p27 is associated with aggressive tumor behavior and poor prognosis in colorectal cancer. The decrease in p27 levels is the result of increased proteasome-dependent degradation, mediated and rate-limited by its specific ubiquitin ligase subunits Skp2 and Cks1. We recently found that overexpression of Skp2 and Cks1 in colorectal cancer correlated with low p27 levels and poor tumor differentiation. The potential role of Skp2 and Cks1 as independent prognostic markers, however, is unknown. Methods: Tissue samples from 100 patients operated for colorectal cancer at 1997 were subjected to Western blot analysis and immunohistochemistry using highly specific monoclonal antibodies against p27, Skp2 and Cks1. Results were plotted against patients’ characteristics, disease stage and overall survival using Cox analysis and the Kaplan-Meier method. Results: Skp2 and Cks1 expression strongly correlated with overall survival (HR 7.672; p < 0.001 and HR 5.026; p < 0.001, respectively). Thus, high levels of these proteins, alone or in combination, accurately predicted poor prognosis whereas low levels predicted good overall survival rates. The strength of these proteins as independent prognostic markers was also valid after controlling for age, sex, grade and stage. Moreover, after having stratified for p27 levels, both Skp2 and Cks1 expression significantly enhanced the predictive value for survival (HR 4.530; p < 0.001 and HR 4.236; p < 0.001, respectively). The strongest additive effect was observed in patients with stage II disease. Conclusions: Skp2 and Cks1 expression strongly correlate with overall survival and may thus be used as novel prognostic markers in colorectal cancer.