The prognostic impact of the ubiquitin ligase subunits Skp2 and Cks1 in colorectal carcinoma.
BACKGROUND
Loss of the cell-cycle inhibitory protein p27Kip1 is associated with poor prognosis in colorectal carcinoma. The decrease in p27Kip1 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.


METHODS
The expression of Skp2, Cks1, and p27Kip1 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 p27Kip1 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 p27Kip1 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.
Shapira
Ma'anit
M
Department of Surgery, Rambam Medical Center and the Technion-Israel Institute of Technology, Haifa, Israel.
Ben-Izhak
Ofer
O
Linn
Shai
S
Futerman
Boris
B
Minkov
Ira
I
Hershko
Dan D
DD
D000368:Aged; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins / Q000378:metabolism; D002454:Cell Differentiation; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D011379:Prognosis; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism*; D016019:Survival Analysis; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D044786:S-Phase Kinase-Associated Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases; C439298:p9(Cks1) protein, human