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 prote...

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Bibliographic Details
Published in:Cancer 2005-04, Vol.103 (7), p.1336-1346
Main Authors: Shapira, Ma'anit, Ben–Izhak, Ofer, Linn, Shai, Futerman, Boris, Minkov, Ira, Hershko, Dan D.
Format: Article
Language:English
Subjects:
Aged
Biological and medical sciences
Biomarkers, Tumor
Cell Cycle Proteins - metabolism
Cell Differentiation
Cks1
colorectal carcinoma
Colorectal Neoplasms - metabolism
Colorectal Neoplasms - mortality
Colorectal Neoplasms - pathology
cyclin kinase subunit 1
Cyclin-Dependent Kinase Inhibitor p27
Cyclin-Dependent Kinases - metabolism
Female
Gastroenterology. Liver. Pancreas. Abdomen
Humans
Immunohistochemistry
Male
Medical sciences
p27Kip1
Prognosis
S-Phase Kinase-Associated Proteins - metabolism
Skp2
Stomach. Duodenum. Small intestine. Colon. Rectum. Anus
Survival Analysis
S‐phase kinase‐associated protein 2
Tumor Suppressor Proteins - metabolism
Tumors
ubiquitin
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Summary: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. MATERIALS AND 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. Cancer 2005. © 2005 American Cancer Society. The expression of S‐phase kinase‐associated protein 2 (Skp2) and cyclin kinase subunit 1 (Cks1), the specific ubiquitin ligase subunits that target p27Kip1 for degradation, are altered in various human cancers. It is shown in the current study that increased expression of Skp2 or Cks1 is strongly associated with poor prognosis and that their increased expression may be used as a prognostic marker for overall survival in colorectal carcinoma.
ISSN:0008-543X
1097-0142
DOI:10.1002/cncr.20917