NEW YORK (Reuters Health) - High levels of the cell-cycle regulatory proteins, S-phase kinase-associated protein 2 (Skp2) and cyclin kinase subunit 1 (Cks1), are associated with decreased survival in colorectal cancer, independent of tumor grade and disease stage, investigators in Israel report in the April 1st issue of the journal Cancer.
Skp2 binds to p27-Kip1, a negative regulator of cell proliferation, and targets it for degradation, explain Dr. Dan D. Hershko and his colleagues at Technion-Israel Institute of Technology in Haifa. Cks1 facilitates the ubiquitin-mediated proteolysis of p27-Kip1 through its interaction with Skp2.
To assess the proteins’ potential roles as prognostic biomarkers, Dr. Hershko’s group obtained samples for immunohistochemical analysis from 80 patients with colorectal adenocarcinoma. Nuclear protein expression was considered low if less than 50% of cell nuclei stained positive for the antibody, and high if more than 50% of nuclei were stained.
Skp2 and Cks1 expression were strongly correlated with each other and inversely related to p27-Kip1 levels, the authors report.
After controlling for age, sex, tumor grade, disease stage, and p27-Kip1 expression, Skp2 and Cks1 were strongly associated with survival (odds ratio 4.431 and 3.371, respectively).
The prognostic role of the biomarkers was so strong that patients with advanced disease and low Skp2 or Cks1 levels had better outcomes than patients with early cancer and high levels, the authors note.
The prognostic value was particularly marked in patients with intermediate disease stage (stages II and III), for whom accurate determination of prognosis is difficult. Of 60 patients with stage II or II disease at the time of diagnosis, those with high Skp2 levels survived for a mean of 37 months, while those with low levels survived for 64 months (p < 0.001). Likewise, those with high or low Cks1 levels survived for an average of 41 or 63 months (p < 0.001).
“It seems that these regulatory proteins may well be considered in the future as novel targets for therapeutic intervention in colorectal carcinoma,” Dr. Hershko and his associates conclude.
Source: Cancer 2005;103:1336-1346. [ Google search on this article ]
MeSH Headings:Biochemistry: Biological Factors: Biological Sciences: Chemistry: Chemistry, Analytical: Colonic Diseases: Cytological Techniques: Digestive System Neoplasms: DNA-Binding Proteins: Gastrointestinal Neoplasms: Health Occupations: Histocytochemistry: Histological Techniques: Human Activities: Immunochemistry: Immunohistochemistry: Immunologic and Biological Factors: Immunologic Techniques: Intestinal Neoplasms: Investigative Techniques: Neoplasms: Neoplasms by Site: Physical Sciences: Retroviridae Proteins: Survival: Technology: Technology, Industry, and Agriculture: Technology, Medical: Viral Proteins: Colorectal Neoplasms: Biological Markers: Viral Regulatory Proteins: Retroviridae Proteins, Oncogenic: Gene Products, rex: Allied Health Occupations: Protein-Serine-Threonine Kinases: Cell Cycle Proteins: Cyclin-Dependent Kinases: Chemical Actions and Uses: Chemical Actions: Analytical, Diagnostic and Therapeutic Techniques and Equipment: Anthropology, Education, Sociology and Social Phenomena: Biological Sciences: Chemicals and Drugs: Diseases: Physical Sciences: Technology, Food and BeveragesCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
