Prognostic role of p27Kip1 deregulation in colorectal cancer.
p27Kip1, an inhibitor of cyclin-dependent kinases, is a negative cell cycle regulator that plays an important role in tumor suppression. Deregulation of p27 is commonly observed in many human cancers secondary to enhanced ubiquitin-mediated degradation, mediated and rate-limited by its specific ubiquitin ligase subunits Skp2 and Cks1. In the present study the prognostic implications of p27 and the mechanisms that down-regulate its expression in colorectal cancer (CRC) are reviewed. A review and analysis of the English literature was conducted. Loss of p27 was strongly associated with aggressive tumor behavior and poor clinical outcome in CRC. Overexpression of Skp2 and Cks1 was observed in aggressive CRC and is responsible for down-regulation of p27 levels. Both Skp2 and Cks1 were found to be independent prognostic markers for survival and provide predictive information additional to that provided by p27 alone. Deregulation of p27 has a profound effect on tumor progression in CRC and was found to be an accurate and independent prognostic marker. Thus, determination of levels of p27 and of its ubiquitin ligase subunits by readily available immunohistochemical studies may be a useful tool in the assessment of prognosis, especially in patients with intermediate disease, and may potentially assist in the planning of adjuvant therapy and development of novel interventional therapy.
Hershko
Dan D
DD
Department of Surgery, Rambam Medical Center, Haifa, Israel. d_hershko@rambam.health.gov.il
Shapira
Ma'anit
M
D014408:Biomarkers, Tumor; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D011379:Prognosis; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism
D014408:Biomarkers, Tumor; D044786:S-Phase Kinase-Associated Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases; C439298:p9(Cks1) protein, human