Inverse relationship between Skp2 ubiquitin ligase and the cyclin dependent kinase inhibitor p27Kip1 in prostate cancer.
OBJECTIVE
Prostate carcinomas show a low level of the cell cycle inhibitor p27, which correlates with tumor aggressiveness. In tumors p27 is of the WT species and its deregulation is due to aberrant ubiquitin mediated degradation. The p27 is degraded following phosphorylation and subsequent recognition by SCFSkp2 ubiquitin ligase. We examined the relationship between p27 and its specific ligase Skp2 in normal and malignant prostate tissues. A possible correlation among the levels of these proteins, tumor grading and clinical state was also investigated.


METHODS
Using immunohistochemistry immunofluorescence microscopy and Western blot analysis 51 samples from needle biopsies, transurethral resection and radical prostatectomy were analyzed for p27 and Skp2 expression. Correlation with tumor grading (Gleason) was performed. In 22 proven metastatic or organ confined cases correlation was also done with the Ki67 proliferative marker.


RESULTS
Skp2 expression demonstrated a significant and direct correlation with malignancy (p <0.0001). Furthermore, a significant correlation was found between Skp2 level and tumor aggressiveness graded by Gleason score (p <0.0002) and prostate specific antigen. Patients with metastases had significantly higher Skp2 and Ki67 expression than those with organ confined disease (p <0.0001). In addition, Skp2 levels significantly correlated with Ki67 (r = 0.73, p <0.0001). An inverse correlation was found between p27 and Skp2 ligase.


CONCLUSIONS
Skp2 expression in prostate biopsies may be used as an additional marker for tumor aggressiveness. The results also suggest a role for Skp2 in the pathogenesis of prostate malignancy.
Ben-Izhak
Ofer
O
Department of Pathology, Rambam Medical Center, Haifa, Israel.
Lahav-Baratz
Shirly
S
Meretyk
Shimon
S
Ben-Eliezer
Shoshana
S
Sabo
Edmond
E
Dirnfeld
Martha
M
Cohen
Shai
S
Ciechanover
Aaron
A
D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000378:metabolism*; D044786:S-Phase Kinase-Associated Proteins; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*
D018797:Cell Cycle Proteins; D044786:S-Phase Kinase-Associated Proteins; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases; D017430:Prostate-Specific Antigen