Increased SKP2 and CKS1 gene expression contributes to the progression of human urothelial carcinoma.
OBJECTIVE
SKP2 and CKS1 promote aggressive tumor behavior via the regulation of p27 degradation. Our previous DNA microarray analysis of human urothelial carcinoma and normal urothelial epithelium showed that in urothelial carcinoma the 2 most highly up-regulated genes among SKP2-p27 interaction related genes are SKP2 (4.7-fold) and CKS1 (2.2-fold). We hypothesized that SKP2 and CKS1 gene expression is associated with urothelial carcinoma invasiveness and prognosis.


METHODS
A total of 84 urothelial carcinoma specimens from patients with bladder (71) and upper urinary tract (13) cancer were examined by real-time reverse transcriptase-polymerase chain reaction and immunohistochemical study.


RESULTS
Real-time reverse transcriptase-polymerase chain reaction showed that the average mRNA expression level of SKP2 and CKS1 significantly correlated with tumor stage, that is superficial vs invasive urothelial carcinoma (SKP2 and CKS1, p<0.001 and 0.006) and grade (p<0.001 and 0.009, respectively). Of the superficial urothelial carcinomas examined the SKP2 and CKS1 expression level was significantly higher in pT1 than in pTa samples (p=0.005 and 0.017, respectively). Immunohistochemical expression patterns of SKP2 and CKS1 also significantly correlated with tumor stage (p<0.001 and 0.048) and grade (p=0.003 and 0.025, respectively). In contrast, p27 expression inversely correlated with tumor stage and grade (p<0.001 and 0.011, respectively). Logistic regression analysis revealed that while SKP2 mRNA expression was a significant dependent predictor of p27 expression (p=0.021), there was no correlation between CKS1 mRNA expression and p27 (p=0.748). Kaplan-Meier curves and log rank tests revealed that the high mRNA expression levels of SKP2 and CKS1 had a significant adverse effect on prognosis (p=0.043 and 0.003, respectively).


CONCLUSIONS
Our results suggest that SKP2 has a major role in the regulation of p27 degradation and CKS1 has a supporting role for SKP2 function in human urothelial carcinoma.
Kawakami
Kazumori
K
Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
Enokida
Hideki
H
Tachiwada
Tokushi
T
Nishiyama
Kenryu
K
Seki
Naohiko
N
Nakagawa
Masayuki
M
D042846:CDC2-CDC28 Kinases; D002352:Carrier Proteins / Q000235:genetics*; D018844:Cyclin-Dependent Kinases / Q000235:genetics*; D018450:Disease Progression; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D016015:Logistic Models; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism*; D001749:Urinary Bladder Neoplasms / Q000378:metabolism*; D014571:Urologic Neoplasms / Q000378:metabolism*
C093090:CKS1B protein, human; D002352:Carrier Proteins; D018809:Proliferating Cell Nuclear Antigen; D044786:S-Phase Kinase-Associated Proteins; C413374:p27 antigen; D042846:CDC2-CDC28 Kinases; D018844:Cyclin-Dependent Kinases