Decreasing of p27(Kip1) and cyclin E protein levels is associated with progression from superficial into invasive bladder cancer

The p27(Kip1) (p27) protein is a cyclin-dependent kinase inhibitor of the t ransition from G1 to S phase. It has been reported that decreased p27 prote in level is a negative prognostic indicator in human tumours including blad der cancer. We studied the relationship between protein levels of p27, cycl in E and Ki-67 and clinicopathological features of 145 consecutive Japanese patients with transitional cell carcinoma of the bladder using immunohisto chemical staining. Low protein levels of p27 were associated with low stain ing of cyclin E (P = 0.0302), high Ki-67 index (P = 0.0306), poorly differe ntiated grade (P = 0.0006), muscle invasion (P = 0.0019) and lymph node met astsis (P = 0.0002). Low staining of cyclin E and high Ki-67 index correlat ed with poorly differentiated grade, muscle invasion and lymph node metasts is. Cyclin E protein levels was inversely related with Ki-67 index (P = 0.0 002). Kaplan-Meier plots of survival rate in patients with low versus high p27 staining showed that low protein levels of p27 were associated with a s hortened disease-free and overall survival (P < 0.0001 and P < 0.0001, resp ectively). Similarly, low staining of cyclin E and high Ki-67 index correla ted with a shortened disease-free and overall survival. On multivariate ana lysis using Cox proportional hazards model, low protein levels of p27 and h igh Ki-67 index were independent predictors of shortened disease-free (P < 0.0001, P = 0.0031, respectively), and low protein levels of p27, low stain ing of cyclin E and high Ki-67 index of overall survival (P = 0.0017, P = 0 .0009, P = 0.0003, respectively). In superficial bladder tumours (Ta, T1; 8 6 patients), significant correlations were observed between low p27 stainin g and high Ki-67 index and early recurrence (P = 0.0048, P = 0.0178, respec tively). Among the recurrenced superficial tumours (35 patients), the tumou rs which remained at a low stage showed high protein levels of p27 and cycl in E, and the tumours which progressed to invasive disease showed a gradual decrease in p27 and cyclin E protein levels over time. Our findings sugges t that decreased protein levels of p27 and cyclin E play a role in the prog ression of bladder cancer and to evaluate these protein levels may be usefu l in management of the diseases. (C) 2001 Cancer Research Campaign.