Cell cycle regulators in bladder cancer: a multivariate survival study with emphasis on p27Kip1
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Updated: Aug 7, 2026

Analysis of Cell Cycle Position in Mammalian Cells
Published on: January 21, 2012
P Korkolopoulou1, P Christodoulou, A E Konstantinidou
1Department of Pathology, National University of Athens, Greece.
Abstract:
Cyclin-dependent kinase inhibitors (CKIs) prevent cyclin-dependent kinases from phosphorylating critical substrates such as retinoblastoma gene protein (pRb), hence blocking the cascade of events leading to cell proliferation. Currently, the list of CKIs includes p21WAF1/Cip1, p27Kip1, p57Kip2 (the Cip/Kip family), p15/ INK4b, p16/INK4a, p18/INK4c, and p19/INK4d (the INK4 family). Among them, p27 plays a crucial role linking extracellular growth-regulatory signals to progression to or exit from the cell cycle. Unlike p53, p16, and Rb, mutations in Kip1 and WAF1 genes are distinctly rare in bladder cancer. We analyzed immunohistochemically the expression of p27 and other interacting G1 proteins (ie, p21, p16, pRb, p53) in 120 consecutive cases of transitional cell carcinomas (TCCs) and related it to proliferation rate, clinicopathologic parameters, and survival. p27 levels were significantly higher in low-grade (P = .001), superficial (Ta-T1) (P = .001), papillary (P < .001), and slowly proliferating TCCs (rs = -0.235, P = .05). p27 also positively correlated with p16 expression (rs = 0.212, P = .05). In univariate analysis, decreased p27 expression was associated with poor overall (P = .0109) and postrelapse (P = .0344) survival, especially if combined to increased Ki-67 expression (P = .0004 and P = .036, respectively). Furthermore, in multivariate analysis, Ki-67/p27 status had the strongest bearing on the overall survival of muscle-invasive TCCs (P = .0019). Our results indicate that low p27 expression is more common in poorly differentiated muscle-invasive TCCs and is a major player in cell cycle control in these neoplasms. More importantly, the combined Ki-67/p27 expression provides prognostic information beyond that provided by conventional parameters or other cell cycle-related proteins, concerning overall survival in muscle-invasive TCCs.
Insights
Low p27 expression in bladder cancer correlates with aggressive tumors and poor survival. Combining p27 and Ki-67 levels offers significant prognostic value for muscle-invasive transitional cell carcinomas.
Area of Science:
- Oncology
- Cell Biology
- Cancer Research
Background:
- Cyclin-dependent kinase inhibitors (CKIs) regulate cell proliferation by inhibiting cyclin-dependent kinases.
- p27Kip1 (p27) is a key CKI linking growth signals to cell cycle progression.
- Mutations in p27 are rare in bladder cancer, suggesting altered expression plays a role.
Purpose of the Study:
- To investigate the expression of p27 and other G1 cell cycle proteins in transitional cell carcinomas (TCCs).
- To correlate p27 expression with proliferation rates, clinicopathologic parameters, and patient survival.
- To evaluate the prognostic significance of p27, alone and in combination with Ki-67, in TCCs.
Main Methods:
- Immunohistochemical analysis of p27, p21, p16, pRb, and p53 expression in 120 TCC cases.
- Correlation of protein expression with proliferation rate (Ki-67), clinicopathologic features, and survival data.
- Univariate and multivariate survival analyses were performed.
Main Results:
- Higher p27 levels were associated with low-grade, superficial, papillary, and slowly proliferating TCCs.
- Decreased p27 expression correlated with poorer overall and postrelapse survival.
- The combination of low p27 and high Ki-67 expression was a strong predictor of poor survival in muscle-invasive TCCs.
Conclusions:
- Low p27 expression is linked to poorly differentiated, muscle-invasive TCCs and impaired cell cycle control.
- The combined Ki-67/p27 status provides significant prognostic information for muscle-invasive TCCs.
- This combined marker offers prognostic value beyond conventional parameters.
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