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. 2001 May;84(9):1242–1251. doi: 10.1054/bjoc.2000.1736

Decreasing of p27Kip1 and cyclin E protein levels is associated with progression from superficial into invasive bladder cancer

T Kamai 1,2, K Takagi 2, H Asami 3, Y Ito 3, H Oshima 4, K-I Yoshida 1
PMCID: PMC2363875  PMID: 11336477

Abstract

The p27Kip1(p27) protein is a cyclin-dependent kinase inhibitor of the transition from G1 to S phase. It has been reported that decreased p27 protein level is a negative prognostic indicator in human tumours including bladder cancer. We studied the relationship between protein levels of p27, cyclin E and Ki-67 and clinicopathological features of 145 consecutive Japanese patients with transitional cell carcinoma of the bladder using immunohistochemical staining. Low protein levels of p27 were associated with low staining of cyclin E (P = 0.0302), high Ki-67 index (P = 0.0306), poorly differentiated grade (P = 0.0006), muscle invasion (P = 0.0019) and lymph node metastsis (P = 0.0002). Low staining of cyclin E and high Ki-67 index correlated with poorly differentiated grade, muscle invasion and lymph node metastsis. Cyclin E protein levels was inversely related with Ki-67 index (P = 0.0002). 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 shortened disease-free and overall survival (P< 0.0001 and P< 0.0001, respectively). Similarly, low staining of cyclin E and high Ki-67 index correlated with a shortened disease-free and overall survival. On multivariate analysis using Cox proportional hazards model, low protein levels of p27 and high Ki-67 index were independent predictors of shortened disease-free (P< 0.0001, P = 0.0031, respectively), and low protein levels of p27, low staining 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; 86 patients), significant correlations were observed between low p27 staining and high Ki-67 index and early recurrence (P = 0.0048, P = 0.0178, respectively). Among the recurrenced superficial tumours (35 patients), the tumours which remained at a low stage showed high protein levels of p27 and cyclin E, and the tumours which progressed to invasive disease showed a gradual decrease in p27 and cyclin E protein levels over time. Our findings suggest that decreased protein levels of p27 and cyclin E play a role in the progression of bladder cancer and to evaluate these protein levels may be useful in management of the diseases. © 2001 Cancer Research Campaign http://www.bjcancer.com

Keywords: bladder, neoplasm, cell cycle, p27Kip1, cyclin E, Ki-67

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Selected References

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  1. Catzavelos C., Bhattacharya N., Ung Y. C., Wilson J. A., Roncari L., Sandhu C., Shaw P., Yeger H., Morava-Protzner I., Kapusta L. Decreased levels of the cell-cycle inhibitor p27Kip1 protein: prognostic implications in primary breast cancer. Nat Med. 1997 Feb;3(2):227–230. doi: 10.1038/nm0297-227. [DOI] [PubMed] [Google Scholar]
  2. Connor J. P., Olsson C. A., Benson M. C., Rapoport F., Sawczuk I. S. Long-term follow-up in patients treated with methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) for transitional cell carcinoma of urinary bladder: cause for concern. Urology. 1989 Dec;34(6):353–356. doi: 10.1016/0090-4295(89)90440-8. [DOI] [PubMed] [Google Scholar]
  3. Cordon-Cardo C., Wartinger D., Petrylak D., Dalbagni G., Fair W. R., Fuks Z., Reuter V. E. Altered expression of the retinoblastoma gene product: prognostic indicator in bladder cancer. J Natl Cancer Inst. 1992 Aug 19;84(16):1251–1256. doi: 10.1093/jnci/84.16.1251. [DOI] [PubMed] [Google Scholar]
  4. Del Pizzo J. J., Borkowski A., Jacobs S. C., Kyprianou N. Loss of cell cycle regulators p27(Kip1) and cyclin E in transitional cell carcinoma of the bladder correlates with tumor grade and patient survival. Am J Pathol. 1999 Oct;155(4):1129–1136. doi: 10.1016/S0002-9440(10)65216-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Esposito V., Baldi A., De Luca A., Groger A. M., Loda M., Giordano G. G., Caputi M., Baldi F., Pagano M., Giordano A. Prognostic role of the cyclin-dependent kinase inhibitor p27 in non-small cell lung cancer. Cancer Res. 1997 Aug 15;57(16):3381–3385. [PubMed] [Google Scholar]
  6. Fujii Y., Fukui I., Kihara K., Tsujii T., Ishizaka K., Kageyama Y., Kawakami S., Oshima H. Significance of bladder neck involvement on progression in superficial bladder cancer. Eur Urol. 1998;33(5):464–468. doi: 10.1159/000019636. [DOI] [PubMed] [Google Scholar]
  7. Geller N. L., Sternberg C. N., Penenberg D., Scher H., Yagoda A. Prognostic factors for survival of patients with advanced urothelial tumors treated with methotrexate, vinblastine, doxorubicin, and cisplatin chemotherapy. Cancer. 1991 Mar 15;67(6):1525–1531. doi: 10.1002/1097-0142(19910315)67:6<1525::aid-cncr2820670611>3.0.co;2-8. [DOI] [PubMed] [Google Scholar]
  8. Heney N. M., Ahmed S., Flanagan M. J., Frable W., Corder M. P., Hafermann M. D., Hawkins I. R. Superficial bladder cancer: progression and recurrence. J Urol. 1983 Dec;130(6):1083–1086. doi: 10.1016/s0022-5347(17)51695-x. [DOI] [PubMed] [Google Scholar]
  9. Hunter T., Pines J. Cyclins and cancer. II: Cyclin D and CDK inhibitors come of age. Cell. 1994 Nov 18;79(4):573–582. doi: 10.1016/0092-8674(94)90543-6. [DOI] [PubMed] [Google Scholar]
  10. Kamai T., Takagi K., Asami H., Ito Y., Arai K., Yoshida K. I. Prognostic significance of p27Kip1 and Ki-67 expression in carcinoma of the renal pelvis and ureter. BJU Int. 2000 Jul;86(1):14–19. doi: 10.1046/j.1464-410x.2000.00726.x. [DOI] [PubMed] [Google Scholar]
  11. Katayose Y., Kim M., Rakkar A. N., Li Z., Cowan K. H., Seth P. Promoting apoptosis: a novel activity associated with the cyclin-dependent kinase inhibitor p27. Cancer Res. 1997 Dec 15;57(24):5441–5445. [PubMed] [Google Scholar]
  12. Keyomarsi K., Conte D., Jr, Toyofuku W., Fox M. P. Deregulation of cyclin E in breast cancer. Oncogene. 1995 Sep 7;11(5):941–950. [PubMed] [Google Scholar]
  13. Kuczyk M., Machtens S., Hradil K., Schubach J., Christian W., Knüchel R., Hartmann J., Bokemeyer C., Jonas U., Serth J. Predictive value of decreased p27Kip1 protein expression for the recurrence-free and long-term survival of prostate cancer patients. Br J Cancer. 1999 Nov;81(6):1052–1058. doi: 10.1038/sj.bjc.6690806. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Lamm D. L., Riggs D. R., Traynelis C. L., Nseyo U. O. Apparent failure of current intravesical chemotherapy prophylaxis to influence the long-term course of superficial transitional cell carcinoma of the bladder. J Urol. 1995 May;153(5):1444–1450. [PubMed] [Google Scholar]
  15. Lee C. C., Ichihara T., Yamamoto S., Wanibuchi H., Sugimura K., Wada S., Kishimoto T., Fukushima S. Reduced expression of the CDK inhibitor p27(KIP1) in rat two-stage bladder carcinogenesis and its association with expression profiles of p21(WAF1/Cip1) and p53. Carcinogenesis. 1999 Sep;20(9):1697–1708. doi: 10.1093/carcin/20.9.1697. [DOI] [PubMed] [Google Scholar]
  16. Lee C. C., Yamamoto S., Morimura K., Wanibuchi H., Nishisaka N., Ikemoto S., Nakatani T., Wada S., Kishimoto T., Fukushima S. Significance of cyclin D1 overexpression in transitional cell carcinomas of the urinary bladder and its correlation with histopathologic features. Cancer. 1997 Feb 15;79(4):780–789. doi: 10.1002/(sici)1097-0142(19970215)79:4<780::aid-cncr15>3.0.co;2-w. [DOI] [PubMed] [Google Scholar]
  17. Loda M., Cukor B., Tam S. W., Lavin P., Fiorentino M., Draetta G. F., Jessup J. M., Pagano M. Increased proteasome-dependent degradation of the cyclin-dependent kinase inhibitor p27 in aggressive colorectal carcinomas. Nat Med. 1997 Feb;3(2):231–234. doi: 10.1038/nm0297-231. [DOI] [PubMed] [Google Scholar]
  18. Loening S., Narayana A., Yoder L., Slymen D., Weinstein S., Penick G., Culp D. Factors influencing the recurrence rate of bladder cancer. J Urol. 1980 Jan;123(1):29–31. doi: 10.1016/s0022-5347(17)55763-8. [DOI] [PubMed] [Google Scholar]
  19. Logothetis C. J., Xu H. J., Ro J. Y., Hu S. X., Sahin A., Ordonez N., Benedict W. F. Altered expression of retinoblastoma protein and known prognostic variables in locally advanced bladder cancer. J Natl Cancer Inst. 1992 Aug 19;84(16):1256–1261. doi: 10.1093/jnci/84.16.1256. [DOI] [PubMed] [Google Scholar]
  20. Masciullo V., Sgambato A., Pacilio C., Pucci B., Ferrandina G., Palazzo J., Carbone A., Cittadini A., Mancuso S., Scambia G. Frequent loss of expression of the cyclin-dependent kinase inhibitor p27 in epithelial ovarian cancer. Cancer Res. 1999 Aug 1;59(15):3790–3794. [PubMed] [Google Scholar]
  21. Mori M., Mimori K., Shiraishi T., Tanaka S., Ueo H., Sugimachi K., Akiyoshi T. p27 expression and gastric carcinoma. Nat Med. 1997 Jun;3(6):593–593. doi: 10.1038/nm0697-593. [DOI] [PubMed] [Google Scholar]
  22. Orlow I., LaRue H., Osman I., Lacombe L., Moore L., Rabbani F., Meyer F., Fradet Y., Cordon-Cardo C. Deletions of the INK4A gene in superficial bladder tumors. Association with recurrence. Am J Pathol. 1999 Jul;155(1):105–113. doi: 10.1016/S0002-9440(10)65105-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Porter P. L., Malone K. E., Heagerty P. J., Alexander G. M., Gatti L. A., Firpo E. J., Daling J. R., Roberts J. M. Expression of cell-cycle regulators p27Kip1 and cyclin E, alone and in combination, correlate with survival in young breast cancer patients. Nat Med. 1997 Feb;3(2):222–225. doi: 10.1038/nm0297-222. [DOI] [PubMed] [Google Scholar]
  24. Rakkar A. N., Li Z., Katayose Y., Kim M., Cowan K. H., Seth P. Adenoviral expression of the cyclin-dependent kinase inhibitor p27Kip1: a strategy for breast cancer gene therapy. J Natl Cancer Inst. 1998 Dec 2;90(23):1836–1838. doi: 10.1093/jnci/90.23.1836. [DOI] [PubMed] [Google Scholar]
  25. Richter J., Wagner U., Kononen J., Fijan A., Bruderer J., Schmid U., Ackermann D., Maurer R., Alund G., Knönagel H. High-throughput tissue microarray analysis of cyclin E gene amplification and overexpression in urinary bladder cancer. Am J Pathol. 2000 Sep;157(3):787–794. doi: 10.1016/s0002-9440(10)64592-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Sgambato A., Migaldi M., Faraglia B., Garagnani L., Romano G., De Gaetani C., Ferrari P., Capelli G., Trentini G. P., Cittadini A. Loss of P27Kip1 expression correlates with tumor grade and with reduced disease-free survival in primary superficial bladder cancers. Cancer Res. 1999 Jul 1;59(13):3245–3250. [PubMed] [Google Scholar]
  27. Shin K. Y., Kong G., Kim W. S., Lee T. Y., Woo Y. N., Lee J. D. Overexpression of cyclin D1 correlates with early recurrence in superficial bladder cancers. Br J Cancer. 1997;75(12):1788–1792. doi: 10.1038/bjc.1997.305. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Steeg P. S., Abrams J. S. Cancer prognostics: past, present and p27. Nat Med. 1997 Feb;3(2):152–154. doi: 10.1038/nm0297-152. [DOI] [PubMed] [Google Scholar]
  29. Sternberg C. N., Yagoda A., Scher H. I., Watson R. C., Ahmed T., Weiselberg L. R., Geller N., Hollander P. S., Herr H. W., Sogani P. C. Preliminary results of M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) for transitional cell carcinoma of the urothelium. J Urol. 1985 Mar;133(3):403–407. doi: 10.1016/s0022-5347(17)48996-8. [DOI] [PubMed] [Google Scholar]
  30. Toyoshima H., Hunter T. p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21. Cell. 1994 Jul 15;78(1):67–74. doi: 10.1016/0092-8674(94)90573-8. [DOI] [PubMed] [Google Scholar]
  31. Tsihlias J., Kapusta L. R., DeBoer G., Morava-Protzner I., Zbieranowski I., Bhattacharya N., Catzavelos G. C., Klotz L. H., Slingerland J. M. Loss of cyclin-dependent kinase inhibitor p27Kip1 is a novel prognostic factor in localized human prostate adenocarcinoma. Cancer Res. 1998 Feb 1;58(3):542–548. [PubMed] [Google Scholar]
  32. Vegt P. D., Debruyne F. M., van der Meijden A. P. Bacillus Calmette-Guérin in superficial bladder cancer: consensus and controversies. Eur Urol. 1995;27(2):89–95. doi: 10.1159/000475135. [DOI] [PubMed] [Google Scholar]
  33. Vlach J., Hennecke S., Amati B. Phosphorylation-dependent degradation of the cyclin-dependent kinase inhibitor p27. EMBO J. 1997 Sep 1;16(17):5334–5344. doi: 10.1093/emboj/16.17.5334. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Yang R. M., Naitoh J., Murphy M., Wang H. J., Phillipson J., deKernion J. B., Loda M., Reiter R. E. Low p27 expression predicts poor disease-free survival in patients with prostate cancer. J Urol. 1998 Mar;159(3):941–945. [PubMed] [Google Scholar]

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