Korean J Urol.  2006 Nov;47(11):1149-1154. 10.4111/kju.2006.47.11.1149.

The Effects of p21 on Bladder Cancers

• Jung W
• Cho IC
• Ha YS
• Jo SH
• Park MS
• Lee YS
• Yoon SJ
• Kim WJ

• KMID: 2294271
• DOI: http://doi.org/10.4111/kju.2006.47.11.1149

Abstract

Purpose
p21 protein is an inhibitor of cyclin-dependent kinases, which may be able to arrest the cell cycle at the G1 phase by inhibiting DNA replication through the interaction with proliferating cell nuclear antigen. From experimental studies, p21 has been considered a tumor suppressor gene. Herein, the effects of p21 on the development, stage, grade, recurrence, progression and patient's survival in human bladder cancers were evaluated.
Materials and Methods
The mRNA expression levels of p21 were examined in 149 tumor specimens obtained from patients with primary bladder cancer and in 18 normal bladder mucosae using real-time polymerase chain reaction (PCR).
Results
p21 was significantly expressed in human bladder tumor tissues at high levels (7.11+/-0.69pg/ml), but was not expressed in the normal bladder mucosae. Compared with invasive bladder cancer (5.03+/-0.95), the p21 expression levels were significantly enhanced in superficial bladder cancer (7.96+/-0.88pg/ml) (p=0.0250); whereas, the grade was not related to the expression of p21. The levels of p21 expression were enhanced in non-recurred (9.33+/-1.38) and non-progressed (8.13+/-0.86) compared with recurred (6.03+/-0.75) and progressed (3.67+/-0.52) patients (each p<0.05). The level of p21 expression was significantly correlated with the disease free survival in patients the bladder cancers.
Conclusions
The enhanced expression of p21 is strongly associated with the development of bladder cancer. Moreover, increased expressions of p21 are also positively associated with the low rate of recurrence and progression of bladder cancer. Conversely, an enhanced expression of p21 provides a survival benefit for patients with bladder cancer. These results suggest that p21 might be useful as a marker in assessing tumor diagnosis, recurrence, progression and the survival in human bladder cancer patients.

Keyword

Cyclin-dependent kinase inhibitor p21; Bladder tumor; Polymerase chain reaction

MeSH Terms

Cell Cycle
Cyclin-Dependent Kinase Inhibitor p21
Cyclin-Dependent Kinases
Diagnosis
Disease-Free Survival
DNA Replication
G1 Phase
Genes, Tumor Suppressor
Humans
Mucous Membrane
Polymerase Chain Reaction
Proliferating Cell Nuclear Antigen
Real-Time Polymerase Chain Reaction
Recurrence
RNA, Messenger
Urinary Bladder Neoplasms*
Urinary Bladder*
Cyclin-Dependent Kinase Inhibitor p21
Cyclin-Dependent Kinases
Proliferating Cell Nuclear Antigen
RNA, Messenger

Figure

• 

  Fig. 1 Survival probabilities with respect to the level of p21; ≥7pg/ml and <7pg/ml, in patients with a bladder tumor.

Reference

1. Annual clinical statistics in KUA training hospital. Korean J Urol. 2001. 42:1349–1360.

2. Lee R, Droller MJ. The natural history of bladder cancer. Implications for therapy. Urol Clin North Am. 2000. 27:1–13.

3. Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell. 1996. 86:353–364.

4. Stein JP, Grossfeld GD, Ginsberg DA, Esrig D, Freeman JA, Figueroa AJ, et al. Prognostic markers in bladder cancer: a contemporary review of the literature. J Urol. 1998. 160:645–659.

5. Korkolopoulou P, Konstantinidou AE, Thomas-Tsagli E, Christodoulou P, Kapralos P, Davaris P. WAF1/p21 protein expression is an independent prognostic indicator in superficial and invasive bladder cancer. Appl Immunohistochem Mol Morphol. 2000. 8:285–292.

6. Clasen S, Schulz WA, Gerharz CD, Grimm MO, Christoph F, Schmitz-Drager BJ. Frequent and heterogeneous expression of cyclin-dependent kinase inhibitor WAF1/p21 protein and mRNA in urothelial carcinoma. Br J Cancer. 1998. 77:515–521.

7. Malkowicz SB, Tomaszewski JE, Linnenbach AJ, Cangiano TA, Maruta Y, McGarvey TW. Novel p21WAF1/CIP1 mutations in superficial and invasive transitional cell carcinomas. Oncogene. 1996. 13:1831–1837.

8. Pfister C, Larue H, Moore L, Lacombe L, Veilleux C, Tetu B, et al. Tumorigenic pathways in low-stage bladder cancer based on p53, MDM2 and p21 phenotypes. Int J Cancer. 2000. 89:100–104.

9. Chen WC, Wu HC, Hsu CD, Chen HY, Tsai FJ. p21 gene codon 31 polymorphism is associated with bladder cancer. Urol Oncol. 2002. 7:63–66.

10. Lipponen P, Aaltomaa S, Eskelinen M, Ala-Opas M, Kosma VM. Expression of p21 (waf1/cip1) protein in transitional cell bladder tumours and its prognostic value. Eur Urol. 1998. 34:237–243.

11. Lee H, Sohn HG, Ha DB, Kim KK, Lee KS. Expression of p21 protein in bladder cancer and its prognostic value. Korean J Urol. 2000. 41:826–832.

12. Jeong YB, Kim HJ, Lee DG. The clinical significance and relationship of p53 and p21 in bladder cancer. Korean J Urol. 1999. 40:1620–1625.

13. Miao TJ, Wang Z, Sang N. Correlation between the expression of the p21 ras oncogene product and the biological behavior of bladder tumors. Eur Urol. 1991. 20:307–310.

14. Pfister C, Moore L, Allard P, Larue H, Lacombe L, Tetu B, et al. Predictive value of cell cycle markers p53, MDM2, p21, and Ki-67 in superficial bladder tumor recurrence. Clin Cancer Res. 1999. 5:4079–4084.

15. Leissner J, Hohenfellner R, Thuroff JW, Koppen C, Wolf HK. Prognostic significance of histopathological grading and immunoreactivity for p53 and p21/WAF1 in grade 2 pTa transitional cell carcinoma of the urinary bladder. Eur Urol. 2001. 39:438–445.

16. Shariat SF, Kim J, Raptidis G, Ayala GE, Lerner SP. Association of p53 and p21 expression with clinical outcome in patients with carcinoma in situ of the urinary bladder. Urology. 2003. 61:1140–1145.

17. Chatterjee SJ, Datar R, Youssefzadeh D, George B, Goebell PJ, Stein JP, et al. Combined effects of p53, p21, and pRb expression in the progression of bladder transitional cell carcinoma. J Clin Oncol. 2004. 22:1007–1013.

18. Koga F, Kitahara S, Arai K, Honda M, Sumi S, Yoshida K. Negative p53/positive p21 immunostaining is a predictor or favorable response to chemotherapy in patients with locally advanced bladder cancer. Jpn J Cancer Res. 2000. 91:416–423.

19. Jahnson S, Karlsson MG. Tumor mapping of regional immunostaining for p21, p53, and mdm2 in locally advanced bladder carcinoma. Cancer. 2000. 89:619–629.

20. Garcia del Muro X, Condom E, Vigues F, Castellsague X, Figueras A, Munoz J, et al. p53 and p21 Expression levels predict organ preservation and survival in invasive bladder carcinoma treated with a combined-modality approach. Cancer. 2004. 100:1859–1867.