Clinical significance of mdm2 and p53 expression in bladder cancer. A comparison with cell proliferation and apoptosis.
BACKGROUND
Clinical significance of immunohistochemically detectable level of p53 protein has been reported, but with some limitation as a prognosticator of bladder cancer patients. Whether or not simultaneous evaluation of mdm2 and p53 expression in bladder cancer exceed the prognostic significance of conventional histological findings, cell proliferation markers and apoptotic parameters remains unclear.


METHODS
The paraffin-embedded materials taken from 84 patients with transitional cell carcinoma of the bladder who were treated with total cystectomy were used in this study. Immunostainings of p53 protein, mdm2 protein and Ki67 antigen were performed using monoclonal antibodies (clone DO7, clone 1B10 and clone MIB1, respectively). In addition, the apoptotic cells were determined using a terminal deoxynucleotidyl transferase (TdT) mediated dUTP biotin nick end labeling (TUNEL) technique. The results were quantitatively evaluated using a CAS 200 Image Analyzer (Cell Analysis System, Elmhurst, Ill., USA) and were compared with histological findings and clinical course.


RESULTS
The mean values of mdm2 expression, p53 immunoreactivity, Ki67 expression and apoptotic index were 19.2, 20.5, 22.4 and 0.96%, respectively. Histological grade and pT category were significantly positively correlated with 53 immunoreactivity (p < 0.05 and p < 0.05, respectively), Ki67 expression (p < 0.005 and p < 0.0001, respectively) and apoptotic index (p < 0.01 and p < 0.0001, respectively), while both were not correlated with mdm2 expression. Using univariate analysis, the prognostic relevance for both survival and disease progression was noted in histological grade, pT category, p53 expression, Ki67 index and apoptotic index, whereas it was not in mdm2 expression. However, when analyzing the simultaneous evaluation of mdm2 and p53 expression (mdm2-p53 category), the relationship of the mdm2-p53 category with Ki67 expression and apoptotic index showed a statistical significance and a borderline significance (p = 0.0085 and p = 0.0652, respectively). In addition, the patients with both mdm2(-) and p53(-) showed a significant better prognosis as compared with either counterpart of mdm2-p53 category (p < 0.05 for both). Multivariate analysis revealed only pT category and mdm2-p53 category as independent factors for both disease progression and survival.


CONCLUSIONS
Clinical significance of simultaneous evaluation of mdm2 and p53 immunostaining proved to be superior over that of cell proliferation and/or apoptotic markers when elucidating the biological characteristics of bladder cancer.
Shiina
H
H
Department of Urology, Shimane Medical University, Izumo, Japan.
Igawa
M
M
Shigeno
K
K
Yamasaki
Y
Y
Urakami
S
S
Yoneda
T
T
Wada
Y
Y
Honda
S
S
Nagasaki
M
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020287:In Situ Nick-End Labeling; D019394:Ki-67 Antigen / Q000032:analysis; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009363:Neoplasm Proteins / Q000032:analysis*; D009367:Neoplasm Staging; D009687:Nuclear Proteins; D011237:Predictive Value of Tests; D011518:Proto-Oncogene Proteins / Q000032:analysis*; D051736:Proto-Oncogene Proteins c-mdm2; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000032:analysis*; D001749:Urinary Bladder Neoplasms / Q000737:chemistry* / Q000473:pathology
D019394:Ki-67 Antigen; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2