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Annals of Surgical Oncology 9:450-456 (2002)
© 2002 Society of Surgical Oncology

ORIGINAL ARTICLES

The Expression of Murine Double Minute 2 Is a Favorable Prognostic Marker in Esophageal Squamous Cell Carcinoma Without p53 Protein Accumulation

Hiroaki Saito, MD, PhD, Shunichi Tsujitani, MD, Shinichi Oka, MD, Masahide Ikeguchi, MD, Michio Maeta, MD and Nobuaki Kaibara, MD

From the First Department of Surgery, Tottori University School of Medicine, Yonago, Japan.

Correspondence: Address correspondence and reprint requests to: Hiroaki Saito, MD, PhD, First Department of Surgery, Tottori University School of Medicine, 36-1 Nishi-cho, Yonago 683-8504, Japan; Fax: 81-859-34-8095; E-mail: KotoriSai10{at}aol.com


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Murine double minute 2 (MDM2) is an oncoprotein that inhibits the function of p53 tumor-suppressor protein. Although there have been a few reports on MDM2 gene abnormalities, there has been no investigation into expression of the product of this gene in esophageal squamous cell carcinoma. Thus, the clinicopathological and prognostic significance of the product of the MDM2 gene is as yet unknown.

Methods: MDM2 protein expression status was analyzed in surgically resected materials by immunohistochemical procedures.

Results: The expression of MDM2 significantly correlated inversely with tumor size, depth of invasion, lymph node metastasis, lymphatic vessel invasion, and stage of disease. However, the expression of MDM2 correlated with neither p53 protein accumulation status nor Ki-67 labeling index. The prognosis with MDM2-positive status was significantly better than that with MDM2-negative status for patients with p53-negative tumors, but not in those with p53-positive tumors. Moreover, multivariate analysis showed that the expression of MDM2 was an independent prognostic factor in patients with p53-negative tumors.

Conclusions: These findings indicate that MDM2 immunohistochemical analysis may provide useful information concerning the prognosis in esophageal squamous cell carcinoma patients with p53-negative tumors.

Key Words: Murine double minute 2 • p53 • Ki-67 • Esophageal carcinoma


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The murine double minute 2 (MDM2) gene was originally identified and cloned by amplification in a transformed tumorigenic BALB/c 3T3 fibroblast cell line.1–3 Its product, p90, is now considered to form a tight complex with both wild-type and mutant p53 tumor-suppressor gene protein and to inactivate wild-type p53 function by masking the N-terminal acidic transactivating domain of the p53 protein.4,5 This indicates that abnormalities of the MDM2 gene or overexpression of its product might be closely associated with tumorigenesis, tumor development, or both. Indeed, MDM2 gene amplification and overexpression of its product have been described in several types of malignancies in humans.

In esophageal cancer, p53 abnormalities have been well examined. However, although there have been a few reports on MDM2 gene abnormalities,6,7 there has been no investigation into expression of the product of this gene in this disease. Thus, the clinicopathological and prognostic significance of the product of the MDM2 gene is as yet unknown.

In this study, the expression of MDM2 and p53 and the Ki-67 labeling index (LI) were immunohistochemically examined in 93 primary esophageal carcinomas to determine their clinicopathological and prognostic significance.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
Primary esophageal squamous cell carcinoma tumor specimens were obtained from 93 patients treated surgically at our institution from April 1981 to October 1994. The patients’ ages ranged from 45 to 81 years (average, 63.9 years); 81 were men and 12 were women. The clinicopathologic findings were determined according to the new tumor-node-metastasis classification.8 No other previous or concomitant primary cancer was present. Patients had received neither chemotherapy nor radiotherapy before surgery. Chemotherapy was given after surgery in 36 patients as follows: (1) intramuscular injection with bleomycin (Nihon Kayaku, Tokyo, Japan) or peplomycin sulfate (Nihon Kayaku) 5 mg/kg was given to 13 patients and (2) intravenous infusion with fluorouracil 350 mg/m2 (Kyowo, Tokyo, Japan) and cisplatin 5 mg/m2 (Nihon Kayaku) was given to 23 patients. Radiotherapy at a dose of 20 to 60 Gy was given to 31 patients after surgery. Data concerning patient outcomes, including overall survival and either development or lack of development of metastases, were available for 89 patients. Informed consent was obtained from all subjects or guardians.

Immunohistochemistry
MDM2 Expression
Four-micrometer sections were dewaxed in xylene, dehydrated in ethanol, and then heated in a microwave oven (700 W) for 10 minutes for retrieval of antigens. Endogenous peroxidase activity was blocked by incubation of samples in a 3% solution of hydrogen peroxide in methanol. After washing with phosphate-buffered saline, the samples were incubated overnight with a mouse monoclonal antibody against MDM2 (dilution, 1/40; Oncogene Science, Cambridge, MA). The samples were then incubated with Envision+ reagent (Dako Co., Ltd., Glostrup, Denmark) for 30 minutes at room temperature. Envision+ reagent is a peroxidase-labeled polymer conjugated to goat antimouse immunoglobulins in Tris-HCl buffer containing carrier protein and an antimicrobial agent. The reaction products were visualized with diaminobenzidine as the chromogen, and the sections were counterstained with methyl green. Normal mouse immunoglobulin G was used instead of the primary antibodies for negative controls. Immunoreactivity was graded as follows: positive, more than 10% of carcinoma cells were stained; and negative, no expression was detectable or fewer than 10% of carcinoma cells were stained.9

p53 Expression
The expression of p53 was detected with monoclonal antibodies against p53 (BP-53, dilution, 1/40; Novocastra Laboratories Ltd., Newcastle Upon Tyne, UK). Immunoreactivity was graded as follows: positive, more than 20% of carcinoma cells were stained; negative, no expression was detectable or fewer than 20% of carcinoma cells were stained.10

Ki-67 LI
The primary antibody Ki-67 (MIB-1, dilution, 1/50; Immunotech International, Marseille, France) was used. In the case of immunostaining with Ki-67, all labeled nuclei in specimens of tumors were regarded as positive. To determine the average frequency of immunolabeling with Ki-67 in nuclei, we monitored 20 randomly chosen microscopic fields in each case and examined 1000 to 2000 cancer cells per field. The result was expressed as the Ki-67 LI (percentage of Ki-67–immunostained cancer cells).10 Characterization of MDM2 expression, p53 expression, and Ki-67 LI was performed by two investigators (S.T. and M.I.) who had no knowledge of the other clinicopathological features or clinical outcomes.

Statistical Analysis
The association of factors was evaluated by the {chi}2 test or Fisher’s exact test. The significance of differences among means was determined by the Mann-Whitney U-test. Survival curves were constructed by the Kaplan-Meier method, and differences between them were examined by the generalized Wilcoxon test. Multivariate analysis was performed by the Cox proportional hazards model. The accepted level of significance for all comparisons was P < .05. A Macintosh (Apple Inc., Cupertino, CA) personal computer system (StatView software; Abacus Concepts, Inc., Berkeley, CA) was used for all statistical analyses.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Correlation Between MDM2 Expression and Clinicopathological Features
The immunostaining pattern was exclusively nuclear and heterogeneous for antibody against MDM2 protein. MDM2 nuclear staining was not confined only to dysplastic or neoplastic regions but was also detected in normal esophageal cells (Fig. 1). In normal mucosa, MDM2 expression was predominant in the basal and suprabasal layers. Variations of the staining intensity of nuclei within the same tumor were observed. Forty-three (46.2%) of 93 carcinomas showed immunoreactivity for MDM2 protein (95% confidence interval, .36–.56). The correlation between MDM2 expression and the clinicopathological features is shown in Table 1. MDM2 expression was inversely correlated with tumor size, depth of invasion, lymph node metastasis, lymphatic vessel invasion, and stage of disease.



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  		FIG. 1. (A) An example of normal esophageal squamous cells showing murine double minute 2 (MDM2) immunoreactivity. The expression of MDM2 was predominant in the basal and suprabasal layers (original magnification, x400). (B) An example of esophageal squamous cell carcinomas showing MDM2 immunoreactivity. The immunostaining is limited to the nucleus, and its intensity ranges from weak to strong (original magnification, x400).

 

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  		TABLE 1. Correlation between MDM2 expression and clinicopathologic features
 
Correlations Among MDM2 Expression, p53 Protein Accumulation, and Ki-67 LI
Thirty (32.2%) of 93 carcinomas showed immunoreactivity for p53 protein. There were 33 patients (35.5%) in the MDM2-/p53- subtype, 17 patients (18.3%) in the MDM2-/p53+ subtype, 30 patients (32.3%) in the MDM2+/p53- subtype, and 13 patients (13.9%) in the MDM2+/p53+ subtype. There was no significant correlation between the expression of MDM2 and p53 protein accumulation (Table 1).

The Ki-67 LI ranged from 11.5 to 84.5, with a mean value of 48.3. Among MDM2-positive tumors, it ranged from 16.7 to 80.1, with a mean value of 47.9, and among MDM2-negative tumors, it ranged from 11.5 to 84.5, with a mean value of 48.8. The difference between these groups was not statistically significant (Table 1).

Correlation Between MDM2 Expression and Prognosis
Data concerning patient outcomes were available for 89 patients, as mentioned in Materials and Methods. Nine patients died of surgical complications and were excluded from this analysis. Of the remaining 80 patients, 46 died of recurrence of disease, and 11 died of another malignancy or disease. Deaths not from esophageal cancer were considered lost to follow-up as of the time of death for the statistical analysis of cumulative survival rate. The 5-year survival rate was 30.8% in patients who received postoperative chemotherapy and was 48.8% in patients who had not received postoperative chemotherapy. The difference between these groups was not statistically significant. The good prognosis in patients who received postoperative chemotherapy seems to be due to a higher percentage of early-stage disease. Thus, postoperative chemotherapy did not seem to improve the prognosis in this study. The 5-year survival rate was 47.9% in MDM2-positive patients and 30.7% in MDM2-negative patients. The prognosis of MDM2-positive patients tended to be better than that of MDM2-negative patients (P = .085; Fig. 2A). To consider a biophysiological function of MDM2 and p53 proteins, survival was separately analyzed according to p53 protein status. In the p53-positive group, the 5-year survival rate was 53.0% in MDM2-positive patients and 41.0% in MDM2-negative patients; the difference between these groups was not statistically significant (P = .569; Fig. 2B). However, in the p53-negative group, the 5-year survival rate was 46.3% in MDM2-positive patients and 25.5% in MDM2-negative patients. The prognosis of MDM2-positive patients was significantly better than that of MDM2-negative patients (P < .05; Fig. 2C). In the multivariate analysis using the Cox proportional hazards model, MDM2 expression, depth of invasion, lymph node metastasis, and lymphatic vessel invasion were found to be independent prognostic factors in the p53-negative group (Table 2).



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  		FIG. 2. (A) Correlation between the expression of murine double minute 2 (MDM2) and prognosis in all cases. The expression of MDM2 tended to correlate with favorable prognosis (P = .085). (B) Correlation between the expression of MDM2 and prognosis in patients with p53-positive esophageal carcinoma. There was no correlation between the expression of MDM2 and prognosis (P = .569). (C) Correlation between the expression of MDM2 and prognosis in patients with p53-negative esophageal carcinoma. The expression of MDM2 was significantly correlated with favorable prognosis (P < .05).

 

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  		TABLE 2. Association of various factors with overall survival determined by the Cox proportional hazards model
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
MDM2 is an oncoprotein that inhibits the function of p53 tumor-suppressor protein. Prior experiences with MDM2 in malignant tumors are listed in Table 3. The frequency of MDM2 gene amplification and MDM2 protein overexpression was different in each malignant tumor.9,11–24 MDM2 protein accumulation in neoplastic cells is known to be due to gene amplification,25 but it is possible that another mechanism is involved, because a fraction of tumors with a normal gene copy number have also been reported to express MDM2 protein.26–28 In this respect, it is noteworthy that enhanced translation represents an alternative mechanism by which the MDM2 oncogene is overexpressed in human choriocarcinoma cell lines.29 Moreover, it has been reported that human breast carcinoma cell lines were found to express high levels of MDM2 messenger RNA, although no amplification of the MDM2 gene was seen in these cell lines.30 Thus, mechanisms for MDM2 overexpression are not only gene amplification, but also enhanced transcription and enhanced translation. These data suggest that the immunohistochemical approach would be a reliable method of detecting MDM2 abnormalities in esophageal carcinoma. However, to the best of our knowledge, there has not been immunohistochemical analysis of the expression of MDM2 in esophageal squamous cell carcinoma.


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  		TABLE 3. The prior experience with MDM2 in various malignant tumors
 
The expression of MDM2 was significantly correlated with favorable prognosis in p53-negative patients, but not in p53-positive patients. In terms of the biophysiological function of MDM2 and p53 proteins, mutant-type p53 itself may have lost its p53 function, and thus MDM2 abnormalities would have had little or no effect on the p53-mediated pathway. The findings we observed among esophageal squamous cell carcinoma patients with p53-positive tumors support this hypothesis. In contrast, we had hypothesized that MDM2 abnormalities were an alternative mechanism, escaping from p53-regulated growth control in wild-type p53 tumors in the same fashion as in mutant-p53 tumors. In fact, it was reported that MDM2 correlated with unfavorable prognosis in some malignant tumors. Thus, the findings we obtained in esophageal squamous cell carcinomas seem to be rather paradoxical. However, Higashiyama et al.19 reported that the expression of MDM2 was correlated with a favorable prognosis in non–small-cell lung cancer patients without p53 protein accumulation. In breast cancers, MDM2 overexpression is strongly associated with estrogen receptor expression, suggesting that MDM2 expression status may also be a favorable prognostic factor.12 In bladder cancer, Lianes et al.20 reported that MDM2 overexpression was observed in patients with relatively early-staged and low-grade tumors, suggesting that MDM2 overexpression may be an early event or possibly a favorable factor associated with low-grade malignancy, although no reports have clearly described its association with prognosis. Recently, Oda et al.31 reported that in the early stage of p53 activation after DNA damage, phosphorylation of Ser-15, Ser-20, and some other sites occurs, and this in turn promotes the binding of p53 to promoters of G1-arrest genes (e.g., p21Waf1), DNA-repair genes (e.g., p53R2), and other genes, such as MDM2. However, if DNA damage is severe and repair is impossible, Ser-46 kinase is activated. This leads to phosphorylation of Ser-46, a subtle change of p53 conformation, and a stronger affinity to promoters of apoptosis-related genes, such as p53AIP1, compared with promoters of G1 arrest or DNA repair–related genes. This may mean that the expression of MDM2 may reflect the activation of p53 function. Thus, the expression of MDM2 was correlated with favorable prognoses in p53-negative patients.

In this study, there was no correlation among MDM2 expression, p53 protein accumulation, and Ki-67 LI. Dellas et al.32 reported that the expression of MDM2 was correlated with p53 accumulation and was inversely correlated with Ki-67 LI in cervical neoplasia. Pruneri et al.18 reported that there was a significant correlation between the expression of MDM2 and wild-type p53 protein accumulation in laryngeal squamous cell carcinoma. In this respect, p53 positivity is not diagnostic of gene mutation, and it is unclear whether accumulated protein is due to p53 gene mutation. Because BP-53, the antibody used here, detects both wild-type and mutated p53 protein, p53 expression may be partially due to wild-type accumulation. Additional studies are needed to resolve this underlying problem.

In conclusion, MDM2 immunohistochemical analysis may provide useful information concerning the prognosis in p53-negative esophageal carcinomas. However, the correlation between MDM2 expression and p53 abnormalities remains to be clarified. Thus, additional studies are needed to resolve this underlying problem.

Received for publication May 31, 2001. Accepted for publication March 5, 2002.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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