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J Thorac Cardiovasc Surg 2008;135:1029-1035
© 2008 The American Association for Thoracic Surgery

General Thoracic Surgery

Reduced membranous β-catenin protein expression is associated with metastasis and poor prognosis in squamous cell carcinoma of the esophagus

Po-Kuei Hsu, MDa, Anna Fen-Yau Li, MD, PhDb, Yi-Ching Wang, PhDc, Chih-Cheng Hsieh, MDa, Min-Hsiung Huang, MDa, Wen-Hu Hsu, MDa, Han-Shui Hsu, MD, PhDa,*

a Division of Thoracic Surgery, Department of Surgery, Taipei Veterans General Hospital, National Yang-Ming University, School of Medicine, Taipei, Taiwan
b Department of Pathology, Taipei Veterans General Hospital, National Yang-Ming University, School of Medicine, Taipei, Taiwan
c Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan

Received for publication July 10, 2007; revisions received August 29, 2007; accepted for publication November 9, 2007.

* Address for reprints: Han-Shui Hsu, MD, PhD, Division of Thoracic Surgery, Department of Surgery, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei, Taiwan. (Email: hsuhs{at}vghtpe.gov.tw).


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Objectives: The aim of this study was to evaluate, by immunohistochemical analysis, the protein expression of β-catenin and p53 in resected esophageal squamous cell carcinoma specimens. The clinical relevance and prognostic significance of the expression of these proteins were also analyzed.

Methods: Immunohistochemistry was performed on paraffin-embedded tissue specimens from 68 resected esophageal squamous cell carcinoma tumor specimens to detect the expression of β-catenin and p53. The correlation between the results of immunoexpression and the clinicopathologic parameters and patient survival was processed statistically.

Results: Reduced membranous β-catenin expression was noted in 43 (63.2%) of 68 tumor specimens. Increased expression of p53 was observed in 43 (63.2%) of 68 specimens. Reduced membranous β-catenin protein expression was associated with the presence of distant metastasis (P = .006). Patients with reduced membranous β-catenin expression had a worse prognosis than patients with normal membranous β-catenin expression (P = .005). Patients with combined increased p53 and reduced membranous β-catenin protein expression had the worst prognosis (P = .012). In a multivariate survival analysis, reduced membranous β-catenin expression and nodal involvement were independent prognostic factors (P = .004 and .019, respectively).

Conclusions: Immunohistochemical analysis revealed that reduced membranous β-catenin protein expression was associated with the presence of distant metastasis and a poor prognosis in patients with esophageal squamous cell carcinoma. Combined increased p53 and reduced membranous β-catenin protein expression indicated a very poor prognosis in patients with esophageal squamous cell carcinoma. Further investigation is needed to understand the roles of β-catenin and p53 in the tumorigenesis and metastasis of esophageal squamous cell carcinoma.

Abbreviations and Acronyms ESCC = esophageal squamous cell carcinoma; GSK3β = glycogen synthase kinase 3β


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
Esophageal squamous cell carcinoma (ESCC) is associated with poor patient survival despite aggressive treatments. The 5-year survival in patients with ESCC is usually approximately 20% to 25% after standard esophagectomy. Many clinicopathologic variables, including the tumor invasion depth, the lymph node involvement, lymphovascular invasion, and distant metastasis, have been examined in patients with ESCC as aids to predict the prognosis.1Go Some molecular changes have also been investigated to elucidate the tumorigenesis of ESCC. Recently, β-catenin has drawn much attention because its connection to tumorigenesis has been reported in many types of gastrointestinal cancers, including colorectal, gastric, and esophageal cancers.2Go The multifunctional β-catenin plays crucial roles in signal transduction and maintenance of cell–cell adhesion.3,4Go Under normal circumstances, the cytoplasmic β-catenin level is kept low through a large multiprotein destruction complex. Within this complex, β-catenin is phosphorylated by casein kinase I{alpha}/glycogen synthase kinase 3β (GSK3β), ubiquitinated by β-transducin-repeat–containing protein, and subsequently degraded in proteasomes.5Go Either β-catenin gene mutation or dysfunction of the destruction complex may lead to accumulation of cytoplasmic β-catenin. Should β-catenin inappropriately enter the nucleus, it forms a complex with T cell–specific factor/lymphoid enhancer binding factor protein and activates aberrant transcription after binding to DNA.3-5Go In addition, β-catenin also links E-cadherin at the cell membrane and associates with the actin cytoskeleton through {alpha}-catenin.6Go In a multi-institutional study enrolling 416 patients with ESCC, the investigators found that loss of E-cadherin expression was associated with a poor prognosis in patients with ESCC.7Go Reduced membranous β-catenin expression may also downregulate the E-cadherin–catenin complex, which may disrupt the integrity of cell architecture and contribute to enhanced tumor cell migration, leading to invasion and metastasis.3,8Go Deregulated β-catenin, either increased cytoplasmic levels or reduced membranous levels, would contribute to tumorigenesis by inappropriate transcription of target genes and the loss of cell–cell adhesion.9Go

A possible cross-talk between the β-catenin and p53 pathways during cancer progression has long been suggested, most notably in human colorectal cancers.10,11Go Activation of p53 occurs in response to a stress signal and leads to either cell cycle arrest or cellular apoptosis.11Go The functional p53 protein safeguards against deregulated cells by eliminating cells with damaged genomes as well as facilitating the repair of such damage.12Go Authors of some studies have demonstrated that β-catenin levels can induce the p14ARF gene, which negatively regulates MDM2 and results in higher p53 levels.10,11Go An activated p53 protein, in turn, positively regulates the transcription of Siah, Axin, and GSK3β proteins, which subsequently act to degrade the β-catenin protein.13-15Go

There are few studies in the literature in which the relationship between β-catenin and p53 protein expression in ESCC is investigated. In this study, we evaluated the protein expression of β-catenin and p53 in resected ESCC specimens by using immunohistochemical analysis. The clinical relevance and prognostic significance of these protein expressions were also analyzed.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients
Tumor specimens were obtained from 68 patients with ESCC who underwent subtotal esophagectomy and reconstruction through a retrosternal approach between 1996 and 2000 at Taipei Veterans General Hospital. There were 2 women and 66 men. The mean age was 65 years (range 36–83 years). None of these patients received chemotherapy or radiotherapy preoperatively. The pathologic tumor stage was determined according to the TNM classification.16Go The clinicopathologic data, including gender, age, depth of tumor invasion, lymph node involvement, and presence of distant metastasis, were collected retrospectively. Postoperative adjuvant therapy was given in patients with lymph node metastasis or in patients who were found to have tumor recurrence or metastasis during the follow-up period. The survival data were obtained from the Cancer Registry Database in the Taipei Veterans General Hospital. Overall patient survival, defined as the time from operation to death, was used as a measure of prognosis. This study was approved by the Institutional Review Board in the Taipei Veterans General Hospital.

Immunohistochemical Staining
Immunohistochemical staining was performed on 3-µm–thick sections of formalin-fixed, paraffin-embedded tissue. After deparaffinization and rehydration, all sections were treated with microwaves in 10 mmol/L citrate buffer (pH 6.0) for 10 minutes at 121°C for antigen retrieval. To block endogenous peroxidase activity, we immersed the sections in serum for 10 minutes. Then all sections were incubated at 4°C overnight with the following antibodies: mouse monoclonal antibody to β-catenin (1:100; Transduction Laboratories, Lexington, Ky) and monoclonal antibody DO-7 (1:150; DAKO, Glostrup, Denmark), which recognizes both wild-type and mutant-type p53 proteins. Monoclonal antibody Ab-5 (1:20; Oncogene, Boston, Mass), which recognizes only wild-type p53 protein, was also used to clarify the type of overexpressed p53. Color reaction was performed by the labeled streptavidin biotin technique with 3,3'-diaminobenzidine as a chromogen (LSAB+ kit, HRP; DAKO). Tissues were counterstained with hematoxylin and then dehydrated. Adjacent normal esophageal epithelium was used as the internal control.

Evaluation of the immunohistochemical staining was conducted by a pathologist who had no knowledge of the clinical characteristics of the patients. The expression was scored as 3 if more than 75% of tumor cells were immunostained positive, as 2 if 25% to 75% of cells were positive, as 1 if less than 25% of cells were positive, and as 0 if less than 5% were positive. The normal esophageal epithelium was positively stained by β-catenin at the cell membrane but negative for β-catenin in the cytoplasm and negative for p53/DO-7 in the nucleus. On the basis of the normal epithelium expression, the membranous β-catenin expression was defined as reduced if the score was 0, 1, or 2 and normal if the score was 3. Cytoplasmic β-catenin expression was defined as increased if the score was 2 or 3 and normal if the score was 0 or 1. Four typical β-catenin expression patterns were described and are shown in Go Figure 1. The p53 expression was defined as normal if the score was 0 or 1 and increased if the score was 2 or 3. In the study, the p53 (Ab-5) antibody was positively stained at the basal proliferative layer of normal esophageal epithelium only, reflecting its role as cell cycle checkpoints at G1 and G2 phase. The positive stain at the basal layer of normal esophageal epithelium served as internal control.


Figure 1
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  		Figure 1. Immunohistochemical staining patterns of β-catenin in ESCC (original magnification x400). A, Preserved β-catenin staining at the cell membrane and normal staining in the cytoplasm. B, Reduced staining at the cell membrane and increased β-catenin staining in the cytoplasm. C, Reduced β-catenin staining at the cell membrane and no staining in the cytoplasm. D, Preserved β-catenin staining at the cell membrane and increased staining in the cytoplasm.

 
Statistical Analyses
The correlations between immunohistochemical results and clinicopathologic variables were analyzed by {chi}2 test. Survival curves were estimated by the Kaplan–Meier method and compared by the log–rank test. Multivariate analysis was performed by the Cox regression model. Covariates were selected in a stepwise fashion with Backward:Ward method. All calculations were performed with SPSS 13.0 software (SPSS, Inc, Chicago, Ill).


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Go Table 1 shows the demographic data and the results of survival analysis in 68 patients with ESCC. The 5-year survival was 23.5%, with a median survival of 20 months. Reduced membranous β-catenin expression was noted in 43 (63.2%) of 68 tumor specimens. Increased expression of cytoplasmic β-catenin was noted in 15 (22.1%) of 68 specimens. Increased protein expression of p53/DO-7 was observed in 43 (63.2%) of 68 specimens. None of the specimens stained positively for wild-type p53 (Ab-5). In the survival analysis, nodal involvement and distant metastasis were associated with poor prognosis (P = .032 and .013, respectively). Patients with reduced membranous β-catenin expression had a worse prognosis than patients with normal membranous β-catenin expression (Go Figure 2, P = .005). Patients with increased p53 expression also had a worse prognosis; however, the difference did not reach statistical significance. In the combined analysis of membranous β-catenin and p53 protein expression in the prognostic significance of patients with ESCC, we observed that patients with increased p53 and reduced membranous β-catenin protein expression had the worst prognosis (Go Figure 3, P = .012). Go Table 2 showed that there was no significant correlation between p53 and membranous or cytoplasmic β-catenin protein expression in ESCC specimens. Go Table 3 shows the relationship between the clinicopathologic parameters and the immunohistochemical staining results. The results showed that reduced membranous β-catenin expression was associated with the presence of distant metastasis (P = .006). There was no relationship between cytoplasmic β-catenin expression and any T, N, or M factors. The increased p53 protein expression correlated with lymph node involvement (P = .047). In multivariate survival analysis, reduced membranous β-catenin expression and nodal involvement were independent prognostic factors (Go Table 4, P = .004 and .019, respectively).


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  		Table 1 Patient demographics and univariate survival analysis results
 

Figure 2
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  		Figure 2. The Kaplan–Meier survival curve for protein expression of membranous β-catenin, indicating that patients with reduced membranous β-catenin protein expression had a poor prognosis (log–rank test, P = .005).

 

Figure 3
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  		Figure 3. The Kaplan–Meier survival curve for protein expression of p53 and membranous β-catenin, showing that combined increased p53 expression and reduced β-catenin expression was associated with a poor prognosis (log–rank test, P = .012).

 

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  		Table 2 Relationship between p53 and β-catenin expression in the cell membrane and cytoplasm
 

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  		Table 3 Relationship between clinicopathologic features and immunohistochemical staining results
 

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  		Table 4 Multivariate survival analysis results
 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
In the present study, we showed for the first time, using immunohistochemical analysis, that reduced membranous β-catenin protein expression is associated with distant metastasis and poor prognosis and that combined increased p53 and reduced membranous β-catenin protein expression are indicative of a very poor prognosis in patients with ESCC. In our study, 63.2% of tumor specimens had reduced β-catenin staining in the cell membrane, which is compatible with some previous reports in the literature.17-22Go In contrast to our study, Castro,17Go Nair,18Go and their colleagues found no correlation between membranous β-catenin expression and any clinicopathologic features including tumor grade and patient survival. In Japan, Takayama,19Go Nakanishi,20Go and their associates reported that although downregulation of membranous β-catenin was associated with poor tumor differentiation, membranous β-catenin expression did not have prognostic significance in ESCC. In another study by Takayama and coworkers,21Go reduction in membranous β-catenin expression was associated with the depth of tumor invasion and lymph node involvement. In China, Zhao and colleagues22Go reported that there was a correlation between membranous β-catenin expression and tumor histologic grade. Patients harboring tumors with low membranous β-catenin expression had shorter survival times than those with higher expression, but the difference did not reach statistical significance in that study. In our study, all 11 patients with distant metastasis had reduced membranous β-catenin expression. In contrast, none of patients with normal membranous β-catenin expression had distant metastasis. In a multivariate survival analysis, reduced membranous β-catenin expression was also an independent prognostic factor.

A possible explanation for the correlation between reduced membranous β-catenin expression and distant metastasis may be disruption of cell–cell junction integrity. The metastasis cascade includes steps of local invasion, intravasation, extravasation, and re-establishment at distant organs.23Go In the initial steps of local invasion and intravasation, the cancer cells undergo the epithelial–mesenchymal transition, which is a process that stable cell–cell and cell–matrix interaction was lost, and the tumor invasiveness was increased.24Go The hallmark of epithelial–mesenchymal transition is the loss of the adherens junction, which consists of β-catenin and E-cadherin (E-cadherin–catenin complex).25Go Following the logic of this theory, it is intuitive that reduced membranous β-catenin expression causes the dysfunction of the E-cadherin–catenin complex, promotion of cancer cell detachment from primary site, and facilitation of cancer cell dissemination. The results of our study indicated that membranous β-catenin is important in maintaining the cell–cell junction in ESCC and that loss of membranous β-catenin may contribute to enhanced tumor metastasis.

Cytoplasmic β-catenin is a member of the WNT pathway, which had been investigated extensively in colorectal carcinogenesis2-5Go; however, its role in ESCC tumorigenesis is less clear. Authors of previous works have reported that increased cytoplasmic β-catenin expression was found in approximately 18% to 68% of ESCC.17,26,27Go In the study by Zhang and colleagues,26Go which included 44 patients with ESCC, the authors observed that increased cytoplasmic β-catenin expression was associated with lymph node metastasis. In another study, Shiozaki and associates27Go showed that patients with increased cytoplasmic β-catenin expression had worse prognoses; however, in multivariate analysis, cytoplasmic β-catenin expression was not an independent significant prognostic factor in ESCC. In our study, increased cytoplasmic β-catenin was noted in 22.1% of ESCC tumor specimens. Cytoplasmic β-catenin protein expression was not associated with any clinicopathologic parameters or patient survival.

The clinical significance of p53 protein expression in ESCC is controversial. In our study, increased p53 expression was observed in 63.2% of ESCC tumor specimens and was associated with the nodal involvement. Although patients with increased p53 expression have a worse prognosis than those with normal p53 expression, the difference did not reach statistical significance. Some in vitro studies have revealed cross-talk between β-catenin and p53. Accumulation of β-catenin can serve as a stimulus for activation of p53 through interaction with p14ARF and MDM2.10,11Go On the other hand, activated p53 is able to enhance the expression of Siah, Axin, and GSK3β proteins, which mediate the degradation of the β-catenin protein.13-15Go In one study based on the Drosophila eye disc model, Yamaguchi and colleagues28Go observed that mutation of the Armadillo (Drosophila β-catenin) gene, which is essential for adherens junctions integrity, leads to enhancement of p53-induced apoptosis, suggesting that abnormality at the adherens junction is a signal for p53 activation and activated p53 consequently induces apoptosis to remove abnormal cells from tissue. These interactions between β-catenin and p53, however, could not be confirmed by immunohistochemistry methods in human cancers. In hepatocellular carcinoma, Torbenson and associates29Go found no association between cytoplasmic β-catenin and p53 expression. In lung adenocarcinoma, Nozawa and colleagues30Go concluded that there was no association between membranous β-catenin and p53 expression. The relationship between β-catenin and p53 has never been evaluated in ESCC. In this study, we found no correlation between β-catenin and p53 expression by using immunohistochemical methods; however, we did show for the first time that combined increased p53 and reduced membranous β-catenin expression indicated a very poor prognosis in ESCC. Further study to elucidate the relationship between membranous β-catenin and p53 protein expression may be mandatory.

In conclusion, using immunohistochemical analysis, we found that reduced membranous β-catenin protein expression was associated with the presence of distant metastasis and poor prognosis in ESCC. Combined increased p53 and reduced membranous β-catenin protein expression indicated a very poor prognosis in patients with ESCC. Further investigation is needed to understand the roles of β-catenin and p53 in the tumorigenesis and metastasis of ESCC.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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