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Clinical Cancer Research Vol. 11, 1174-1180, February 2005
© 2005 American Association for Cancer Research

Imaging, Diagnosis, Prognosis

Slug Expression in the E-cadherin Preserved Tumors Is Related to Prognosis in Patients with Esophageal Squamous Cell Carcinoma

Yasuto Uchikado, Shoji Natsugoe, Hiroshi Okumura, Tetsuro Setoyama, Masataka Matsumoto, Sumiya Ishigami and Takashi Aikou

Department of Surgical Oncology, Digestive Surgery, Graduate School of Medicine, Kagoshima University, Kagoshima, Japan

Requests for reprints: Yasuto Uchikado, Department of Surgical Oncology, Digestive Surgery, Graduate School of Medicine, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan. Phone: 81-99-275-5361; Fax: 81-99-265-7426; E-mail: just-u{at}m.kufm.kagoshima-u.ac.jp.


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Purpose: The expression of E-cadherin correlates with the development, progression, and metastasis of esophageal squamous cell carcinoma (ESCC). Slug, a member of the snail family of transcriptional factors, is a newly identified suppressive transcriptional factor of E-cadherin. The purpose of the present study was to evaluate the clinical significance of E-cadherin and Slug expression in ESCC.

Experimental Design: Immunohistochemistry was used to investigate the expression of E-cadherin and Slug proteins in 203 patients with ESCC. The relationships between expression of these proteins and clinicopathologic factors, including prognosis, were analyzed.

Results: Positive expression of E-cadherin and Slug was observed in 43% and 48% of cases, respectively. The tumors with reduced E-cadherin expression or positive Slug expression invaded deeper, had more lymph node metastasis, and had more lymphatic invasion than the tumors with preserved E-cadherin expression or negative Slug expression. Slug expression significantly correlated with reduced E-cadherin expression. Sixty-seven of the 98 (68.4%) tumors with positive Slug expression had reduced E-cadherin expression (P = 0.0011). Patients with reduced E-cadherin expression or positive Slug expression had poor clinical outcomes. In the preserved E-cadherin group, the 5-year survival rate was better for patients who were negative for Slug expression than for those who were positive for Slug expression (P = 0.035). Multivariate analysis indicated that E-cadherin expression and Slug expression were not independent prognostic factors.

Conclusions: Evaluation of not only the expression of E-cadherin but also the co-expression of E-cadherin and Slug in preserved E-cadherin group is useful for predicting malignant properties of ESCC.

Key Words: cell adhesion • transcriptional factor • immunohistochemistry • malignant property


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive carcinomas of the gastrointestinal tract. There have been studies of the effects of various biological factors on the malignant potential of ESCC. One of those factors is E-cadherin, which is a major cell-to-cell adhesion molecule that plays a critical role in the development and maintenance of cell polarity and tissue architecture (1, 2). The expression of E-cadherin is regulated at the genetic level via processes such as mutation, loss of heterozygosity, and hypermethylation of its promoter (3–5). In ESCC, loss of E-cadherin expression is associated with tumor invasiveness, metastasis, and prognosis (6, 7).

Slug is a member of the snail family of repressors, and is expressed in the neural crest and in mesodermal cells emigrating from the primitive streak in chick embryos (8). Recently, another critical role of Slug has been reported. Slug binds to E-box elements in the proximal E-cadherin promoter and represses transcription of the E-cadherin gene (9).

The purpose of the present study was to examine the clinical significance of Slug expression in ESCC and correlation between Slug expression and E-cadherin expression in ESCC.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients and Specimens. The subjects were 203 patients with ESCC (181 males and 22 females) who underwent esophagectomy with lymph node dissection between 1987 and 1998 at Kagoshima University Hospital, Kogoshima, Japan. The patients ranged in age from 36 to 85 years (mean, 64.2 years). None of these patients underwent endoscopic mucosal resection, palliative resection, preoperative chemotherapy, or radiotherapy, and none of them had synchronous or metachronous multiple cancer in other organs. Specimens of cancer tissues and noncancerous adjustment tissue were collected from the patients after informed consent had been obtained in accordance with the institutional guidelines of our hospital.

Using the tumor node metastasis classification of the International Union Against Cancer (10), all of the M1 tumors were attributable to distant lymph node metastases (Table 1). All patients were followed up after discharge, with X-ray examination and tumor marker assays (squamous cell carcinoma antigen and carcinoembryonic antigen) done every 1 to 3 months, computed tomography done every 3 to 6 months, and ultrasonography done every 6 months. Bronchoscopic and endoscopic examinations were done when necessary. Postoperative follow-up data were obtained from all patients, with a median follow-up period of 30 months (range, 1-173 months).


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  		Table 1 E-cadherin and Slug expression in relation to clinicopathologic findings

 
Immunohistochemical Staining and Evaluation. The specimens were cut into 3-µm-thick sections, which were mounted on glass slides. Immunohistochemical staining was done using the streptavidin-biotin peroxidase method as described previously (11). Briefly, after sections were deparaffinized in xylene and dehydrated in ethanol, endogenous peroxidase activity was blocked by incubating sections for 15 minutes in 0.3% hydrogen peroxide in methanol. Then, the sections were heated in a citrate buffer (0.01 mol/L, pH 6.5) at 120°C for 10 minutes (microwave oven/450 W) to reveal the antigen. After cooling, the sections were preincubated in 3% skim milk/PBS for 30 minutes. Next, sections were incubated with either anti-E-cadherin monoclonal antibody (1:100, E-cadherin, Takara Biotechnology, Inc., Takara, CA) or anti-Slug polyclonal antibody (1:100, Slug: D-19, Santa Cruz Biotechnology, Inc., Santa Cruz, CA) overnight at 4°C. The sections were then incubated with biotinylated anti-goat IgG and streptavidin-biotin peroxidase [Histofine SAB-PO (G) kit, Nichirei Corporation, Tokyo, Japan], and reactions were visualized using diaminobenzidine tetrahydrochloride.

Evaluation of immunohistochemistry was independently done by two investigators (Y.U. and S.N.). Expression of E-cadherin was compared between malignant cells and normal epithelial cells located distant from the tumor. Tumor cells that stained as strongly as normal epithelial cells were considered to have preserved expression, whereas those that exhibited weaker staining patterns than normal epithelial cells or did not stain at all were considered to have reduced expression (12). For Slug, positive expression was defined as detectable immunoreaction in perinuclear and other cytoplasmic regions of >10% of the cancer cells. To evaluate expression of Slug and E-cadherin, 10 fields (within the tumor and at the invasive front) were selected and expression in 1,000 tumor cells (100 cells/field) was evaluated using high-power (x200) microscopy.

Statistical Analysis. Statistical analysis of group differences was done using the {chi}2 test and t test. The Kaplan-Meier method was used for survival analysis, and differences in survival were estimated using the log rank test. The prognostic factors were examined by univariate and multivariate analyses (Cox proportional hazards regression model). P < 0.05 was considered to indicate statistical significance. All statistical analyses were done using the JMP 5 for Windows software (SAS Institute, Inc., Cary, NC).


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Expression of E-cadherin and Slug in Esophageal Squamous Cell Carcinoma. E-cadherin expression was observed on the cell membrane of cancer cells, indicating preserved expression, in 43% of all patients (88 of 203; Fig. 1A and B). Expression of Slug was observed in the cytoplasm of cancer cells in 48% of all patients (98 of 203; Fig. 1C and D).



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  		Fig. 1 Expression of E-cadherin and Slug in ESCCs. A, preserved expression of E-cadherin is detected in the cell membrane (x400); B, reduced expression of E-cadherin (x400); C, expression of Slug is detected in the cytoplasm (x400); D, no expression of Slug (x400).

 
Relationship between E-cadherin and Slug Expression and Clinicopathologic Variables. E-cadherin expression was significantly associated with the following clinicopathologic parameters: depth of tumor invasion, lymph node metastasis, stage, and lymphatic invasion (Table 1). The tumors with reduced E-cadherin expression invaded deeper, had more lymph node metastasis, and had more lymphatic invasion than the tumors with preserved expression (P < 0.0001, respectively).

Expression of Slug was associated with depth of tumor invasion, lymph node metastasis, stage, lymphatic invasion, and venous invasion (Table 1). The tumors that were positive for Slug expression invaded deeper, had more lymph node metastasis, had more lymphatic invasion, and had more venous invasion than those that were negative for Slug expression (P = 0.0001, 0.002, 0.0025, and 0.013, respectively).

Presence of Slug expression significantly correlated with reduced E-cadherin expression (Table 2). Sixty-seven of the 98 (68.4%) tumors that were positive for Slug expression had reduced E-cadherin expression (P = 0.0011).


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  		Table 2 Comparison of Slug expression between preserved and reduced expression of E-cadherin

 
Relationship between Expression of Slug and Clinicopathologic Variables According to E-cadherin Expression. The tumors were divided into the preserved E-cadherin group and reduced E-cadherin group. In the E-cadherin preserved group, the expression of Slug was related to depth of tumor invasion, stage, and venous invasion; in the E-cadherin reduced group, the expression of Slug was related to histology, stage, and lymphatic invasion (Table 3).


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  		Table 3 Relationship between Slug expression and clinicopathologic findings according to E-cadherin expression

 
Relationship between Prognosis and Expression of E-cadherin and Slug. Six of the patients died of postoperative complications within 30 days of the beginning of the study period, leaving 197 patients for survival analysis. The 5-year survival rate of patients with tumors with preserved E-cadherin expression was 35.2%, whereas the rate for reduced E-cadherin expression was 20.9%. There was a significant difference in 5-year survival between preserved and reduced expression of E-cadherin (P = 0.005; Fig. 2A). The 5-year survival rate of patients negative and positive for expression of Slug was 32.4% and 21.4%, respectively, and the difference was significant (P = 0.014; Fig. 2B).



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  		Fig. 2 The postoperative 5-year survival curve of patients according to the expression of E-cadherin (A) or Slug (B). There was a significant difference in survival between the patients with preserved and reduced expression of E-cadherin (P = 0.005). There was also a significant difference in 5-year survival between the patients with (+) and without (–) expression of Slug (P = 0.014).

 
Relationship between Prognosis and Slug Expression in the Preserved and Reduced E-cadherin Groups. In the preserved E-cadherin group, the 5-year survival rate was significantly higher for patients negative for Slug expression than for those positive for Slug expression (P = 0.035; Fig. 3A). However, in the E-cadherin reduced group, there was no significant difference between patients positive and negative for Slug expression (Fig. 3B).



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  		Fig. 3 The postoperative survival curves between the patients with (+) and without (–) Slug expression according to E-cadherin expressions. A, in the preserved E-cadherin expression group, the patients without Slug expression (–) had a better outcome than those with Slug expression (+; P = 0.035). B, in the reduced E-cadherin expression group, there was no difference between the patients with Slug expression (+) and without Slug expression (–).

 
Univariate and Multivariate Analyses of Survival. Tables 4 and 5 show the univariate and multivariate analyses of factors related to patient prognosis. The univariate analysis showed that the following factors were significantly related to postoperative survival: depth of tumor invasion, lymph node metastasis, stage, lymphatic invasion, venous invasion, E-cadherin expression, Slug expression, and combination of E-cadherin and Slug expression (P < 0.05). Multivariate regression analysis indicated that depth of invasion and lymph node metastasis were independent prognostic factors but indicated that E-cadherin expression, Slug expression, and the combination of E-cadherin and Slug expression were not independent prognostic factors.


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  		Table 4 Univariate analyses of prognostic factors in ESCC

 

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  		Table 5 Multivariate analyses of prognostic factors in ESCC

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Previous studies indicate that reduction of expression of E-cadherin ranges from 18.2% to 87% of baseline in specimens of ESCC, and that reduced expression of E-cadherin is associated with lymph node metastasis and poor prognosis (2, 6, 13–16). In the present study, 57% of patients with ESCC showed reduced expression of E-cadherin, which was associated with depth of invasion, lymph node metastasis, stage, lymphatic invasion, and poor prognosis. Thus, the present results are consistent with previous reports.

In the present study and in previous studies, although some patients with preserved E-cadherin expression had lymph node metastases and died of recurrence after surgery, most survived for a relatively long period without lymph node metastases or recurrence (6). In the present study, to investigate a molecular factor involved in regulation of the function of E-cadherin, we examined expression of Slug, which is a suppressive transcriptional factor of E-cadherin (17). In the present study, we found that positive Slug expression is associated with reduced E-cadherin expression, tumor invasion, and worse clinical outcomes. In the preserved E-cadherin group, the patients that were positive for Slug expression had deeper tumor invasion and worse prognosis. Thus, it seems that Slug not only suppresses the function of E-cadherin but also promotes tumor invasion in the preserved E-cadherin group (Fig. 4A).



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  		Fig. 4 Different signaling pathways of Slug between E-cadherin preserved and reduced tumors. A, in the tumors with preserved E-cadherin expression, Slug is related not only to suppression of E-cadherin function but also to anti-apoptotic or down-regulatory function of other adhesion molecules, including desmoplakin, Muc-1, and cytokeratin-18. B, in the tumors with reduced E-cadherin expression, E-cadherin expression may be regulated not only by Slug function but also by DNA mutation or CpG methylation.

 
Slug has an anti-apoptotic effect on leukemia cells (18, 19) and down-regulates epithelial markers including desmoplakin, Muc-1, and cytokeratin-18 (20, 21). These previous findings imply that the anti-apoptotic or down-regulatory function of certain adhesion molecules can worsen the outcome of patients with preserved E-cadherin expression. In contrast, in the patients with reduced E-cadherin expression, expression of Slug did not have a marked effect on prognosis. When E-cadherin expression is reduced in ESCC, E-cadherin expression may be regulated not only by suppressive transcriptional factors, such as Slug, but also by genetic or epigenetic alterations, such as DNA mutation or methylation (4, 5, 22; Fig. 4B).

Although preserved E-cadherin expression without Slug expression was an independent prognostic factor in univariate analyses, it was not an independent prognostic factor in multivariate analyses. Expression of Slug may play a particularly important role in tumors with preserved E-cadherin expression.

In conclusion, E-cadherin and Slug expression were associated with tumor properties, including depth of invasion, lymph node metastasis, stage, lymphatic invasion, and prognosis. Although E-cadherin expression and Slug expression were not independent prognostic factors, evaluation of both expression of E-cadherin and co-expression of E-cadherin and Slug is useful for predicting malignant properties of ESCC.


   FOOTNOTES
 
Grant support: Grant-in-Aid for scientific research from the Ministry of Education, Science, Sports, and Culture of Japan.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 9/13/04; revised 11/ 5/04; accepted 11/11/04.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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