Prognostic impact of EMT (epithelial-mesenchymal-transition)-related protein expression in endometrial cancer

Abstract

Objectives: The epithelial-mesenchymal-transition (EMT) is an important step in the invasion and metastasis of cancer. A critical molecular feature of this process is the downregulation of E-cadherin expression, which is mainly controlled by Snail-related zinc-finger transcription factors (Snail and Slug). The aim of this study was to evaluate the prognostic impact of EMT-related protein (E-cadherin, Snail and Slug) expression in endometrial cancer.

Methods: An immunohistochemical analysis was conducted using tissue microarray samples of 354 primary tumors and 30 metastases of endometrial carcinomas, and the relationship between protein expression, clinicopathological features and outcomes were investigated.

Results: Reduced E-cadherin was seen in 39.8% of primary tumors. Reduced E-cadherin was seen in 19.5%, 40.8% and 72.7% of G₁, G₂ and G₃ endometrioid adenocarcinomas, respectively. The nuclear expression of Snail and Slug were positive in 16.9% and 3.7% of primary tumors, respectively. EMT status, which was represented by both reduced E-cadherin and nuclear expression of Snail, was significantly associated with histological type, FIGO stage, myometrial invasion, positive peritoneal cytology and patient survival (p < 0.01). There was no difference in the rates of EMT status between the primary tumors and metastases. A multivariate analysis showed that EMT-positive status was a significant predictor for both the progression-free survival and overall survival (p < 0.01).

Conclusions: These data indicate that EMT status has a prognostic impact in endometrial cancer. Therefore, the clarification and control of EMT signaling is a promising molecular targeting therapy in endometrial cancer.

Figure 1. Representative examples of immunohistochemically sequential sections stained by E-cadherin, Snail and Slug in endometrioid adenocarcinoma G₁ (A and B) and carcinosarcoma (C) (A, B, C 40X original magnification). (A), E-cadherin expression was preserved (positive) in G₁endometrioid adenocarcinoma. Snail expression was detected mainly in the cytoplasm of tumor specimens because Snail is a transcription factor (negative), but no Slug expression was detected. Endometrioid adenocarcinoma G₁ (B) sections showed reduced E-cadherin (negative) and nuclear expression of Snail (positive) but no Slug staining. Carcinosarcoma (C) showed the nuclear expression of Snail and Slug, in addition to reduced E-cadherin (positive). Scale bars represent 100 µm.

Figure 2. Survival curves generated by using the Kaplan-Meier method in 354 endometrial cancer patients. The progression-free survival and overall survival of patients were stratified according to the EMT status. An EMT status which was represented by both reduced E-cadherin expression and nuclear Snail expression was defined as positive. P values were calculated using the log-rank test.