Impact of positive ZEB1 expression in patients with epithelial ovarian carcinoma as an oncologic outcome-predicting indicator

Abstract

Several previous studies have revealed that the expression of zinc finger E-box binding homeobox 1 (ZEB1) in solid malignancies has an important significance on the clinical outcome of patients. However, the association between ZEB1 expression and survival in patients with epithelial ovarian carcinoma (EOC) remains unclear. The objective of the present study was to examine the extent of ZEB1 expression in EOC using immunohistochemical staining and investigate its association with patient outcome. A total of 40 patients with EOC initially treated with cytoreductive surgery and systematic chemotherapy were enrolled. ZEB1 expression was immunohistochemically categorized as negative, weak, moderate and strong according to the size of the staining area, and intensity. Subsequently, the associations between ZEB1 expression and recurrence/progression-free survival (RFS) rate were examined. The median age of patients in the current study was 54 years old (range, 22-72 years old). Among these patients, 15 (37.5%) exhibited International Federation of Gynecology and Obstetrics stage I disease, and 10 (25.0%), 13 (32.5%), and 2 (5%) had stage II, III, and IV disease, respectively. No patients with negative expression of ZEB1 experienced recurrence. In addition, ZEB1 expression was identified to be a significant predictor of a poorer RFS rate compared with negative expression (negative vs. weak, moderate and strong, P=0.0126). Furthermore, multivariate analyses revealed that moderate and strong ZEB1 expression levels were significant prognostic indicators of a poorer RFS rate in patients with EOC (hazard ratio, 2.265; 95% confidence interval, 1.072-8.021; P=0.0349). Confining analysis to patients with the clear-cell/mucinous histological type, those with moderate/strong ZEB1 expression demonstrated a significantly poorer RFS rate (P=0.0025). Positive ZEB1 expression may be an indicator to predict unfavorable RFS in patients with EOC.

Keywords: epithelial ovarian carcinoma; epithelial-mesenchymal transition; immunohistochemical staining; recurrence/progression-free survival; zinc finger E-box binding homeobox 1.

Figure 1.

Survival impact of ZEB1 expression in EOC tissues. Immunoreactivity of ZEB1 observed in surgical EOC samples (paraffin sections), positive or negative expression of ZEB1 in EOCs. (A) Negative (serous carcinoma), (B) weakly positive (clear-cell carcinoma), (C) moderately positive (serous carcinoma), (D) strongly positive (mucinous carcinoma); magnification ×100. (E and F) Negative controls (the primary antibody was replaced with normal rabbit IgG: Clear-cell carcinoma), Bars: 100 µm.

Figure 2.

The frequency of recurrence according to the extent of ZEB1 positivity. There was no patient with negative expression of ZEB1 who experienced recurrence. Patients with higher ZEB1 positivity showed a higher rate of recurrence (Cochran-Armitage test for trend, P=0.042).

Figure 3.

The frequency of recurrence according to the extent of ZEB1 positivity in patients with the clear-cell/mucinous histological type. Confining analysis to patients with the clear-cell/mucinous histological type, the frequency of an unfavorable oncologic outcome (death) was higher in patients with a higher ZEB1 positivity (Moderate + strong expression) (Fisher's exact test: P=0.0086).

Figure 4.

Kaplan-Meier progression-free survival curves for primary EOC patients according to the immunoreactivity of ZEB1. (A) Solid line indicates negative ZEB1 expression (negative: N=7). The discontinuous line represents positive ZEB1 immunoexpression (weakly, moderately, and strongly positive: N=33). Patients with positive ZEB1 expression showed a significantly poorer recurrence/progression-free survival (P=0.0126). (B) The solid line represents negative, weakly, and moderately positive ZEB1 expression (N=32). The discontinuous line represents strongly positive ZEB1 immunoexpression (N=8). Patients with strongly positive ZEB1 expression showed a significantly poorer recurrence/progression-free survival (P=0.0188).

Figure 5.

Kaplan-Meier progression-free survival curves in patients with the mucinous/clear-cell histological type according to the immunoexpression of ZEB1. The solid line represents negative-weakly positive ZEB1 expression (negative: N=14). The discontinuous line represents moderately-strongly positive ZEB1 immunoexpression (N=7). Patients with moderate-strong ZEB1 expression showed a significantly poorer recurrence/progression-free survival (P=0.0025).