Down-regulated γ-catenin expression is associated with tumor aggressiveness in esophageal cancer

AIM: To evaluate the significance of gamma-catenin in clinical pathology, cellular function and signaling mechanism in esophageal squamous cell carcinoma (ESCC). METHODS: The mRNA expression of gamma-catenin was detected by real-time quantitative reverse transcription-polymerase chain reaction in 95 tissue specimens and evaluated for association with the clinicopathologic characteristics and survival time of patients with ESCC. siRNAs against human gamma-catenin were used to inhibit gamma-catenin expression. Hanging drop aggregation assay and dispase-based dissociation assay were performed to detect the effect of gamma-catenin on ESCC cell-cell adhesion. Transwell assay was performed to determine cell migration. Luciferase-based transcriptional reporter assay (TOPflash) was used to measure beta-catenin-dependent transcription in cells with reduced gamma-catenin expression. The expression and subcellular localizations of beta-catenin and E-cadherin were examined using Western blot and immunofluorescence analysis. RESULTS: gamma-catenin mRNA expression was significantly associated with tumor histological grade (P = 0.017) in ESCC. Kaplan-Meier survival analysis showed that gamma-catenin expression levels had an impact on the survival curve, with low gamma-catenin indicating worse survival (P = 0.003). The multivariate Cox regression analysis demonstrated that gamma-catenin was an independent prognostic factor for survival. Experimentally, silencing gamma-catenin caused defects in cell-cell adhesion and a concomitant increase in cell migration in both KYSE150 and TE3 ESCC cells. Analysis of Wnt signaling revealed no activation event associated with gamma-catenin expression. Total beta-catenin and Triton X-100-insoluble beta-catenin were significantly reduced in the gamma-catenin-specific siRNA-transfected KYSE150 and TE3 cells, whereas Triton X-100-soluble beta-catenin was not altered. Moreover, knocking down gamma-catenin expression resulted in a significant decrease of E-cadherin and Triton X-100-insoluble desmocollin-2, along with reduced beta-catenin and E-cadherin membrane localization in ESCC cells. CONCLUSION: gamma-catenin is a tumor suppressor in ESCC and may serve as a prognostic marker. Dysregulated expression of gamma-catenin may play important roles in ESCC progression. (C) 2014 Baishideng Publishing Group Inc. All rights reserved.