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

To evaluate the significance of γ-catenin in clinical pathology, cellular function and signaling mechanism in esophageal squamous cell carcinoma (ESCC).

The mRNA expression of γ-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 γ-catenin were used to inhibit γ-catenin expression. Hanging drop aggregation assay and dispase-based dissociation assay were performed to detect the effect of γ-catenin on ESCC cell-cell adhesion. Transwell assay was performed to determine cell migration. Luciferase-based transcriptional reporter assay (TOPflash) was used to measure β-catenin-dependent transcription in cells with reduced γ-catenin expression. The expression and subcellular localizations of β-catenin and E-cadherin were examined using Western blot and immunofluorescence analysis.

γ-catenin mRNA expression was significantly associated with tumor histological grade (P = 0.017) in ESCC. Kaplan-Meier survival analysis showed that γ-catenin expression levels had an impact on the survival curve, with low γ-catenin indicating worse survival (P = 0.003). The multivariate Cox regression analysis demonstrated that γ-catenin was an independent prognostic factor for survival. Experimentally, silencing γ-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 γ-catenin expression. Total β-catenin and Triton X-100-insoluble β-catenin were significantly reduced in the γ-catenin-specific siRNA-transfected KYSE150 and TE3 cells, whereas Triton X-100-soluble β-catenin was not altered. Moreover, knocking down γ-catenin expression resulted in a significant decrease of E-cadherin and Triton X-100-insoluble desmocollin-2, along with reduced β-catenin and E-cadherin membrane localization in ESCC cells.

γ-catenin is a tumor suppressor in ESCC and may serve as a prognostic marker. Dysregulated expression of γ-catenin may play important roles in ESCC progression.