γ-Catenin acts as a tumor suppressor through context-dependent mechanisms in colorectal cancer.

PURPOSE: γ-Catenin is a protein closely related to ß-catenin. While the overexpression of ß-catenin has been linked with impaired prognosis and survival in various malignancies, both oncogenic and tumor suppressor functions have been described for γ-catenin. Thus, its role in cancer remains controversial. In this study, we examined the impact of γ-catenin expression on the malignant potential of colorectal cancer cells. METHODS: γ-Catenin was knocked down by short interfering RNA in the γ-catenin-proficient DLD-1 cell line and stably overexpressed in the γ-catenin-deficient cell line RKO. The effects of these molecular manipulations on the malignant potential of the cell lines were tested in vitro and in vivo in a xenograft tumor model. RESULTS: γ-Catenin contributed to Wnt signaling independent of the cellular context. Unlike its sister molecule ß-catenin, γ-catenin inhibited cellular invasion and anoikis in cells endogenously expressing γ-catenin. In line with this tumor suppressor function, its de novo expression in RKO cells inhibited proliferation via cell cycle arrest. In a xenograft tumor model, overexpression of γ-catenin starkly reduced tumor growth in vivo. CONCLUSIONS: This is the first report demonstrating a tumor-suppressive effect of γ-catenin in colorectal cancer both in vitro and in vivo. Detailed in vitro analysis revealed that effects of γ-catenin differ in γ-catenin proficient and deficient cells, indicating that its function in colorectal cancer is dependent on the cellular context. This finding adds to our understanding of γ-catenin and may have implications for future studies of catenin/Wnt targeted cancer therapies.

γ-Catenin is an independent prognostic marker in early stage colorectal cancer.

PURPOSE: Expression and role of γ-catenin in colorectal carcinogenesis is not well understood. We aimed at characterizing γ-catenin's expression pattern during colorectal carcinogenesis. METHODS: The expression pattern of γ-catenin was characterized in adenomas, primary colorectal carcinomas, and their corresponding metastases. Since this descriptive immunohistochemical analysis revealed upregulation of γ-catenin in the invasive front of both primary tumors and metastases, a tissue microarray (TMA) was performed, allowing for correlation of subcellular expression patterns with disease recurrence and cancer-specific survival. Comparison of γ-catenin expression with that of ß-catenin was performed. RESULTS: In normal colonic epithelium and adenomas, γ-catenin was weakly expressed at the membrane. In central areas of primary colorectal carcinomas, membranous and cytoplasmatic expression was present, with cytoplasmatic and nuclear upregulation of γ-catenin in the invasive fronts. Expression patterns found in metastases resembled those of their respective primary tumors. Subsequent TMA analysis showed that upregulation of cytoplasmatic γ-catenin in the invasive fronts of curatively resected early T2 and T3 colorectal carcinomas was associated with shortened disease-free survival and an increased risk of death (p=0.003; hazard ratio = 2.98; 95% confidence interval, 1.44-6.18). CONCLUSIONS: The correlation of upregulated cellular γ-catenin levels with higher recurrences and impaired survival suggests a tumor promoting role of γ-catenin in colorectal cancer. γ-Catenin may therefore serve as a marker for identifying patients who are at increased risk of disease recurrence who may benefit from closer follow-up and adjuvant therapy.