γ-catenin acts as a tumor suppressor in Colorectal Cancer in a context-dependent manner

γ-catenin (plakoglobin) is a protein closely related with ß-catenin. Overexpression of γ-catenin has been shown to suppress tumor formation independent of γ-catenin's function in cell-cell adhesion, but tumor-promoting effects have also been reported.

To investigate into γ-catenin's role in colorectal cancer cells with and without endogenous expression of γ-catenin.

In DLD-1 cells with high levels of γ-catenin, γ-catenin expression was silenced by siRNA. In γ-catenin negative RKO cells, a mutant, non-degradable form of γ-catenin was stably overexpressed.

Knock-down of γ-catenin reduced Wnt-activity by 30%, whereas knock-down of β-catenin in DLD-1 cells did not affect g-catenin expression and virtually abolished Wnt signalling activity. Knock-down of γ-catenin did not lead to changes in DLD-1 cell cycle but increased tumor cell invasion, suggesting a migration-suppression role for γ-catenin. In a methylcellulose assay, knock-down of γ-catenin did not change colony formation. Thus, γ-catenin contributes to Wnt-signaling in DLD1 colon cancer cells without being able to compensate for loss of β-catenin, and in this context acts as an inhibitor of invasiveness without affecting cell proliferation, pointing out a role for γ-catenin as an inhibitor of invasion.

γ -catenin overexpressing RKO clones activated Wnt signalling, but proliferation was reduced in cells overexpressing g-catenin. They did not show different invasive behaviour from mock transfectants in the invasion assay. In a subcutaneous xenograft model, overexpression of γ-catenin almost completely inhibited tumor growth, with the majority of mice (n = 16) having only minimal tumors (n = 10) or no tumor (n = 4) detectable at the injection site. Only two mice had a comparable tumor size to mock transfectant tumors at day 24 (p = 0,0005).

Our results suggest that γ-catenin inhibits invasion in γ-catenin proficient cells, and inhibits proliferation in γ-catenin deficient cells. The function of γ-catenin in colorectal cancer is dependent on the cellular context, suggesting a role for γ-catenin independent of its enhancing Wnt signalling. γ-catenin overexpression in RKO colorectal cancer cells inhibited tumor growth in vivo in a model of xenograft tumor growth in mice.