P120-catenin Mediates Calcium-suppressed Squamous Cell Carcinogenesis

Objective:Calcium is the most abundant mineral in the body. It combines with phosphorus to form calcium phosphate in bones and teeth. In addition, calcium plays a critical role in blood coagulation, muscle contraction and relaxation, and nerve transmission. It has been found that calcium regulates proliferation and differentiation of epithelial cells, suggesting that calcium may suppresse squamous cell carcinogenesis. Previous studies indicate that calcium-induced formation of the E-cadherin/β-catenin/p120-catenin complex in the plasma membrane triggers an intracellular signaling pathway essential for keratinocyte differentiation. The stability of cadherin/catenin complex depends on the presence of p120-catenin. To determine the role of p120-catenin in mediating calcium-suppressed oral carcinogenesis in vivo, we generated a p120-catenin conditional knockout (p120-KO) model and examined the expression levels of proliferation and differentiation markers in the oral epithelium of p120-KO mice on different calcium diets.Methods:We observed the expression levels of proliferation and differentiation markers in the oral epithelium of p120-KO mice on different calcium diets, as well as the expression levels of E-cadherin, β-catenin and PLC-γ1.Results:(1) p120-catenin was effectively deleted in the oral squamous epithelium of p120-KO.(2) Control (Floxed-p120) mice on the high calcium diet had lower levels of proliferation and higher levels of differentiation than those on the normal calcium diet. Floxed-p120mice on the low calcium diet had higher levels of proliferation and lower levels of differentiation than those on the normal calcium diet. However, there was no difference in the levels of proliferation, levels of differentiation of p120-KO mice between the high or low calcium diet group and the normal calcium diet group.(3) Floxed-p120mice on the high calcium diet had lower levels of PLC-yl, higher levels of E-cadherin, P-catenin than those on the normal calcium diet. Floxed-p120mice on the low calcium diet had higher levels of PLC-yl, lower levels of E-cadherin, β-catenin than those on the normal calcium diet. However, there was no difference in the levels of E-cadherin, β-catenin and PLC-yl in p120-KO mice between the high or low calcium diet group and the normal calcium diet group.Conclusion:p120-catenin mediates dietary calcium-regulated oral squamous cell proliferation and differentiation and may participate in the mechanism by which calcium suppresses squamous cell carcinogenesis.