Aims: CXXC finger protein 4 (CXXC4) is an identified negative regulator of the Wnt/β-catenin pathway, and it is involved in cancer cell proliferation. In this study, we sought to clarify whether CXXC4 is involved in glucose-stimulated β-cell proliferation.
Materials and methods: We investigated the biological function of CXXC4 in glucose-induced β-cell proliferation, and we investigated the underlying mechanism of this activity. First, we analyzed CXXC4 expression in established rat models treated for 24 h with a high glucose infusion and in INS-1 cells and primary rat islets treated with different concentrations of glucose. Subsequently, we used an adenovirus to overexpress CXXC4 in INS-1 cells and primary islets. The proliferation rate of β-cells was evaluated by CCK-8 and EdU incorporation methods. Cell cycle analysis was performed by flow cytometry. Finally, the Wnt signaling pathway and its downstream genes were assessed by Western blot.
Results: CXXC4 mRNA levels were significantly lower in islets isolated from glucose-infused rats than they were in those isolated from saline-infused rats. Decreased expression of CXXC4 also correlated with high glucose treatment of INS-1 cells and primary rat β-cells. Furthermore, adenovirus-mediated overexpression of CXXC4 inhibited cell proliferation induced by the high glucose treatment in vitro, which was mechanistically mediated by Wnt signaling and a decrease in cyclin D2 expression.
Conclusions: Glucose inhibits CXXC4 expression and hence promotes pancreatic β-cell proliferation. Our findings may provide a new potential target for the treatment of diabetes.
Keywords: CXXC4; Proliferation; Wnt signaling; β-cell.