Anti-CHI3L1 antibody suppresses colon cancer growth through downregulation of VEGFA and NAMPT expression.

Abstract

Chitinase 3-like 1 (CHI3L1) has been implicated in the pathogenesis of various diseases, including cancer. In our previous study, we found that anti-CHIL1 antibody inhibited lung tumorigenesis. It has been reported that CHI3L1 is highly overexpressed in colon cancer tissue compared with normal tissue, and high levels of serum CHI3L1 have been associated with worse colon cancer prognosis. We investigated the anticancer effect of an anti-CHI3L1 antibody on colon cancer cells. The anti-CHI3L1 antibody inhibited the cell growth of colon cancer cells in a concentration-dependent manner. The anti-CHI3L1 antibody also reduced the migration but increased apoptotic cell death in colon cancer cells. Using STRING (Search Tool for the Retrieval of Interacting Genes/Proteins), we identified an association between VEGFA and CHI3L1 in colon cancer. We confirmed interaction between VEGFA and CHI3L1 through immunoprecipitation. Furthermore, the combination treatment of the anti-CHI3L1 antibody and VEGFA siRNA inhibited cell growth but increased apoptotic cell death. Additionally, using the Human Base database, we found that CHI3L1 and VEGFA are associated with nicotinamide phosphoribosyltransferase (NAMPT). Furthermore, combining the anti-CHI3L1 antibody and NAMPT siRNA more effectively reduced cell growth and the expression of CHI3L1, VEGFA, and cell growth-related proteins, but significantly increased apoptosis-related proteins. The combination of VEGFA siRNA and NAMPT siRNA more effectively inhibited cell growth. Anti-CHI3L1 antibody inhibited the production of ATP and NADH in colon cancer and had a higher inhibitory effect on these levels when combined with NAMPT siRNA These data demonstrated that anti-CHI3L1 antibody is useful as a potential therapy for colon cancer by inhibiting NAMPT-dependent VEGFA expression and ATP and NADH levels.