A novel PI3K/AKT signaling axis mediates Nectin-4-induced gallbladder cancer cell proliferation, metastasis and tumor growth.

Nectin-4 is a Ca(2+)-independent immunoglobulin-like cell adhesion molecule which has diverse functions in cell-cell adhesion via homophilic and heterophilic interactions. Cell-cell adhesive processes are central to cell polarization, differentiation, proliferation, survival and movement. Here we report that Nectin-4 is substantially overexpressed in gallbladder cancer (GBC), the most common biliary tract malignancy with a high risk of local tumor spread and invasion. Further, Nectin-4 high expression in GBC patients was associated with pathologic T stage and lymph node metastasis status, and the expression level of the downstream target Rac1 and poor prognoses were also correlated with Nectin-4. Ectopic expression of Nectin-4 promoted GBC cell growth, motility and tumor growth in a mouse model. The depletion of Nectin-4 inhibited GBC cell proliferation and migration both in cell culture and in mice. Our data suggest that activation of the PI3K/AKT pathway was involved in the oncogenic function of Nectin-4 to activate Rac1 in GBC. Inhibition of PI3K/AKT with LY294002 and/or Rac1 with NSC23766 impaired Nectin-4-mediated GBC cell proliferation and motility. We hypothesize that Nectin-4 is critical for GBC progression via PI3K/AKT pathway activation of Rac1. Nectin-4 may be a novel prognostic factor and therapeutic target in GBC patients.