Collagen triple helix repeat containing 1 (CTHRC1) activates Integrin β3/FAK signaling and promotes metastasis in ovarian cancer

BACKGROUND Metastasis is the major cause of morbidity and mortality in patients with epithelial ovarian cancer (EOC), however the mechanisms that underline this process are poorly understood. Collagen triple helix repeat containing-1 (CTHRC1) is a 28-kDa secreted protein reported to be involved in vascular remodeling, bone formation and morphogenesis. This study aimed to investigate the role of CTHRC1 in promoting the metastasis of EOC and to elucidate the underlying molecular mechanisms. METHODS The biologic functions of CTHRC1 in metastasis were validated both in vivo and in vitro experiments. The phosphor-antibody microarray analysis and Co-immunoprecipitation were performed to detect and identify the integrin β3/FAK signaling pathway that mediated the function of CTHRC1. Seventy two EOC samples were analyzed for association between CTHRC1/integrin β3 expression and patient clinicopathological features. RESULTS We demonstrated that CTHRC1 enhances the biological behavior of EOC including cell migration, invasion, as well as its adhesion capability to cell-extracellular matrix in vitro. Additionally, CTHRC1 promoted metastatic spread of EOC cells in an i.p. ovarian xenograft model and this phenotype was primarily ascribed to the activation of integrin/FAK signaling. Mechanistically, we determined that FAK were phosphorylated on Tyr397, and were activated by integrin β3, which is important for the CTHRC1-mediated migratory and invasive ability of EOC cells in vitro and i.p. metastasis. In addition, we found that attenuated CTHRC1/integrin β3 expression predicted a poor prognostic phenotype and advanced clinical stage of EOC. CONCLUSIONS Our results suggest that CTHRC1, a newly identified regulator of i.p. metastasis through activation of integrin β3/FAK signaling in EOC, may represent a potential therapeutic target for ovarian cancer.