The Mechanism Of CTHRC1 Promoting Peritoneal Dissemination In Human Epithelial Ovarian Cancer

Objective: To investigate the mechanism of CTHRC1 in regulating epithelial ovarian cancer cells adhesion、migration、invasion and nude mouse peritoneal dissemination in vitro and in vivo,and to detect the expression of CTHRC1 and integrin β3 in human EOC tissues and their clinical significance.Methods: Stably overexpressed and knockout CTHRC1 cell lines was constructed using lentivirus.The effect of CTHRC1 on ovarian cancer cells adhesion、migration、invasion and nude mouse peritoneal dissemination were explored in vitro and in vivo.Phospho-antibody microarray、Western blot and co-IP assays were performed to screen and confirm the related signaling pathway regulated by CTHRC1.The inhibitors of integrin β3 and FAK phosphorylation were used to verify whether they could attenuate the impacts of CTHRC1 on EOC cells migration and invasion.Immunohistochemistry assay was used to detect the expression and of CTHRC1 and integrin β3 in 72 human EOC tissues and their clinical significance.Results: The over-expression of CTHRC1 promoted EOC cells adhesion、migration、invasion and nude mouse peritoneal dissemination in vitro and in vivo,and vice versa(P<0.05).CTHRC1 could interacted with integrin β3,up-regulated its expression,and promoted the phosphorylation of FAK at Tyr397.Using MAB1957(anti-integrin β3 antibody)and PF-228(inhibitor of FAK phosphorylation)could reversed the migratory and invasive capabilities of EOC cells promoted by CTHRC1 in vitro and in vivo(P<0.05).Meanwhile,CTHRC1 protein level was remarkably increased in EOC tissues,and bound up with FIGO stage(P=0.018),lymph node metastasis(P= 0.001),distance metastasis(P=0.001),ascites-derived cancer cells(P=0.018)and the expression of integrin β3(P=0.018).Logistic Regression Analysis revealed that CTHRC1 was an independent risk factor for metastasis in patients with EOC.Conclusions: CTHRC1 up-regulated the expression of integrin β3,activated the phosphorylation of FAK at Tyr397 through integrin β3/FAK signaling pathway,thus promoted EOC cells metastasis in vitro and in vivo.The higher expression of CTHRC1 and integrin β3 in EOC tissues was closely related with the development of tumors.