Abstract
BackgroundMetastasis 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.MethodsThe 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.ResultsWe 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.ConclusionsOur 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.
Highlights
Metastasis is the major cause of morbidity and mortality in patients with epithelial ovarian cancer (EOC), the mechanisms that underline this process are poorly understood
In EOC, we found that Collagen triple helix repeat containing-1 (CTHRC1) expression is correlated with clinical stage, peritoneal metastasis status and lymph node metastasis, which was consisted with findings reported by Hou et al [23]
CTHRC1 Enhances ovarian cancer cell migration and invasion in vitro Previous study had pointed out that CTHRC1 expression is up-regulated in EOC patients [23]
Summary
Metastasis is the major cause of morbidity and mortality in patients with epithelial ovarian cancer (EOC), the mechanisms that underline this process are poorly understood. In EOC, peritoneal metastasis requires modifications of tumor cells to facilitate interaction with the peritoneal stroma and mesothelium. The success of this metastatic step depends on alterations in cell-cell and cell-excretal cellular matrix (ECM) adhesion, epithelial-mesenchymal transition (EMT) and anoikis resistance [4, 6,7,8]. The cross-talk signaling events between ovarian cancer cells and peritoneum include increased expression of integrins, chemokine receptors (CXCRs), CXC chemokine ligands (CXCLs), matrix metalloproteinases (MMPs), urokinase-type plasminogen activator (uPA) and lysophosphatidic acid [9,10,11,12]. It was proved that the inhibition of integrin/FAK signaling activation could decrease the migration and invasion of cancer cells [16,17,18]
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