Abstract A16: Thrombin promotes hepatocellular carcinoma metastasis via mediating osteopontin-dependent tumor growth and adhesion activity

Abstract

Abstract In our previous study, osteopontin (OPN) was identified as one of the leading genes that promote the metastasis of hepatocellular carcinoma (HCC), and a potential therapeutic target for HCC metastasis. The serine protease thrombin can interact with OPN and modify its biologic activity. To explore the role of thrombin alone or collaborating with OPN in HCC, we investigated the thrombin level and its correlation to the prognosis of 72 HCCs with different OPN backgrounds using real-time PCR and Western blot, and evaluated the effects of OPN fragments formed by thrombin cleavage on in vitro proliferation and adhesion of HCC cells. We found that the expression level of thrombin was positively related to the metastatic potentials of HCC cell lines, and was remarkably overexpressed in HCCs compared with the adjacent nontumor tissues. In addition, HCC tissues from patients with recurrent disease displayed much higher thrombin levels, particularly in those with OPN overexpressed. In the immunohistochemical study of 230 HCCs, only in those with a higher OPN level, a significant association was found between the higher thrombin level and the overall survival (OS; P < 0.01) and time to recurrence (TTR; P < 0.0001) of patients. Assays in vitro demonstrated that thrombin could promote the proliferation and adhesion of OPN+ HCC cells. And N-terminal of OPN showed better effects on the proliferation and adhesion abilities of HCC cells than the intact protein. Thrombin treatment could activate FAK pathway of OPN+ HCC cells, and this activation was blocked by the inhibition of integrin β1. Conclusions: Thrombin plays an important role in OPN-mediated aggressive phenotype and poor prognosis of HCC, which may be through the activation of the integrin β1 -FAK signaling. So, thrombin might be a potential therapeutic target to combat HCC progression in thrombin+/OPN+ patients. Citation Information: Clin Cancer Res 2010;16(14 Suppl):A16.