The vast majority of cancer deaths result from cancer metastasis, rather than the influence of the primary tumors. In patients with HCC, the early stages of the disease are usually asymptomatic; in addition, the incidence of tumor recurrence is high. As a result, the 5-year survival rate for HCC patients is poor and most patients
die of intrahepatic metastasis. A better understanding of the molecular events governing the pathogenesis of cancer metastasis in HCC is highly desirable for improvement of clinical management. Recently, overexpression of EIF5A2 have been associated with metastasis in multiple cancer types, including colon,20 ovarian,21 and bladder cancer.22 In this study, we first demonstrated that EIF5A2 was frequently overexpressed in HCC, which was associated with the metastatic state of cancer progression. Interestingly, the invasive border between tumor and nontumorous tissues showed a higher level of EIF5A2 expression, indicating selleck products that this oncoprotein may contribute to a more selleck screening library malignant and invasive phenotype of the cancer
cells. A series of in vitro and in vivo assays were carried out to characterize the role of EIF5A2 in regulating liver cancer cell motility and invasiveness, and the results showed that overexpression of EIF5A2 could significantly enhance cell motility and invasiveness. In the tail-vein-injection mouse model of cancer metastasis, overexpression of EIF5A2 led to a significant increase in the number of lesions of liver metastasis. Again, we observed a higher level of EIF5A2 on the tumor margin with an aggressive front. In addition, gene silencing of EIF5A2 by siRNA or disruption of posttranslational hypusination inhibited its effect on cell migration. All these findings strongly supported that overexpression of EIF5A2 played an important role in HCC invasion and metastasis. In the present study we found that overexpression of EIF5A2 had a significant
impact on EMT, as shown by increased expression of mesenchymal markers (fibronectin, N-cadherin, vimentin, and α-SMA) and decreased expression of epithelial markers (E-cadherin and β-catenin). EMT is a key event in tumor invasion and metastasis in which epithelial cells lose epithelial adherence and tight junction proteins, lose polarity and cell-cell contacts, and undergo a remarkable remodeling of the cytoskeleton Aldol condensation to facilitate cell motility and invasion.24–26 Thus, HCC cells overexpressing EIF5A2 probably undergo EMT to achieve higher motility and invasiveness. The role of Rho small GTP binding proteins in the regulation of actin cytoskeleton organization and cell migration has been well documented.27–29 Actin filaments are essential for the maintenance of cytoskeleton networks that determine cell shape and cell motility. Our study, for the first time, provided evidence supporting the role of EIF5A2 in the regulation of cytoskeleton through a Rho-GTPase signaling pathway.