1 HCC shows great geographical variation, with a very high incidence Selleckchem GSK2118436 in Asia and sub-Saharan Africa, but it is now becoming more common in the West. During the past 20 years in the United States, HCC has risen by 114%.2 This paralleled an increase in the incidence of chronic hepatitis, which serves as a main risk factor for HCC.3 At the initiation of hepatic oncogenesis, transformed hepatocytes must elude various cellular defense activities and acquire abnormal capabilities to survive and proliferate.4 Aberrant signaling through receptor tyrosine kinases plays a pivotal role in the development and progression of HCC.5 Eph receptors constitute one of the largest receptor tyrosine kinase families and

have been reported to be involved in a variety of cancers. For example, up-regulation Palbociclib of EphA2 has been observed in many malignant tumors6–8 and is associated with accelerated cell proliferation, enhanced neovascularization, and altered hormone dependence.9, 10 EphB4 is abnormally expressed in melanoma, bladder, colorectal, and breast cancers, although the mechanism underlying the oncogenic effect

remains unclear.11, 12 However, research of Eph/Ephrin members13, 14 in HCC is still rare. EphrinA2, a cognate ligand to several Eph receptors, including EphA3, EphA4, EphA5, and EphA7, is related to neural development.15, 16 It can act as a vital repulsive factor in retinotectal axon guidance through its cleavage by metalloprotease.17 In addition, EphrinA2 regulates RhoA-dependent F-actin turnover,18 as well as the endocytosis of growth cone through modulating Ras-related C3 botulinum toxin substrate 1 (Rac1) activity.19 medchemexpress Although EphrinA2 has been found to be up-regulated in some breast cancer cell lines,20 its function in cancer remains poorly investigated. In this

study, we report that the expression of EphrinA2 is dramatically increased in HCC, especially in the tumors invading into the portal veins. Furthermore, we demonstrate that EphrinA2 activates the Rac1/V-akt murine thymoma viral oncogene homolog (Akt)/nuclear factor-kappa B (NF-κB) pathway in HCC cells, which suppresses apoptosis and thus facilitates cancer cell survival. Our study strongly highlights the significance of EphrinA2 in the tumorigenesis of HCC and therefore provides a potential drug target in liver cancer therapy. Akt, V-akt murine thymoma viral oncogene homolog; HCC, hepatocellular carcinoma; NF-κB, nuclear factor-kappaB; PARP, poly(adenosine diphosphate-ribose) polymerase; PCR, polymerase chain reaction; Rac1, ras-related c3 botulinum toxin substrate 1; siRNA, small interfering RNA; TNF, tumor necrosis factor. This part is included in the Supporting materials. To explore the role of Eph/Ephrin members in HCC, we first examined their expression levels in both normal and cancerous hepatic cell lines by real-time polymerase chain reaction (PCR).