4D). Furthermore, EphrinA2-induced activation of NF-κB was blocked by LY294002, NSC23766, dominant-negative Akt, and dominant-negative Rac1, respectively, despite varied inhibitory effects (Fig. 6D). These results indicated that the Rac1/Akt pathway participates in

the modulation of NF-κB activity stimulated by EphrinA2, thus revealing an exquisite regulatory network between EphrinA2, Rac1, Akt, and NF-κB. We identified the relationship between EphrinA2 expression and the development of HCC. The level of EphrinA2 was lowest in normal hepatocytes and increased in primary HCC cells, and it reached the highest level in portal vein tumor thrombus cells. This gradually increasing expression pattern paralleled with deterioration ABC294640 datasheet of this disease, suggesting a potential role of EphrinA2 in the progression of HCC. In fact, an emerging body of evidence suggests an increasing role of Eph/Ephrins in cancer. For example, EphA2 can

promote growth of breast, prostate, and pancreas cancer cells, perhaps by activating mitogen-activated protein kinases (MAPKs).7, 8 Likewise, EphA2 and EphB4 can stimulate cancer cell migration and invasion.28 The Eph/Ephrins also can enhance angiogenesis during cancer progression.29, 30 In our study, we demonstrated that EphrinA2 could endow the HCC cells with resistance to both basal and cytokine-induced apoptosis, thus providing a growth advantage to cancer cells, which consequently enhanced the development and progression Carnitine dehydrogenase of HCC. Because the mechanism underlying the regulation of cell survival and apoptosis by Eph/Ephrins in cancer cells remains largely unknown,31 our study provides click here novel insights into this mechanism. HCCs are often associated with chronic hepatitis, especially in Asia. TNF-α has been reported to be closely involved in the pathogenesis of chronic liver disease.22, 32, 33 Released by infiltrating lymphocytes,

TNF-α can trigger both pro-survival and pro-apoptosis signaling through the NF-κB pathway and the caspase8 pathway. The cell fate determination mainly depends on the balance between these two pathways. We found that overexpression of EphrinA2 in HCC cells could activate NF-κB, leading to a shift from apoptosis to survival in the circumstance of TNF-α. This may explain how HCC cells tolerate the high level of such potential apoptotic factors. A series of previous studies have suggested that TNF-α is a promising cytokine for cancer therapy34, 35; however, the clinical outcome was disappointing, mainly because of the nonspecific toxicity of this factor at high dose. Efforts have been made to improve its application, such as modification of TNF-α to ameliorate its specificity aiming at tumor tissues.36 Another potential strategy is to increase the sensitivity of cancer cells to TNF-α, which will decrease the effective dose of the cytokine and avoid unexpected systemic toxicity.