1, 17 When overexpressed in human immortal human cells, AEG-1 see more significantly protects from serum starvation-induced apoptosis.18 Overexpression of AEG-1 in healthy immortal cloned rat embryo fibroblasts results in aggressive tumor formation in nude mice.19 These studies indicate that AEG-1 could confer transforming properties to healthy immortal cells. However, whether AEG-1 alone might induce transformation and evoke an explicit carcinogenic phenotype was not clear. Our studies comparing WT and Alb/AEG-1 mice for up to 1 year of age did not identify overt dysplastic

changes in Alb/AEG-1 mice, indicating that a precarcinogenic initiating event, such as mutagenesis by DEN, might be necessary before AEG-1 might contribute to the tumorigenesis process. However, these TG mice need to be followed for a longer time frame, such as 18 months to 2 years, to test whether prolonged steatohepatitis, induced by AEG-1, might ultimately induce frank HCC. Our studies unravel the striking observation that AEG-1 provides strong protection from senescence, a phenomenon that may

not be explicit in immortal healthy cells. AEG-1 provided a strong inhibition to the DNA damage response induced in hepatocytes as they age and protected them from senescence. We observed that during the initial culture period, the endogenous ROS level was ∼30% lower in Alb/AEG-1 hepatocytes selleck screening library versus WT hepatocytes. This initial level of increased endogenous ROS in WT hepatocytes might be sufficient to trigger the DNA damage response resulting in senescence. Senescence is a potential anticancer mechanism,20 and by blocking senescence, AEG-1 may further promote the carcinogenic process. We demonstrate an intriguing aspect of AEG-1 when it is overexpressed, resulting in translational up-regulation of coagulation factors. AEG-1 induces marked up-regulation of FXII protein, while medchemexpress modestly affecting the mRNA level, by increasing the association of FXII mRNA with polysomes, a phenomenon also evident for MDR1 mRNA.9 FXII displays angiogenic activity, which is independent of its function in coagulation. FXII binds to urokinase plasminogen

activator receptor or cross-talks with EGFR on HUVEC membranes, leading to activation of MAPK and Akt with subsequent proliferation and differentiation.21 siRNA-mediated knockdown of FXII resulted in a profound inhibition of AEG-1-induced angiogenesis, indicating a central role of FXII in this process. The question is, does AEG-1 also regulate FXII under normal conditions? Will AEG-1 knock-out (KO) mice suffer from clotting deficiencies? The answer is most likely not. In primary mouse hepatocytes, AEG-1 is predominantly localized in the nucleus or nucleolus. However, when overexpressed, AEG-1 is most abundantly detected in the cytoplasm, a phenomenon also observed in human HCC patients as well as human HCC cells stably overexpressing AEG-1.