23 A similar mechanism might also be applicable to HCC cells as well as in Alb/AEG-1 hepatocytes, and the monoubiquitination of overexpressed AEG-1 was confirmed (Supporting Fig. 9). The promiscuous accumulation of AEG-1 in the cytoplasm might facilitate an interaction with the translational machinery and loading of selective mRNAs to the polysome.

Indeed, ribosomal proteins as well as eukaryotic translation initiation factors were identified as potential AEG-1-interacting proteins, indicating a potential direct role of AEG-1 in regulating translation.8 It is intriguing that AEG-1 facilitates the translation of multiple members of the coagulation pathway, all of which are known mediators of tumor growth, metastasis, and angiogenesis, and this particular aspect of AEG-1 function might play a pivotal role in promoting tumor progression and metastasis. Plasma FXII analysis selleck screening library thus might be a potential biomarker for HCC. We observe that knocking down either FXII or TFF3 results in a marked inhibition of AEG-1-induced angiogenesis. Interestingly, both FXII and TFF3 interacts with EGFR on ECs to augment proliferation and differentiation, BAY 80-6946 hence angiogenesis.21, 24 Thus, there might be a key role of endothelial EGFR

in mediating AEG-1 function, a hypothesis that needs to be experimentally validated. One novel aspect of AEG-1 function is the induction of steatosis. Nonalcoholic fatty liver disease (NAFLD) is one of the precursors leading to nonalcoholic steatohepatitis and HCC.25 It will be interesting to check whether AEG-1 is also overexpressed in NAFLD patients, thus contributing to eventual hepatocarcinogenesis. Apart from significant increases in the expression of some components of fatty acid metabolism, our gene-expression network analysis did not identify the modulation of any major adipogenic or lipogenic pathway, such as the peroxisome proliferator-activated receptor

gamma, liver X receptor, Astemizole or pregnane X receptor pathways. This observation argues that rather than affecting a network, AEG-1 overexpression might lead to promiscuous increases in distinct regulators of fat metabolism resulting in steatosis. The significant increase in SCD2 expression by AEG-1 alone might contribute to steatosis. Induction in SCD2 has also been observed in the transforming growth factor alpha/c-myc TG mouse model of HCC.26 SCDs are crucial lipogenic enzymes for monounsaturated fatty acid biosynthesis. SCD1 expression is induced after weaning in mouse liver, whereas SCD2 expression is detected in livers of mouse embryos and neonates.27 There is a significant reduction in liver and plasma triglycerides in neonatal SCD2 KO mice.27 The increased SCD2 expression by AEG-1 suggests a shift toward embryonic gene-expression pattern, another hallmark of cancer. Crossing SCD2 KO mice with Alb/AEG-1 mice might provide insight into the importance of SCD2 in mediating the AEG-1-induced steatotic phenotype.