New liver cancer biomarkers: PI3K/AKT/mTOR pathway members and eukaryotic translation initiation factors

Hepatocellular carcinoma (HCC) is the third leading cause of cancer related death. The initiation of protein translation is an important rate-limiting step in eukaryotes, and is crucial in the pathogenesis of many viral infections. Eukaryotic translation initiation factors (eIFs) are proteins that are involved in the initiation step of protein translation and are linked to the phosphatidylinositol-3-kinases (PI3K)/AKT/mTOR pathway. We hypothesized that eIFs represent crossroads for carcinogenesis in HCC and might serve as potential biomarkers. The immunohistochemical expression of eIF subunits 2α, 3C, 3 H, 4E, 5 and 6 were investigated in 235 cases of virus-related human HCCs. Additionally, we used immunoblot analysis to investigate the expression of virus-related HCC and non-virus-related HCC in comparison to controls. mTOR pathway members were significantly increased in HCV-associated HCC, in HCC without a viral background, in alcoholic liver disease and Wilson's disease. peIF2α, eIF2α, eiF3B, eIF3D, eIF3J, peIF4B, eIF4G and eIF6 were upregulated in HCV-associated HCC. eIF2α, peIF4B, eIF5 and various eIF3 subunits were significantly increased in HBV-associated HCC. HCC without viral background displayed a significant increase for the eIF subunits p2α, 3C, 3I, 4E and 4G. We noticed engraved differences in the expression pattern between chronic hepatitis B and C, HBV- and HCV associated HCC and non-virus related HCC. Our data demonstrate that mTOR members and eIFs play a crucial role in translational control in chronic hepatitis B and C, HBV- and HCV-associated HCC and non-virus related HCC and therefore serve as novel potential biomarkers.