Protein kinase R is increased and is functional in hepatitis C virus–related hepatocellular carcinoma

OBJECTIVE:Protein kinase R (PKR) interacts with dsRNA and phosphorylates eukaryotic initiation factor-2 (eIF2α), which in turn inhibits host translation initiation as well as hepatitis C virus (HCV) translation. Because PKR inhibits host cell growth and proliferation, it has also been proposed to act as a eukaryotic tumor suppressor. To evaluate the role of PKR in HCV-related hepatocellular carcinoma (HCC), we compared PKR and related protein expression in paired tumor (T) and surrounding nontumor (NT) tissue.METHODS:Tissue samples were obtained from 12 HCV-infected HCCs. To determine PKR and related protein expression, Western blotting and semiquantitative reverse transcriptase–polymerase chain reaction were performed.RESULTS:PKR protein levels were consistently increased in HCV-related HCC compared with NT (p = 0.001); similar increases were seen in total eIF2α and the PKR inhibitor p58IPK in T compared with NT (p = 0.022, p = 0.048, respectively). Relative increases in phosphorylated eIF2α (peIF2α) were also seen, and the ratio of peIF2α/total eIF2α did not change in T compared with NT, suggesting that PKR remains functional within T. Cytoplasmic levels of HCV RNA within T were decreased compared with NT.CONCLUSIONS:These findings indicate that PKR has increased activity in human HCC compared with LC, and suggest that PKR acts as a growth inducer in HCC.

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