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 (eIF2alpha), 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 eIF2alpha and the PKR inhibitor p58IPK in T compared with NT (p=0.022, p=0.048, respectively). Relative increases in phosphorylated eIF2alpha (peIF2alpha) were also seen, and the ratio of peIF2alpha/total eIF2alpha 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.
Hiasa
Yoichi
Y
Gastrointestinal Unit, Cancer Center and Hospital for Children, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Kamegaya
Yoshitaka
Y
Nuriya
Hideko
H
Onji
Morikazu
M
Kohara
Michinori
M
Schmidt
Emmett V
EV
Chung
Raymond T
RT
D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D001707:Biopsy, Needle; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology / Q000821:virology*; D016174:Hepacivirus / Q000235:genetics* / Q000302:isolation & purification; D019698:Hepatitis C, Chronic / Q000235:genetics / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology / Q000821:virology*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D019892:eIF-2 Kinase / Q000235:genetics*
D019892:eIF-2 Kinase