Prevalence of wild-type in NS5A-PKR protein kinase binding domain in HCV-related hepatocellular carcinoma.
OBJECTIVE
Experimental studies have demonstrated that the wild-type PKR-NS5A strain of hepatitis C virus (HCV) may have oncogenic potential through the binding and functional repression of PKR protein kinase. To assess whether the NS5A-PKR-binding domain may be involved in HCV-related liver carcinogenesis, its sequence was analyzed in the sera of 85 patients with hepatocellular carcinoma (HCC) and in 51 patients with chronic active hepatitis (CAH). In 13 HCC cases sequence analysis was also performed in tumor and nontumor liver tissues.


METHODS
The nucleotide sequences of the PKR-binding domain were inferred by direct sequencing of the amplified HCV products and deduced amino acids were compared with the sequence of HCV-J.


RESULTS
A wild-type or single mutated strain which retains PKR-binding activity was found in 88% of HCC and 69% of CAH cases (P=0.0096). All but three HCC cases showed no divergences in amino acid changes between serum and liver tissues. The wild-type strains were equally distributed between the HCC with or without cirrhosis.


CONCLUSIONS
The prevalance of the wild-type NS5A-PKR strain is significantly higher in HCC than in CAH. These data suggest that inhibition of PKR activity by HCV might represent a potential mechanism of HCV-related carcinogenesis.
De Mitri
Maria Stella
MS
Department of Internal Medicine, Cardioangiology, Hepatology, University of Bologna, Bologna, Italy. sdemitri@almadns.unibo.it
Morsica
Giulia
G
Cassini
Romina
R
Bagaglio
Sabrina
S
Zoli
Marco
M
Alberti
Alfredo
A
Bernardi
Mauro
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D001665:Binding Sites / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000453:epidemiology / Q000821:virology*; D005260:Female; D016174:Hepacivirus / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D008103:Liver Cirrhosis / Q000453:epidemiology / Q000235:genetics / Q000821:virology; D008113:Liver Neoplasms / Q000453:epidemiology / Q000821:virology*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D015995:Prevalence; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000235:genetics*; D012324:RNA-Dependent RNA Polymerase
D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase