Association of amino acid variations in the NS5A and E2-PePHD region of hepatitis C virus 1b with hepatocellular carcinoma.
NS5A and E2 proteins of the hepatitis C virus (HCV) have the potential to repress protein kinase R (PKR) that exerts a tumour suppressor function. We investigated the relationship between amino acid variations in the NS5A-PKR-binding domain and E2-PKR-eIF2alpha phosphorylation homology domain (PePHD) region and the development of hepatocellular carcinoma (HCC) in chronic HCV-1b patients. In a cross-sectional, hospital-based setting, we compared the amino acid sequences of NS5A-PKR-binding domain and E2-PePHD in the sera of 104 chronic hepatitis, 44 cirrhosis and 96 HCC patients. The nucleotide sequences were inferred by direct sequencing of the amplified HCV products and deduced amino acid were compared with the sequence of HCV-J. By univariate analysis, old age, lower viral load, fewer amino acid substitutions in the NS5A-PKR-binding domain (codons 2209-2274) and the interferon sensitivity-determining region (ISDR; codons 2209-2248), and wild-type amino acid at codon 2209 and codon 2240 was significantly correlated with HCC, whereas substitutions in the E2-PePHD was not. Patients with a mutated-type (> or = 4) NS5A-ISDR had a lower prevalence of HCC than those with intermediate or wild type (P < 0.05). Based on stepwise logistic regression analysis, age [odds ratio (OR): 1.132, P < 0.001], viral load (OR: 0.305, P < 0.001) and mutated-type ISDR (OR: 0.137, P = 0.001) were independently associated with HCC. In conclusion, NS5A-ISDR variations may play an important role in the development of HCV-related HCC.
Hung
C-H
CH
Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
Chen
C-H
CH
Lee
C-M
CM
Wu
C-M
CM
Hu
T-H
TH
Wang
J-H
JH
Yen
Y-H
YH
Lu
S-N
SN
D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001665:Binding Sites; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000821:virology*; D003430:Cross-Sectional Studies; D018450:Disease Progression; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics*; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D017434:Protein Structure, Tertiary; D012367:RNA, Viral / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D013624:Taiwan; D014759:Viral Envelope Proteins / Q000737:chemistry / Q000235:genetics*; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000235:genetics*; D012324:RNA-Dependent RNA Polymerase
D012367:RNA, Viral; D014759:Viral Envelope Proteins; D017361:Viral Nonstructural Proteins; C091015:glycoprotein E2, Hepatitis C virus; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase