ABSTRACT
Chronic viral infection is the most important oncogenetic factor, and hepatitis B virus (HBV) plays an important role in the development of hepatocellular carcinoma (HCC). HBV-related carcinogenesis is a multi-step process, encompassing the combination of different, not mutually exclusive effects such as the induction of chronic liver inflammation and regeneration, its integration into the hepatocyte genome and the transactivating and transforming activity of several viral proteins (HBx and truncated Pre-S2/S) that may stimulate cellular oncogenes or suppress growth-regulating genes. Data related to the influence of different hepatitis B virus genotypes and the emergence of selective variants as biomarkers of HCC development still remain controversial. At last, recent studies on occult HBV infection, as defined by serologically undetectable hepatitis B surface antigen (HBsAg-), despite the presence of circulating HBV DNA, suggest that the occult viral strains, maintaining the transcriptional activity and the pro-oncogenetic assets of the clear HBV infection (HBsAg+), may harbour a potential risk for liver cancer development.
Subject(s)
Carcinoma, Hepatocellular/virology , Hepatitis B, Chronic/complications , Neoplasms/virology , DNA, Viral/genetics , Genome, Viral/genetics , Genotype , Hepatitis B virus/chemistry , Humans , Liver Cirrhosis/virology , Mutation/genetics , Oncogenes/genetics , Viral Load , Virus ReplicationABSTRACT
BACKGROUND: The interaction between the hepatitis C virus (HCV) non-structural 5A (NS5A) protein of HCV and the protein kinase R (PKR), which is an effector of the cellular antiviral response and has been defined as a tumour suppressor, may affect the control of protein synthesis and cell growth. AIM: We investigated the genetic evolution of the NS5A region in the NS5A PKR-binding domain (NS5A-PKRbd) of patients with HCV 1b-related cirrhosis who subsequently developed or not hepatocellular carcinoma (HCC). PATIENTS AND METHODS: The quasispecies composition of NS5A-PKRbd was inferred by sequencing an average of 15 clones per sample in specimens obtained from 26 patients with cirrhosis who developed or not HCC during a follow-up of 5 years. RESULTS: At baseline, 13/17 patients with final HCC and six out of nine patients with cirrhosis who subsequently did not develop HCC harboured a wild-type (wt) strain master sequence. Over time, the prevalence of wt strain was higher in patients who developed HCC with respect to those who maintained the cirrhosis status (15/17 vs 4/9, respectively; P=0.0166). CONCLUSION: The maintenance of or evolution to the wt strain of the NS5A domain in cirrhotic patients with final HCC highlights the central role of NS5A protein in the viral life cycle and in the progression of liver disease.
Subject(s)
Carcinoma, Hepatocellular/virology , Hepacivirus/genetics , Hepatitis C/complications , Liver Cirrhosis/complications , Liver Neoplasms/virology , Viral Nonstructural Proteins/genetics , Aged , Amino Acid Sequence , Carcinoma, Hepatocellular/enzymology , Cell Transformation, Neoplastic/genetics , DNA Mutational Analysis , DNA, Viral/analysis , Disease Progression , Female , Follow-Up Studies , Hepatitis C/enzymology , Hepatitis C/genetics , Humans , Liver Cirrhosis/enzymology , Liver Cirrhosis/virology , Liver Neoplasms/enzymology , Male , Middle Aged , Molecular Sequence Data , Mutation , RNA, Viral/blood , Sequence Analysis, Protein , Viral Nonstructural Proteins/metabolism , eIF-2 Kinase/metabolismABSTRACT
BACKGROUND/AIMS: 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.
