In viral hepatitis, inflammation is correlated with chronic oxidative stress, one
of the biological events leading to DNA damage and hepatocellular carcinoma (HCC)
development. Aim of this study was to investigate the complex molecular network linking
oxidative damage to telomere length and telomerase activity and regulation in hepatitis
C and B virus–related liver carcinogenesis. We investigated 142 patients: 21 with
HCC (in both tumor and peritumor tissues) and 121 with chronic viral hepatitis in
different stages. We evaluated 8-hydroxydeoxyguanosine (8-OHdG), marker of oxidative
DNA damage, OGG1 gene polymorphism, telomere length, telomerase activity, TERT promoter methylation, and mitochondrial TERT localization. In hepatitis C–related
damage, 8-OHdG levels increased since the early disease stages, whereas hepatitis
B–related liver disease was characterized by a later and sharper 8-OHdG accumulation
(P = 0.005). In C virus–infected patients, telomeres were shorter (P = 0.03), whereas telomerase activity was higher in tumors than that in the less advanced
stages of disease in both groups (P = 0.0001, P = 0.05), with an earlier increase in hepatitis C. Similarly, TERT promoter methylation was higher in tumor and peritumor tissues in both groups (P = 0.02, P = 0.0001). Finally, TERT was localized in mitochondria in tumor and peritumor samples,
with 8-OHdG levels significantly lower in mitochondrial than those in genomic DNA
(P = 0.0003). These data describe a pathway in which oxidative DNA damage accumulates
in correspondence with telomere shortening, telomerase activation, and TERT promoter
methylation with a different time course in hepatitis B and C virus–related liver
carcinogenesis. Finally, TERT localizes in mitochondria in HCC, where it lacks a canonical
function.
Abbreviations:
HCC (hepatocellular carcinoma), HCV (hepatitis C virus), HBV (hepatitis B virus), ROS (reactive oxygen species), 8-OHdG (8-hydroxydeoxyguanosine), TU-HCC (tumor-hepatocellular carcinoma), PTU-HCC (peritumor-hepatocellular carcinoma), F0-F4 (fibrosis stages), nDNA (nuclear DNA), mtDNA (mitochondrial DNA), dG (deoxyguanosine), GAPDH (glyceraldehyde 3-phosphate dehydrogenase), C (control), ELISA (enzyme-linked immunosorbent assay), AP (apurinic), RIBA II (recombinant immunoblot assay), PCR (polymerase chain reaction), HBsAg (hepatitis B surface antigen), HBe (hepatitis B e-antigen), EASL (European Association for the Study of the Liver), SDS-PAGE (sodium dodecyl sulphate-polyacrylamide gel electrophoresis), PBS (phosphate buffered saline), AASLD (American Association for the Study of Liver Diseases), HPLC (high performance liquid chromatography), UV (ultraviolet), RFLP (restriction fragment length polymorphism), BSA (bovine serum albumin), SEM (standard error of the mean), ANOVA (analysis of variance)To read this article in full you will need to make a payment
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Article info
Publication history
Published online: September 05, 2015
Accepted:
August 24,
2015
Received in revised form:
August 19,
2015
Received:
October 3,
2014
Identification
Copyright
© 2016 Elsevier Inc. Published by Elsevier Inc. All rights reserved.
