title: Differential timing of oxidative DNA damage and telomere shortening in hepatitis C and B virus-related liver carcinogenesis.
abstract: 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.
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy. Electronic address: marika.piciocchi@gmail.com.
authors.forename: Marika
authors.initials: M
authors.lastname: Piciocchi
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.
authors.forename: Romilda
authors.initials: R
authors.lastname: Cardin
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.
authors.forename: Umberto
authors.initials: U
authors.lastname: Cillo
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Vitale
authors.affiliation: Department of Experimental and Clinical Medicine, University of Firenze, Firenze, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cappon
authors.affiliation: Department of Medicine, University of Padova, Padova, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Mescoli
authors.affiliation: Department of Medicine, University of Padova, Padova, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Guido
authors.affiliation: Department of Medicine, University of Padova, Padova, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Rugge
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Burra
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.
authors.forename: Annarosa
authors.initials: A
authors.lastname: Floreani
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Farinati
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D063646:Carcinogenesis; D004249:DNA Damage; D045647:DNA Glycosylases / Q000235:genetics / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000235:genetics; D003849:Deoxyguanosine / Q000031:analogs & derivatives; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D016174:Hepacivirus; D006509:Hepatitis B / Q000150:complications* / Q000821:virology; D006515:Hepatitis B virus; D006526:Hepatitis C / Q000150:complications* / Q000821:virology; D006801:Humans; D008113:Liver Neoplasms / Q000209:etiology* / Q000821:virology; D010084:Oxidation-Reduction; D011110:Polymorphism, Genetic; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D059506:Telomere Shortening
chemical_list: D004272:DNA, Mitochondrial; D000080242:8-Hydroxy-2'-Deoxyguanosine; C509186:TERT protein, human; D019098:Telomerase; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human; D003849:Deoxyguanosine