Abstract
BackgroundMicroRNAs expression has been extensively studied in hepatocellular carcinoma but little is known regarding the relationship, if any, with inflammation, production of reactive oxygen species (ROS), host’s repair mechanisms and cell immortalization. This study aimed at assessing the extent of oxidative DNA damage (8-hydroxydeoxyguanosine - 8-OHdG) in different phases of the carcinogenetic process, in relation to DNA repair gene polymorphism, telomeric dysfunction and to the expression of several microRNAs, non-coding genes involved in post-transcriptional regulation, cell proliferation, differentiation and death.MethodsTissue samples obtained either at surgery, [neoplastic (HCC) and adjacent non-cancerous cirrhotic tissues (NCCT)] at percutaneous or laparoscopic biopsy (patients with HCV or HBV-related hepatitis or patients undergoing cholecystectomy) were analysed for 8-OHdG (HPLC-ED), OGG1 (a DNA repair gene) polymorphism (PCR-RFLP), telomerase activity, telomere length (T/S, by RT-PCR), Taqman microRNA assay and Bad/Bax mRNA (RT-PCR). Fifty-eight samples from 29 HCC patients (obtained in both neoplastic and peritumoral tissues), 22 from chronic hepatitis (CH) and 10 controls (cholecystectomy patients - CON) were examined.ResultsEight-OHdG levels were significantly higher in HCC and NCCT than in CH and CON (p=0.001). Telomerase activity was significantly higher in HCC than in the remaining subgroups (p=0.002); conversely T/S was significantly lower in HCC (p=0.05). MiR-199a-b, -195, -122, -92a and −145 were down-regulated in the majority of HCCs while miR-222 was up-regulated. A positive correlation was observed among 8-OHdG levels, disease stage, telomerase activity, OGG1 polymorphisms and ALT/GGT levels. In HCC, miR-92 expression correlated positively with telomerase activity, 8-OHdG levels and Bad/Bax mRNA.ConclusionsThe above findings confirm the accumulation, in the progression of chronic liver damage to HCC, of a ROS-mediated oxidative DNA damage, and suggest that this correlates with induction of telomerase activity and, as a novel finding, with over-expression of miR-92, a microRNA that plays a role in both the apoptotic process and in cellular proliferation pathways.
Highlights
MicroRNAs expression has been extensively studied in hepatocellular carcinoma but little is known regarding the relationship, if any, with inflammation, production of reactive oxygen species (ROS), host’s repair mechanisms and cell immortalization
Our data confirm what ourselves and other authors already published on the relevance of oxidative DNA damage in the progression from chronic liver damage to hepatocellular carcinoma (HCC) in virus-related liver damage, confirming the progressive accumulation of DNA damage that reaches a maximum in both the neoplastic and in the adjacent non-cancerous cirrhotic tissues
There are several other repair enzymes potentially involved in repairing DNA oxidative damage [33] and the lack of association with OGG1 polymorphisms probably indicates that, in the liver, other repair mechanisms are more relevant than OGG1
Summary
MicroRNAs expression has been extensively studied in hepatocellular carcinoma but little is known regarding the relationship, if any, with inflammation, production of reactive oxygen species (ROS), host’s repair mechanisms and cell immortalization. During virus-related liver disease, both in humans and experimental models, an increased production of ROS has been documented, with a strong link between HCV core protein or HBV X protein and an oxidative “burst” [6,7]. These early events are followed in the progression of the disease by a build-up of genomic oxidative damage in patients with chronic hepatitis and cirrhosis, as documented in our own and other authors’ findings [8,9,10,11]. It is located on chromosome 3p26.2 and a CG polymorphism at position 1245 exon 7 of the gene [with substitution of cysteine for serine at codon 326 (Ser326Cys)] has been described, that is associated with a significantly lower DNA repair activity by the coded enzyme [13]
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