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Open Access Highly Accessed Research article

Oxidative DNA damage correlates with cell immortalization and mir-92 expression in hepatocellular carcinoma

Cardin Romilda1, Piciocchi Marika1, Sinigaglia Alessandro2, Lavezzo Enrico2, Bortolami Marina1, Kotsafti Andromachi1, Cillo Umberto1, Zanus Giacomo1, Mescoli Claudia3, Rugge Massimo3 and Farinati Fabio1*

Author affiliations

1 Department of Surgery, Oncology and Gastroenterology, Section of Gastroenterology, University of Padova, Via Giustiniani 2, Padova, 35128, Italy

2 Department of Molecular Medicine, University of Padova, Via A. Gabelli 63, Padova, 35121, Italy

3 Department of Medicine, University of Padova, Via A. Gabelli 61, Padova, 35121, Italy

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Citation and License

BMC Cancer 2012, 12:177  doi:10.1186/1471-2407-12-177

Published: 15 May 2012

Abstract

Background

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. 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.

Methods

Tissue 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.

Results

Eight-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.

Conclusions

The 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.

Keywords:
Hepatocellular carcinoma; 8-hydroxydeoxyguanosine; miR-92; Telomeric dysfunction; OGG1 gene