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

BMC Cancer

Cardin Romilda¹  Piciocchi Marika¹  Sinigaglia Alessandro³  Lavezzo Enrico³  Bortolami Marina¹  Kotsafti Andromachi¹  Cillo Umberto¹  Zanus Giacomo¹  Mescoli Claudia²  Rugge Massimo²  Farinati Fabio¹ 

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

[2] Department of Medicine, University of Padova, Via A. Gabelli 61, Padova, 35121, Italy

[3] Department of Molecular Medicine, University of Padova, Via A. Gabelli 63, Padova, 35121, Italy

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

Others  :  1080430
DOI  :  10.1186/1471-2407-12-177

 received in 2011-12-19, accepted in 2012-05-15,  发布年份 2012

【 摘 要 】

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.

【 授权许可】

   
2012 2012 Cardin et al.; licensee BioMed Central Ltd.

【 图 表 】

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