Roles of oxidative DNA damage, and reactive oxygen and nitrogen species in the evolution of human hepatocellular carcinoma

Li, Pengcheng (2013). Roles of oxidative DNA damage, and reactive oxygen and nitrogen species in the evolution of human hepatocellular carcinoma PhD Thesis, The School of Medicine, The University of Queensland.

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Author Li, Pengcheng
Thesis Title Roles of oxidative DNA damage, and reactive oxygen and nitrogen species in the evolution of human hepatocellular carcinoma
School, Centre or Institute The School of Medicine
Institution The University of Queensland
Publication date 2013
Thesis type PhD Thesis
Supervisor Graeme Macdonald
Grant Ramm
Total pages 258
Language eng
Subjects 0601 Biochemistry and Cell Biology
1101 Medical Biochemistry and Metabolomics
1112 Oncology and Carcinogenesis
Formatted abstract
The aim of this project was to investigate the roles of oxidative DNA damage and abnormal cell proliferations caused by reactive oxygen and nitrogen species (ROS and RNS respectively) in the evolution of hepatocellular carcinoma (HCC). One main features of HCC is uncontrolled growth of tumour cells. The tumour cells exhibit several abnormal physiological traits including disordered metabolism, evasion of cell death, limitless replication, angiogenesis and avoidance of immune destruction. Moreover, HCC tumours exhibit characteristic molecular, cytological, and histological features. Based on these observations, investigators have proposed several mechanisms for hepatic carcinogenesis, in which malignant transformation of HCC is probably caused by gene mutations, genomic instability, epigenetic alteration, telomere shortening, stem cell activation or disordered metabolism. A number of lines of evidence suggest that ROS and RNS generated during the course of chronic liver inflammation are involved in the malignant transformation in the liver. Firstly, the majority of HCCs (up to 90%) occur in patients with various chronic liver diseases. Secondly, a range of cells have been shown to produce and release ROS and RNS during liver inflammation. Thirdly, ROS and RNS react with DNA, protein, lipid and biological macromolecules, inducing gene mutations, altering epigenetics, adjusting gene expression, activating or inactivating enzyme activity and deregulating metabolism. These alterations may cause malignant transformation of hepatocytes to HCC. Therefore, understanding roles of oxidative DNA damage in chronic liver inflammation, and focusing on the roles of abnormal cell proliferation induced by ROS and RNS, may help to decipher the enigma of hepatic carcinogenesis.

8-Oxy-2′-deoxy-guanosine (8-oxodG), a major oxidative product of guanine, may induce gene mutations, resulting in activation of oncogenes and inactivation of tumour suppressor genes. Investigators have previously investigated the links between 8-oxodG concentration and malignant grades of HCCs and risk factors, but a strong correlation has not been found. Hydrogen peroxide, nitric oxide donors, anti-oxidants and nitric oxide scavengers have been widely used to investigate the roles of ROS and RNS in cell proliferation, but data on the roles have been paradoxical.

This study evaluated dose relationships of ratios of 8-oxodG/dG between surrounding non-malignant liver tissues and tumours of 54 HCC patients with various underlying chronic liver diseases, and subsequently examined the effects of ROS and RNS on HepG2 cell growth. This study revealed that there was a trend for increased 8-oxodG/dG ratios in non-malignant liver tissues compared to malignant liver tissues of HCC patients with various underling risk factors, particularly those with HBV infection. This study also revealed that low concentrations of the ROS generator, hydrogen peroxide, and the RNS generator, nitric oxide enhanced HepG2 cell growth, but there was no a dose-dependent relationship. This study indirectly confirmed that hydrogen peroxide and nitric oxide were involved in cell metabolism through reactions with cellular nicotinamide adenine dinucleotide. This study also offered and explanation for the previous controversial conclusions on roles of oxidative DNA damages in hepatic carcinogenesis, and ROS and RNS in cell death and proliferation.

Summarizing the findings in this thesis, it was concluded that oxidative DNA damage in chronic liver inflammation is likely causally linked with malignant transformation of HCC; that ROS and RNS adjust cell proliferation in a concentration dependent manner; and that ROS and RNS participate in cell metabolism through redox reactions. These activities lead to malignant transformation of normal hepatocytes and uncontrolled growth of HCC cells.
Keyword Hepatocellular Carcinoma
Chronic liver inflammation
DNA oxidative damage
Nitric oxide
Free radical
Cell proliferation
Malignant transformation of hepatocyte

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Created: Fri, 13 Dec 2013, 13:03:35 EST by Mr Pengcheng Li on behalf of University of Queensland Graduate School