Prostaglandins, Leukotrienes and Essential Fatty Acids
Altered lipid profile, oxidative status and hepatitis B virus interactions in human hepatocellular carcinoma☆
Introduction
Hepatocellular carcinoma (HCC) is one of the most prevalent human cancers, ranking the fifth most common worldwide [1]. Geographical distribution of this disease varies greatly, i.e. in parts of Asia and Africa the prevalence is more than 100 per 100 000 population while in Europe and North America it is estimated to be 2–4 per 100 000 population [2]. The main risk factors associated with HCC are hepatitis B (HBV) and C (HCV) viral infections, which account for approximately 80% of reported cases worldwide [1], [3]. Other factors that play a role in HCC development, either alone or in conjunction with viral infection include aflatoxin B1 (AFB1) exposure, cigarette smoking, alcohol consumption, p53 gene mutations, repeated cycles of necrosis and regeneration, and chronic inflammation [4]. Experimental and clinical observations suggest that persistent proliferation of genetically altered liver cells plays a key role in the progression of chronic hepatitis into cancer [5]. The development of HCC has also been associated with disorders in plasma lipid and lipoprotein metabolism [6].
Cancer development is associated with alterations in lipid metabolism, affecting cellular function and growth [7]. The development of hepatocyte nodules in rat liver is associated with changes in lipid parameters and oxidative status. These alterations involve increased cholesterol and phosphatidylethanolamine (PE), resulting in increased cholesterol/phospholipid and decreased phosphatidylcholine/phosphatidylethanolamine (PC/PE) ratios. Changes in the phospholipid levels resulted in a decrease in the polyunsaturated fatty acids (PUFAs), especially the long-chain PUFA (LCPUFA), which was associated with low oxidative status [8], [9]. The low levels of PUFA may result from either increased requirement during cell proliferation or impaired functioning of the delta-6 desaturase enzyme, a rate-limiting enzyme in the PUFA metabolic pathway [10], [11]. LCPUFA may play a role in the control of cell proliferation by inhibiting cell growth and stimulating apoptosis either directly [12] or via increased lipid peroxidation (LPO) [7]. Besides their effect on LPO, antitumour effects of the ω3 LCPUFA, such as C20:5ω3 and C22:6ω3, are mainly attributed to the suppression of cell proliferation and induction of apoptosis via various processes, including regulating the level of C20:4ω6 [13], [14]. The ω6 fatty acid (FA) 20:4ω6 is known to stimulate cell proliferation via overexpression of cyclo-oxygenase-2 (COX-2) [15] and subsequent increased formation of PGE2 while on the other hand it may also enhance apoptosis via ceramide [16]. Therefore, regulation of membrane phospholipid content, 20:4ω6 metabolism as well as cellular oxidative status seems to play an important role in determining cell survival. An imbalance in cellular redox state has been observed in various cancer cells compared with normal cells [17], which may be related to oncogenic stimulation and cancer cell survival. Cancer cells exhibit low oxidative status presumably due to low PUFA levels and alterations in the redox status, including the glutathione (GSH)/GSSG ratio and activity of antioxidant enzymes such as superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) [12], [17].
It would appear that the regulatory mechanisms related to lipid metabolism ensuring normal liver homeostasis are disrupted and these changes play a role in the survival and growth of malignant cells [8], [12]. In this regard, the control of cell proliferation and apoptosis has been recognised as a key event in cancer development [18] and the use of dietary constituents such as FAs has been recognised to be an important tool in cancer therapy [19], [20]. The present study investigated the lipid composition and different oxidative parameters in human HCC as compared to those in matching surrounding tissue.
Section snippets
Ethical considerations
Ethical approval for the study was granted by the Ethics Committees of the University of the Witwatersrand and the Medical Research Council of South Africa. Consent for necropsy and removal of cancerous and normal liver tissue was obtained from close relatives of the patient and consent for resection of the tumour from the patient prior to the surgical procedure.
HCC and surrounding non-tumorous liver tissue
HCC and surrounding non-tumorous liver tissue were obtained from 13 patients either at necropsy or at the time of surgical resection
Phospholipid and cholesterol parameters (Table 1)
No significant difference in the phospholipid and cholesterol levels (Table 1) was observed between the HBV− and HBV+ tissue samples. The PC concentration was significantly (P<0.05) decreased in the carcinoma tissue, while no significant effect was observed in the PE concentration, resulting in a significant (P<0.05) decrease in the PC/PE ratio when compared with the surrounding tissue. The cholesterol concentration was marginally (0.05<P<0.1) increased in the carcinoma tissue and with the
Discussion
Alterations in lipid profiles and oxidative status in malignant tissue are of importance due to the effect on membrane integrity, fluidity and regulation of cellular processes related to growth and cell survival [12], [35]. Regarding the lipid profile of the HCC tissue, the present study indicated perturbations in the membrane phospholipid distribution and content as demonstrated by a decreased PC/PE ratio. This is suggestive of increased membrane PE content relative to PC, which could be an
Acknowledgements
The authors wish to thank Mrs Amelia Damons and Mr John Mokotary for technical assistance. This study was funded by the Cancer Association of South Africa (CANSA) and a Technology and Human Resources for Industry Programme grant (THRIP) by the South African Department of Trade and Industry.
References (76)
Epidemiology of hepatocellular carcinoma
Toxicology
(2002)- et al.
The natural history of hepatocellular carcinoma
Toxicology
(2002) - et al.
Can tumour cell drug resistance be reversed by essential fatty acids and their metabolites?
Prost. Leukot. Essent. Fatty Acids
(1998) Nutritional and medical importance of gamma linolenic acid
Prog. Lipid Res.
(1992)- et al.
Dietary polyunsaturated fatty acids and colorectal neoplasia
Biomed. Pharmacother.
(2002) - et al.
Free radicals, metals and antioxidants in oxidative stress-induced cancer
Chem. Biol. Interact.
(2006) - et al.
A simple method for the isolation and purification of total lipids from animal tissues
J. Biol. Chem.
(1957) - et al.
Single plate separation of lung phospholipids including disaturated phosphatidylcholine
J. Lipid Res.
(1983) - et al.
A new micromethod for the colorimetric determination of inorganic phosphate
Clin. Chim. Acta
(1966) - et al.
Effect of dietary lipids and vitamin E on in vitro lipid peroxidation in rat liver and kidney homogenates
J. Nutr.
(1989)
Determination of aldehydic lipid peroxidation products: malonaldehyde and 4-hydroxynonenal
Methods Enzymol.
Enzymatic method for quantitative determination of nanogram amounts of total and oxidized glutathione: applications to mammalian blood and other tissues
Anal. Biochem.
Measurement of cellular oxidation, reactive oxygen species, and antioxidant enzymes during apoptosis
Methods Enzymol.
Catalase in vitro
Methods Enzymol.
A modification of the Lowry procedure to simplify protein determination in membrane and lipoprotein samples
Anal. Biochem.
Effect of zwitterionic buffers on measurement of small masses of protein with bicinchoninic acid
Anal. Biochem.
Polyunsaturated fatty acids (PUFA) and eicosanoids in human health and pathologies
Biomed. Pharmacother.
Lipid distribution and transport across cellular membranes
Sem. Cell Dev. Biol.
Regulation of cellular differentiation and apoptosis by fatty acids and their metabolites
Nutr. Res.
Induction of hepatocyte proliferation after partial hepatectomy is accompanied by a markedly reduced expression of phosphatidylethanolamine N-methyltransferase-2
Biochem. Biophys. Acta
Studies on regenerating liver and hepatoma plasma membranes-II. Membrane fluidity and enzyme activity
Int. J. Biochem.
Effect of average phospholipid curvature on supported bilayer formation on glass by vesicle fusion
Biophys. J.
Characterization of the lipid surrounding the delta-6-desaturase of rat liver microsomes
Biochim. Biophys. Acta
Possible involvement of delta-6-desaturase in control of melanoma growth by gamma-linolenic acid
Prost. Leukot. Essent. Fatty Acids
The ratio of trienoic:tetraenoic acids in tissue lipids as a measure of essential fatty acid requirement
J. Nutr.
Comparison of sulfur amino acid utilization for GSH synthesis between HepG2 cells and cultured rat hepatocytes
Biochem. Pharmacol.
Dihomo-gamma-linolenic acid increases the metabolism of eicosapentaenoic acid in perfused vascular tissue
Prost. Leukot. Med.
Free radicals, metals and antioxidants in oxidative stress-induced cancer
Chem. Biol. Reactions
Glutathione metabolism in hepatomous liver of rats treated with diethylnitrosamine
Biochim. Biophys. Acta
Polyunsaturated (n-3) fatty acids susceptible to peroxidation are increased in plasma and tissue lipids of rats fed docosahexaenoic acid-containing oils
J. Nutr.
Purification and chemical characterization of the inhibitor of lipid peroxidation from intestinal mucosa
Biochim. Biophys. Acta
Hepatitis B virus infection contributes to oxidative stress in a population exposed to aflatoxin B1 and high-risk for hepatocellular carcinoma
Cancer Lett.
Changes in glutathione status and the antioxidant system in blood and in cancer cells associate with tumuor growth in vivo
Free Radical Biol. Med.
Changes in the antioxidant system by TNP-470 in an in vivo model of hepatocarcinoma
Transl. Res.
Catalase activity in human hepatocellular carcinoma (HCC)
Clin. Biochem.
Global cancer statistics, 2002
CA Cancer J. Clin.
Hepatocellular carcinoma
Postgrad. Med. J.
Epidemiological characteristics and risk factors of hepatocellular carcinoma
J. Gastroenterol. Hepatol.
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This study was funded by the Cancer Association of South Africa (CANSA) and the National Research Foundation (NRF) through a grant from the Technology and Human Resources for Industry Programme (THRIP) by the Department of Trade and Industry.