Abstract
Insufficient supplementation with the micronutrient selenium and persistent hepatic inflammation predispose to hepatocellular carcinoma (HCC). Inflammation-associated reactive oxygen species attack membrane lipids and form lipid hydroperoxides able to propagate oxidative hepatic damage. Selenium-containing enzyme glutathione peroxidase 4 (GPx4) antagonizes this damage by reducing lipid hydroperoxides to respective hydroxides. However, the role of GPx4 in HCC remains elusive.We generated two human HCC cell lines with stable overexpression of GPx4, performed xenotransplantation into NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) host mice and characterized the tumors formed. The experimental data were verified using gene expression data from two independent HCC patient cohorts.GPx4 overexpression protected from oxidative stress and reduced intracellular free radical level. GPx4-overexpressing cells displayed impaired tumor growth, reduced proliferation, altered angiogenesis and decreased expression of clinically relevant cytokine interleukin-8 and C-reactive protein. Moreover, GPx4 overexpression impaired migration of endothelial cells in vitro, and enhanced expression of thrombospondin 1, an endogenous inhibitor of angiogenesis. In patients, GPx4 expression in tumors positively correlated with survival and was linked to pathways which regulate cell proliferation, motility, tissue remodelling, immune response and M1 macrophage polarization. The patient data largely confirmed experimental findings especially in a subclass of poor prognosis tumors with high proliferation.GPx4 suppresses formation and progression of HCC by inhibition of angiogenesis and tumor cell proliferation as well as by immune-mediated mechanisms. Modification of GPx4 expression may represent a novel tool for HCC prevention or treatment.
Highlights
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide [1]
We have previously found that linoleic acid hydroperoxide apparently contributes to non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) and that selenium antagonises the effects in HCC [6, 7]
glutathione peroxidase 4 (GPx4) overexpressing cells were more resistant to cell death induced by hydrogen peroxide and peroxidized linoleic acid (LOOH, Figure 1B, 1C)
Summary
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide [1]. HCC epidemiology is currently changing due to the availability of highly-effective antiviral drugs against HBV and HCV infections as well as due to increasing incidence of other cancer-predisposing liver diseases such as alcoholic and non-alcoholic steatohepatitis (ASH, NASH) and non-alcoholic fatty liver disease (NAFLD) [2]. Chronic hepatic inflammation is a common feature of cancer-predisposing liver diseases and favours HCC development [3]. There is a broad consensus that oxidative stress mediated by reactive oxygen species (ROS) plays a pivotal role [4]. ROS initiate peroxidation of polyunsaturated fatty acids resulting in formation of fatty acid hydroperoxides, as shown for heating of dietary oils or inflammation [5]. Fatty acid hydroperoxides can undergo Fenton-type decomposition increasing intracellular radical level, propagating lipid peroxidation and favouring mutagenesis and regenerative cell proliferation
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