Impact of glutathione peroxidase 4 on cell proliferation, angiogenesis and cytokine production in hepatocellular carcinoma
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Nataliya Rohr-Udilova1, Eva Bauer2, Gerald Timelthaler3, Robert Eferl3, Klaus Stolze4,5, Matthias Pinter1, Martha Seif1, Hubert Hayden1, Thomas Reiberger1, Rolf Schulte-Hermann3, Markus Peck-Radosavljevic1,6, Dagmar Stoiber2,7,* and Michael Trauner1,*
1Division of Gastroenterology and Hepatology, Internal Medicine III, Medical University of Vienna, Vienna, Austria
2Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria
3Institute of Cancer Research, Internal Medicine I, Medical University of Vienna, Vienna, Austria
4Department of Life Sciences, Veterinary University of Vienna, Vienna, Austria
5Institute of Animal Nutrition and Functional Plan Compounds, Department of Farm Animals and Veterinary Public Health, Veterinary University of Vienna, Vienna, Austria
6Clinic Klagenfurth, Division of Gastroenterology and Hepatology, Klagenfurt am Woerthersee, Austria
7Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
*These authors contributed equally to this work
Nataliya Rohr-Udilova, email: [email protected]
Keywords: phospholipid glutathione peroxidase; free radicals; cell proliferation; angiogenesis; hepatocellular carcinoma
Received: August 12, 2017 Accepted: November 16, 2017 Published: January 22, 2018
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.
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