2 Similarly, increased VEGF is linked to earlier HCC recurrence and shorter overall survival.3-5 Both VEGF and IL-8 gene expression are regulated by the transcription factor activator protein 1 (AP-1). AP-1 binding sites were found in the promoter regions of VEGF and IL-8 genes.6, 7 AP-1 is supposed to be involved in tumor formation and angiogenesis8 and can be activated by oxidative stress.9 Oxidative stress is defined as an imbalance between production and antioxidative elimination of reactive oxygen species (ROS). Moreover, oxidative stress is a common feature of inflammatory

liver diseases that predispose to cancer10, 11 and is associated with a higher incidence of HCC recurrence in hepatitis C patients.10 Selenium counteracts oxidative stress because selenoproteins such as glutathione Selleck RG-7204 peroxidases (GPx) eliminate ROS.12, 13 Low selenium levels are associated with an increased cancer risk including HCC.14-18 The liver is particularly affected under selenium deficiency because other organs such as brain, testis, and endocrine tissues are supplied preferentially with selenium.19 GPx2 and GPx4 are supposed to attenuate cancer development.20 GPx4 is the only known enzyme that is efficiently able to reduce lipid peroxides13 formed through ROS-mediated oxidation of unsaturated lipids. Lipid peroxides elevate AP-1 activity and VEGF formation in colorectal cancer cells.21 Likewise, in cultured HCC

cells we found an increase of AP-1 components c-jun and c-fos by lipid peroxides.22 We hypothesized that Acalabrutinib AP-1 activation as well as expression of its target genes VEGF and IL-8 in HCC are controlled by the selenium/lipid peroxide antagonism. The results of the present study

support this hypothesis by evidence gathered from cell lines, an HCC animal model, and HCC patients. 2-AAF, 2-acetylaminofluoren; AP-1, activator protein 1; CXCL1, chemokine find more (C-X-C motif) ligand 1; DEN, diethylnitrosamin; DHFC, 2′,7′-dichlorofluorescin diacetate; IL-8, interleukin 8; HCC, hepatocellular carcinoma; HIF-1α, hypoxia inducible factor 1α; LH, linoleic acid; LOOH, linoleic acid hydroperoxides; LOOH-Ab, linoleic acid hydroperoxide related antibodies; ROS, reactive oxygen species; VEGF, vascular endothelial growth factor. Selenium was quantified by an inductively coupled plasma mass spectrometer (ICP-MS). Details are given in Supporting Methods. Twenty-nine adult patients with histologically confirmed HCC (Supporting Table 1) underwent orthotopic liver transplantation at the General Hospital of Vienna, Austria. HCC tissue arrays were constructed.23 Healthy persons from the local population without known liver disorders were used as controls. Data analysis was performed with the permission of the local Ethics Committee. Correlations were also calculated from published microarray human HCC data.24 HCC in Fisher-344 rats (Charles River) was initiated by 200 mg/kg intraperitoneal diethylnitrosamin (DEN) as described.25 Promotion was performed by 0.