title: Antagonistic effects of selenium and lipid peroxides on growth control in early hepatocellular carcinoma.
abstract: Activation of the activator protein 1 (AP-1) transcription factor as well as increased serum levels of vascular endothelial growth factor (VEGF) and interleukin (IL)-8 predict poor prognosis of patients with hepatocellular carcinomas (HCCs). Moreover, HCC patients display reduced selenium levels, which may cause lipid peroxidation and oxidative stress because selenium is an essential component of antioxidative glutathione peroxidases (GPx). We hypothesized that selenium-lipid peroxide antagonism controls the above prognostic markers and tumor growth. (1) In human HCC cell lines (HCC-1.2, HCC-3, and SNU398) linoleic acid peroxide (LOOH) and other prooxidants enhanced the expression of VEGF and IL-8. LOOH up-regulated AP-1 activation. Selenium inhibited these effects. This inhibition was mediated by glutathione peroxidase 4 (GPx4), which preferentially degrades lipid peroxides. Selenium enhanced GPx4 expression and total GPx activity, while knock-down of GPx4 by small interfering RNA (siRNA) increased VEGF, and IL-8 expression. (2) These results were confirmed in a rat hepatocarcinogenesis model. Selenium treatment during tumor promotion increased hepatic GPx4 expression and reduced the expression of VEGF and of the AP-1 component c-fos as well as nodule growth. (3) In HCC patients, increased levels of LOOH-related antibodies (LOOH-Ab) were found, suggesting enhanced LOOH formation. LOOH-Ab correlated with serum VEGF and IL-8 and with AP-1 activation in HCC tissue. In contrast, selenium inversely correlated with VEGF, IL-8, and HCC size (the latter only for tumors smaller than 3 cm).
  
  
  CONCLUSIONS
  Reduced selenium levels result in accumulation of lipid peroxides. This leads to enhanced AP-1 activation and consequently to elevated expression of VEGF and IL-8, which accelerate the growth of HCC. Selenium supplementation could be considered for investigation as a strategy for chemoprevention or additional therapy of early HCC in patients with low selenium levels.
authors: Division of Gastroenterology and Hepatology, Internal Medicine III, Medical University of Vienna, Vienna, Austria.
authors: Nataliya
authors: N
authors: Rohr-Udilova
authors: Wolfgang
authors: W
authors: Sieghart
authors: Robert
authors: R
authors: Eferl
authors: Dagmar
authors: D
authors: Stoiber
authors: Linda
authors: L
authors: Björkhem-Bergman
authors: Lennart C
authors: LC
authors: Eriksson
authors: Klaus
authors: K
authors: Stolze
authors: Hubert
authors: H
authors: Hayden
authors: Bernhard
authors: B
authors: Keppler
authors: Sandra
authors: S
authors: Sagmeister
authors: Bettina
authors: B
authors: Grasl-Kraupp
authors: Rolf
authors: R
authors: Schulte-Hermann
authors: Markus
authors: M
authors: Peck-Radosavljevic
mesh_terms: D000328:Adult; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004052:Diethylnitrosamine / Q000009:adverse effects; D004195:Disease Models, Animal; D005979:Glutathione Peroxidase / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D019787:Linoleic Acid / Q000494:pharmacology*; D008054:Lipid Peroxides / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D051381:Rats; D011916:Rats, Inbred F344; D012643:Selenium / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D016209:Interleukin-8; D008054:Lipid Peroxides; D018808:Transcription Factor AP-1; D042461:Vascular Endothelial Growth Factor A; D004052:Diethylnitrosamine; D019787:Linoleic Acid; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D005979:Glutathione Peroxidase; D012643:Selenium