Antagonistic effects of selenium and lipid peroxides on growth control in early hepatocellular carcinoma
- Author(s)
- Nataliya Rohr-Udilova, Wolfgang Sieghart, Robert Eferl, Dagmar Stoiber, Linda Bjorkhem-Bergman, Lennart C. Eriksson, Klaus Stolze, Hubert Hayden, Bernhard Keppler, Sandra Sagmeister, Bettina Grasl-Kraupp, Rolf Schulte-Hermann, Markus Peck-Radosavljevic
- 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). Conclusion: 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.
- Organisation(s)
- Department of Inorganic Chemistry
- External organisation(s)
- Medizinische Universität Wien, Ludwig Boltzmann Institut für Krebsforschung, Karolinska Institute, Veterinärmedizinische Universität Wien
- Journal
- Hepatology
- Volume
- 55
- Pages
- 1112-1121
- No. of pages
- 10
- ISSN
- 0270-9139
- DOI
- https://doi.org/10.1002/hep.24808
- Publication date
- 2012
- Peer reviewed
- Yes
- Austrian Fields of Science 2012
- 302025 Hepatology, 301305 Medical chemistry
- Portal url
- https://ucrisportal.univie.ac.at/en/publications/1bda3a80-e2a7-468d-8143-f4d1de835fce