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Selenoprotein deficiency and high levels of selenium compounds can effectively inhibit hepatocarcinogenesis in transgenic mice

Abstract

The micronutrient element selenium (Se) has been shown to be effective in reducing the incidence of cancer in animal models and human clinical trials. Selenoproteins and low molecular weight Se compounds were implicated in the chemopreventive effect, but specific mechanisms are not clear. We examined the role of Se and selenoproteins in liver tumor formation in TGFα/c-Myc transgenic mice, which are characterized by disrupted redox homeostasis and develop liver cancer by 6 months of age. In these mice, both Se deficiency and high levels of Se compounds suppressed hepatocarcinogenesis. In addition, both treatments induced expression of detoxification genes, increased apoptosis and inhibited cell proliferation. Within low-to-optimal levels of dietary Se, tumor formation correlated with expression of most selenoproteins. These data suggest that changes in selenoprotein expression may either suppress or promote tumorigenesis depending on cell type and genotype. Since dietary Se may have opposing effects on cancer, it is important to identify the subjects who will benefit from Se supplementation as well as those who will not.

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Abbreviations

GPx1:

glutathione peroxidase 1

HCC:

hepatocellular carcinoma

Se:

selenium

SelR:

selenoprotein R

Sep15:

15 kDa selenoprotein

TGFα:

transforming growth factor α

TPS:

triphenylselenonium chloride

TR1:

thioredoxin reductase 1 (cytosolic enzyme* also called TxnRd1 and TrxR1)

TR3:

thioredoxin reductase 3 (mitochondrial enzyme* also called TxnRd2 and TrxR2)

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Acknowledgements

Services of the University of Nebraska-Lincoln genomics facility, headed by Dr Yuannan Xia and the bioinformatics facility, headed by Dr Guoqing Lu, are acknowledged. We thank Dr Ian Mason for providing hydroxysteroid dehydrogenase antibodies and Dr Hwa-Young Kim for help with methionine sulfoxide reductase assays. Supported by NIH CA080946 and in part by GM061603 and AG021518 (to VNG).

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Novoselov, S., Calvisi, D., Labunskyy, V. et al. Selenoprotein deficiency and high levels of selenium compounds can effectively inhibit hepatocarcinogenesis in transgenic mice. Oncogene 24, 8003–8011 (2005). https://doi.org/10.1038/sj.onc.1208940

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Keywords

  • selenoprotein
  • selenocysteine
  • selenium
  • cancer prevention
  • redox regulation

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