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Review
. 2017 Nov:112:464-479.
doi: 10.1016/j.freeradbiomed.2017.08.013. Epub 2017 Aug 24.

Extracellular superoxide dismutase and its role in cancer

Brandon Griess  1 , Eric Tom  1 , Frederick Domann  2 , Melissa Teoh-Fitzgerald  3
Affiliations
Review

Extracellular superoxide dismutase and its role in cancer

Brandon Griess et al. Free Radic Biol Med. 2017 Nov.

Abstract

Reactive oxygen species (ROS) are increasingly recognized as critical determinants of cellular signaling and a strict balance of ROS levels must be maintained to ensure proper cellular function and survival. Notably, ROS is increased in cancer cells. The superoxide dismutase family plays an essential physiological role in mitigating deleterious effects of ROS. Due to the compartmentalization of ROS signaling, EcSOD, the only superoxide dismutase in the extracellular space, has unique characteristics and functions in cellular signal transduction. In comparison to the other two intracellular SODs, EcSOD is a relatively new comer in terms of its tumor suppressive role in cancer and the mechanisms involved are less well understood. Nevertheless, the degree of differential expression of this extracellular antioxidant in cancer versus normal cells/tissues is more pronounced and prevalent than the other SODs. A significant association of low EcSOD expression with reduced cancer patient survival further suggests that loss of extracellular redox regulation promotes a conducive microenvironment that favors cancer progression. The vast array of mechanisms reported in mediating deregulation of EcSOD expression, function, and cellular distribution also supports that loss of this extracellular antioxidant provides a selective advantage to cancer cells. Moreover, overexpression of EcSOD inhibits tumor growth and metastasis, indicating a role as a tumor suppressor. This review focuses on the current understanding of the mechanisms of deregulation and tumor suppressive function of EcSOD in cancer.

Keywords: Cancer; EcSOD; Epigenetic; Heparin binding domain; Loss of heterozygosity; Metastasis; Oxidative tumor microenvironment; Reactive oxygen species; Recurrence; Relapse free survival; SOD3; Single nucleotide polymorphism; Tumor suppressor; microRNA-21.

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Conflict of interest statement

The authors declare no potential conflicts of interest

Figures

Figure 1
Figure 1
Schematic illustration of human EcSOD protein structure. The 240 amino acid pro-peptide features an N-terminal signal peptide (green) cleaved to generate the 222 amino acid matured protein. Asparagine 89 is depicted as the singular glycosylated residue. The C-terminal heparin binding domain is depicted (blue).
Figure 2
Figure 2
Oncomine gene summary view comparing the number of datasets that had significant changes in mRNA expression for EcSOD (SOD3), CuZnSOD (SOD2), and MnSOD (SOD2) in cancer versus normal tissues. Thresholds were set for P<0.01 and top 10% score in gene rank for most significantly changed genes. Blue boxes indicate downregulation and red represents upregulation. Number in each box shows the number of analyses that met the thresholds.
Figure 3
Figure 3
Analysis of breast cancer data by Kaplan-Meier Plotter (http://kmplot.com) shows that low EcSOD expression is significantly associated with poor outcome (relapse free survival, RFS) in all types of breast cancer examined. Left panel shows analyses performed on all patients regardless of treatments while systemically untreated patients were excluded in analyses shown on the right. In red, patients with expression above the median and in black, patients with expressions below the median. The numbers of samples in each group are indicated in parentheses, and the hazard ratios (HR) and log rank p values are shown. Gene expression data and survival information are downloaded from GEO (Affymetrix HGU133A and HGU133+2 microarrays), EGA and TCGA.
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