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Antioxid Redox Signal. 2016 Aug 20;25(6):283-99. doi: 10.1089/ars.2015.6524.

Manganese Superoxide Dismutase Expression Regulates the Switch Between an Epithelial and a Mesenchymal-Like Phenotype in Breast Carcinoma.

Loo SY1,2,3, Hirpara JL1,4, Pandey V1, Tan TZ1, Yap CT4,5, Lobie PE1,6, Thiery JP1,3, Goh BC1,5,7, Pervaiz S4,5,8,9, Clément MV3,9, Kumar AP1,5,6,8,10.

Author information

1
1 Cancer Science Institute of Singapore, National University of Singapore , Singapore, Singapore .
2
2 Genome Institute of Singapore , Agency for Science, Technology and Research (A*STAR), Singapore, Singapore .
3
3 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore , Singapore, Singapore .
4
4 Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore , Singapore, Singapore .
5
5 National University Cancer Institute, National University Health System , Singapore, Singapore .
6
6 Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore , Singapore, Singapore .
7
7 Department of Haematology-Oncology, National University Health System , Singapore, Singapore .
8
8 Curtin Health Innovation Research Institute, School of Biomedical Sciences, Curtin University , Perth, Australia .
9
9 NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore , Singapore, Singapore .
10
10 Department of Biological Sciences, University of North Texas , Denton, Texas.

Abstract

AIM:

Epithelial-mesenchymal transition (EMT) is characterized by the acquisition of invasive fibroblast-like morphology by epithelial cells that are highly polarized. EMT is recognized as a crucial mechanism in cancer progression and metastasis. In this study, we sought to assess the involvement of manganese superoxide dismutase (MnSOD) during the switch between epithelial-like and mesenchymal-like phenotypes in breast carcinoma.

RESULTS:

Analysis of breast carcinomas from The Cancer Genome Atlas database revealed strong positive correlation between tumors' EMT score and the expression of MnSOD. This positive correlation between MnSOD and EMT score was significant and consistent across all breast cancer subtypes. Similarly, a positive correlation of EMT score and MnSOD expression was observed in established cell lines derived from breast cancers exhibiting phenotypes ranging from the most epithelial to the most mesenchymal. Interestingly, using phenotypically distinct breast cancer cell lines, we provide evidence that constitutively high or induced expression of MnSOD promotes the EMT-like phenotype by way of a redox milieu predominantly driven by hydrogen peroxide (H2O2). Conversely, gene knockdown of MnSOD results in the reversal of EMT to a mesenchymal-epithelial transition (MET)-like program, which appears to be a function of superoxide (O2(-•))-directed signaling.

INNOVATION AND CONCLUSION:

These data underscore the involvement of MnSOD in regulating the switch between the EMT and MET-associated phenotype by influencing cellular redox environment via its effect on the intracellular ratio between O2(-•) and H2O2. Strategies to manipulate MnSOD expression and/or the cellular redox milieu vis-a-vis O2(-•):H2O2 could have potential therapeutic implications. Antioxid. Redox Signal. 25, 283-299.

PMID:
27400860
PMCID:
PMC4991580
DOI:
10.1089/ars.2015.6524
[Indexed for MEDLINE]
Free PMC Article

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