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MnSOD Expression Regulates the Switch between an Epithelial to a Mesenchymal-like Phenotype in Mammary Carcinoma. (Antioxid Redox Signal, Jul 2016)

Loo SY1,2, Hirpara J3, Pandey V4, Tuan ZT5, Yap CT6, Lobie PE7, Thiery JP8, Goh BC9, Pervaiz S10,11, Clement MV12, Kumar AP13

1National University of Singapore, Biochemistry, Centre for Translational Medicine (CeTM), 14 Medical Drive,  Singapore, Singapore, 117599.
2National University of Singapore, Cancer Science Institute, Singapore, Singapore; sayolooseryue@gmail.com.
3National University of Singapore, Physiology, Singapore, Singapore; jayshree_hirpara@nuhs.edu.sg.
4National University of Singapore, Cancer Science Institute of Singapore, Singapore, Singapore; csivkp@nus.edu.sg.
5National University of Singapore, Cancer Science Institute, Singapore, Singapore; csittz@nus.edu.sg.
6National University of Singapore, Physiology, Block MD 9, 2 Medical Drive, Singapore, Singapore, 117597; celestial_therese_yap@nuhs.edu.sg.
7National University of Singapore, Cancer Science Institute of Singapore, Singapore, Singapore; csipel@nus.edu.sg.
8National University of Singapore, Department of Biochemistry, Singapore, Singapore; bchtjp@nus.edu.sg.
9National University of Singapore, Cancer Science Institute, Singapore, Singapore; phcgbc@nus.edu.sg.
10National University of Singapore, Physiology, 2 Medical Drive , MD9, #01-05 , Singapore, Singapore , 117597.
11Duke-NUS Graduate Medical School, Cancer and Stem Cell Biology Program, Singapore; phssp@nus.edu.sg.
12National University of Singapore, Biochemistry, 8 Medical Drive, Singapore, Singapore, 117597; bchmvc@nus.edu.sg.
13National University of Singapore, Cancer Science Institute of Singapore, MD6, 14 Medical Drive, #11-01M, Singapore, Singapore, 117599; csiapk@nus.edu.sg.

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. Here 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 (TCGA) 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 frombreast 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 inducedexpression 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 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 theswitch 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.

 

PMID: 27400860