Mitochondrial SOD2 regulates epithelial–mesenchymal transition and cell populations defined by differential CD44 expression

• Published in: Oncogene Vol. 34; no. 41; pp. 5229 - 5239
• Main Authors: Kinugasa, H, Whelan, K A, Tanaka, K, Natsuizaka, M, Long, A, Guo, A, Chang, S, Kagawa, S, Srinivasan, S, Guha, M, Yamamoto, K, St Clair, D K, Avadhani, N G, Diehl, J A, Nakagawa, H
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.10.2015; Nature Publishing Group
• Subjects: 13; 13/31; 38/109; 38/89; 631/67/327; Antioxidants; Apoptosis; Cancer; CD44 antigen; Cell Biology; Cell death; Cell Line; Cellular biology; Epithelial cells; Epithelial-Mesenchymal Transition; Esophagus; Flow cytometry; Gene expression; Gene Expression Regulation, Enzymologic; Gene regulation; Genetic aspects; Genetic engineering; Health aspects; Homeodomain Proteins - metabolism; Human Genetics; Humans; Hyaluronan Receptors; Immune response; Internal Medicine; Keratinocytes; Medicine; Medicine & Public Health; Mesenchyme; Metastases; Metastasis; Mitochondria; Mitochondria - enzymology; NF-kappa B - metabolism; NF-κB protein; Oncology; original-article; Phenotypes; Properties; Reactive oxygen species; Repressor Proteins - metabolism; Ribonucleic acid; RNA; RNA-mediated interference; Senescence; Superoxide dismutase; Superoxide Dismutase - physiology; Transcription; Zinc Finger E-box Binding Homeobox 2
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2014.449

Epithelial–mesenchymal transition (EMT) promotes cancer cell invasion, metastasis and treatment failure. EMT may be activated in cancer cells by reactive oxygen species (ROS). EMT may promote conversion of a subset of cancer cells from a CD44 low -CD24 high (CD44L) epithelial phenotype to a CD44 high -CD24 −/low (CD44H) mesenchymal phenotype, the latter associated with increased malignant properties of cancer cells. ROS are required for cells undergoing EMT, although excessive ROS may induce cell death or senescence; however, little is known as to how cellular antioxidant capabilities may be regulated during EMT. Mitochondrial superoxide dismutase 2 (SOD2) is frequently overexpressed in oral and esophageal cancers. Here, we investigate mechanisms of SOD2 transcriptional regulation in EMT, as well as the functional role of this antioxidant in EMT. Using well-characterized genetically engineered oral and esophageal human epithelial cell lines coupled with RNA interference and flow cytometric approaches, we find that transforming growth factor (TGF)-β stimulates EMT, resulting in conversion of CD44L to CD44H cells, the latter of which display SOD2 upregulation. SOD2 induction in transformed keratinocytes was concurrent with suppression of TGF-β-mediated induction of both ROS and senescence. SOD2 gene expression appeared to be transcriptionally regulated by NF-κB and ZEB2, but not ZEB1. Moreover, SOD2-mediated antioxidant activity may restrict conversion of CD44L cells to CD44H cells at the early stages of EMT. These data provide novel mechanistic insights into the dynamic expression of SOD2 during EMT. In addition, we delineate a functional role for SOD2 in EMT via the influence of this antioxidant upon distinct CD44L and CD44H subsets of cancer cells that have been implicated in oral and esophageal tumor biology.