title: Mitochondrial SOD2 regulates epithelial-mesenchymal transition and cell populations defined by differential CD44 expression.
abstract: 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.
authors: Gastroenterology Division, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.|Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
authors: H
authors: H
authors: Kinugasa
authors: Gastroenterology Division, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
authors: K A
authors: KA
authors: Whelan
authors: Gastroenterology Division, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
authors: K
authors: K
authors: Tanaka
authors: Gastroenterology Division, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.|Department of Gastroenterology and Hepatology, Hokkaido University, Sapporo, Japan.
authors: M
authors: M
authors: Natsuizaka
authors: Gastroenterology Division, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
authors: A
authors: A
authors: Long
authors: Gastroenterology Division, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
authors: A
authors: A
authors: Guo
authors: Gastroenterology Division, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
authors: S
authors: S
authors: Chang
authors: Gastroenterology Division, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
authors: S
authors: S
authors: Kagawa
authors: Department of Animal Biology and Mari Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors: S
authors: S
authors: Srinivasan
authors: Department of Animal Biology and Mari Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors: M
authors: M
authors: Guha
authors: Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
authors: K
authors: K
authors: Yamamoto
authors: Department of Toxicology and Cancer Biology, University of Kentucky College of Medicine, Lexington, KY, USA.
authors: D K
authors: DK
authors: St Clair
authors: Department of Animal Biology and Mari Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors: N G
authors: NG
authors: Avadhani
authors: Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.|Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA.
authors: J A
authors: JA
authors: Diehl
authors: Gastroenterology Division, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
authors: H
authors: H
authors: Nakagawa
mesh_terms: D002460:Cell Line; D058750:Epithelial-Mesenchymal Transition; D015971:Gene Expression Regulation, Enzymologic; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors; D008928:Mitochondria / Q000201:enzymology; D016328:NF-kappa B / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D013482:Superoxide Dismutase / Q000502:physiology*; D000074165:Zinc Finger E-box Binding Homeobox 2; D000099156:Superoxide Dismutase 2
chemical_list: D018398:Homeodomain Proteins; D018960:Hyaluronan Receptors; D016328:NF-kappa B; D012097:Repressor Proteins; D013482:Superoxide Dismutase; D000074165:Zinc Finger E-box Binding Homeobox 2; D000099156:Superoxide Dismutase 2; C497483:CD44 protein, human; C492363:ZEB2 protein, human