title: Increased CD13 expression reduces reactive oxygen species, promoting survival of liver cancer stem cells via an epithelial-mesenchymal transition-like phenomenon.
abstract: BACKGROUND
  Recently, it has been reported that a small population of cancer stem cells (CSCs) play a role in resistance to chemotherapy and radiation therapy. We reported that CD13(+) liver CSCs survive in hypoxic lesions after chemotherapy, presumably through increased expression of CD13/Aminopeptidase N, which is a scavenger enzyme in the reactive oxygen species (ROS) metabolic pathway. On the other hand, the concept of epithelial-mesenchymal transition (EMT) was indicated by a recent study showing an increased plasticity linked to the cellular "stemness" of CSCs.
  
  
  METHODS
  To study the relationship between CSCs and EMT, we examined biological characteristics of liver cancer cell lines with EMT by exposing transforming growth factor-β (TGF-β).
  
  
  RESULTS
  We showed that a TGF-β-induced EMT-like phenomenon is associated with increased CD13 expression in liver cancer cells. This phenomenon prevents further increases in the ROS level as well as the induction of apoptosis, promoting the survival of CD13(+) CSCs, whereas inhibition of CD13 stimulates apoptosis. Immunohistochemical analysis also indicated that after chemotherapy, CD13 was coexpressed with N-cadherin in surviving cancer cells within fibrous capsules. We have demonstrated that CD13 expression plays a role in supporting the survival of CSCs and that there is an EMT-associated reduction in ROS elevation.
  
  
  CONCLUSIONS
  This novel and consistent linkage between functional CSC markers and the EMT phenomenon suggests a bona fide candidate for targeted therapy for EMT-mediated invasion and metastasis of liver cancer.
authors: Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
authors: Ho Min
authors: HM
authors: Kim
authors: Naotsugu
authors: N
authors: Haraguchi
authors: Hideshi
authors: H
authors: Ishii
authors: Masahisa
authors: M
authors: Ohkuma
authors: Miho
authors: M
authors: Okano
authors: Koshi
authors: K
authors: Mimori
authors: Hidetoshi
authors: H
authors: Eguchi
authors: Hirofumi
authors: H
authors: Yamamoto
authors: Hiroaki
authors: H
authors: Nagano
authors: Mitsugu
authors: M
authors: Sekimoto
authors: Yuichiro
authors: Y
authors: Doki
authors: Masaki
authors: M
authors: Mori
mesh_terms: D017209:Apoptosis; D018826:CD13 Antigens / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015820:Cadherins / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D016009:Chi-Square Distribution; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D015870:Gene Expression; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D063150:Polycomb Repressive Complex 1 / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000378:metabolism; D018709:Statistics, Nonparametric; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014410:Tumor Stem Cell Assay
chemical_list: C069077:BMI1 protein, human; D015820:Cadherins; C497761:NOTCH1 protein, human; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D051881:Receptor, Notch1; D016212:Transforming Growth Factor beta; D063150:Polycomb Repressive Complex 1; D018826:CD13 Antigens