Annals of Surgical Oncology

, Volume 19, Supplement 3, pp 539–548 | Cite as

Increased CD13 Expression Reduces Reactive Oxygen Species, Promoting Survival of Liver Cancer Stem Cells via an Epithelial–Mesenchymal Transition-like Phenomenon

  • Ho Min Kim
  • Naotsugu Haraguchi
  • Hideshi Ishii
  • Masahisa Ohkuma
  • Miho Okano
  • Koshi Mimori
  • Hidetoshi Eguchi
  • Hirofumi Yamamoto
  • Hiroaki Nagano
  • Mitsugu Sekimoto
  • Yuichiro Doki
  • Masaki Mori
Translational Research and Biomarkers



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.


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).


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.


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.


Tace Reactive Oxygen Species Level Intracellular Reactive Oxygen Species Liver Cancer Cell Intracellular Reactive Oxygen Species Level 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This study was supported in part by a grant from Core Research for Evolutional Science and Technology (CREST), a Grant-in-Aid for scientific research on Priority Areas (20012039), Grants-in-Aid for scientific research S (21229015) and C (20590313) from the Ministry of Education, Culture, Sports, Science, and Technology, and a grant from the Tokyo Biochemical Research Foundation, Japan.

Supplementary material

10434_2011_2040_MOESM1_ESM.tif (253 kb)
Supplementary material 1 (TIFF 253 kb)
10434_2011_2040_MOESM2_ESM.tif (137 kb)
Supplementary material 2 (TIFF 137 kb)


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Copyright information

© Society of Surgical Oncology 2011

Authors and Affiliations

  • Ho Min Kim
    • 1
  • Naotsugu Haraguchi
    • 1
  • Hideshi Ishii
    • 1
    • 2
  • Masahisa Ohkuma
    • 1
    • 3
  • Miho Okano
    • 1
  • Koshi Mimori
    • 2
  • Hidetoshi Eguchi
    • 1
  • Hirofumi Yamamoto
    • 1
  • Hiroaki Nagano
    • 1
  • Mitsugu Sekimoto
    • 1
  • Yuichiro Doki
    • 1
  • Masaki Mori
    • 1
  1. 1.Department of Gastroenterological SurgeryOsaka University Graduate School of MedicineOsakaJapan
  2. 2.Department of Molecular and Cellular Biology, Division of Molecular and Surgical OncologyKyushu University, Medical Institute of BioregulationBeppuJapan
  3. 3.Department of Gastroenterological SurgeryJikei Collage Graduate School of MedicineTokyoJapan

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