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CD133+ liver cancer stem cells from methionine adenosyl transferase 1A–deficient mice demonstrate resistance to transforming growth factor (TGF)-β–induced apoptosis

Authors

  • Wei Ding,

    1. Department of Pediatrics, The Pennsylvania State University College of Medicine, Penn State Children's Hospital, Hershey, PA
    2. Department of Pharmacology, The Pennsylvania State University College of Medicine, Penn State Children's Hospital, Hershey, PA
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  • Marialena Mouzaki,

    1. Department of Pediatrics, The Pennsylvania State University College of Medicine, Penn State Children's Hospital, Hershey, PA
    2. Department of Pharmacology, The Pennsylvania State University College of Medicine, Penn State Children's Hospital, Hershey, PA
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  • Hanning You,

    1. Department of Pediatrics, The Pennsylvania State University College of Medicine, Penn State Children's Hospital, Hershey, PA
    2. Department of Pharmacology, The Pennsylvania State University College of Medicine, Penn State Children's Hospital, Hershey, PA
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  • Joshua C. Laird,

    1. Department of Pediatrics, The Pennsylvania State University College of Medicine, Penn State Children's Hospital, Hershey, PA
    2. Department of Pharmacology, The Pennsylvania State University College of Medicine, Penn State Children's Hospital, Hershey, PA
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  • Jose Mato,

    1. CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology, Park of Bizkaia, Bizkaia, Spain
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  • Shelly C. Lu,

    1. Division of Gastroenterology and Liver Diseases, USC Research Center for Liver Diseases, USC-UCLA Research Center for Alcoholic Liver and Pancreatic Diseases, Keck School of Medicine, University of Southern California, Los Angeles, CA
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  • C. Bart Rountree

    Corresponding author
    1. Department of Pediatrics, The Pennsylvania State University College of Medicine, Penn State Children's Hospital, Hershey, PA
    2. Department of Pharmacology, The Pennsylvania State University College of Medicine, Penn State Children's Hospital, Hershey, PA
    • Department of Pediatrics and Pharmacology, Penn State University College of Medicine, 500 University Drive, H085, Hershey, PA 17033
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    • fax: 717-531-0653.


  • Potential conflict of interest: Nothing to report.

Abstract

Methionine adenosyltransferase (MAT) is an essential enzyme required for S-adenosylmethionine biosynthesis. Hepatic MAT activity falls during chronic liver injury, and mice lacking Mat1a develop spontaneous hepatocellular carcinoma by 18 months. We have previously demonstrated that CD133+CD45 oval cells isolated from 16-month-old Mat1a−/− mice represent a liver cancer stem cell population. The transforming growth factor β (TGF-β) pathway constitutes a central signaling network in proliferation, apoptosis, and tumorigenesis. In this study, we tested the response of tumorigenic liver stem cells to TGF-β. CD133+CD45 oval cells were isolated from premalignant 16-month-old Mat1a−/− mice by flow cytometry and expanded as five clone lines derived from a single cell. All clone lines demonstrated expression of both hepatocyte and cholangiocyte markers and maintained a small population (0.5% to 2%) of CD133+ cells in vitro, and three of five clone lines produced tumors. Although TGF-β1 inhibited cell growth equally in CD133 and CD133+ cells from each clone line, the CD133+ population demonstrated significant resistance to TGF-β–induced apoptosis compared with CD133 cells. Furthermore, CD133+ cells demonstrated a substantial increase in mitogen-activated protein kinase (MAPK) pathway activation, as demonstrated by phosphorylated extracellular signal-regulated kinase levels before and after TGF-β stimulation. MAPK inhibition using mitogen-activated protein kinase kinase 1 (MEK1) inhibitor PD98059 led to a significant increase in TGF-β–induced apoptosis in CD133+ cells. Conversely, a constitutively active form of MEK1 blocked the apoptotic effects of TGF-β in CD133 cells. Conclusion: CD133+ liver cancer stem cells exhibit relative resistance to TGF-β–induced apoptosis. One mechanism of resistance to TGF-β–induced apoptosis in CD133+ cancer stem cells is an activated mitogen-activated protein kinase/extracellular signal-regulated kinase pathway. (HEPATOLOGY 2009.)

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