Disordered purinergic signaling and abnormal cellular metabolism are associated with development of liver cancer in Cd39/Entpd1 null Mice

Authors

  • Xiaofeng Sun,

    1. Department of Medicine, Gastroenterology/Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
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    • These authors contributed equally to this work

  • Lihui Han,

    1. Department of Medicine, Gastroenterology/Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
    Current affiliation:
    1. Department of Immunology, Shandong University School of Medicine, Jinan, PR. of China
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    • These authors contributed equally to this work

  • Pankaj Seth,

    1. Department of Medicine, Division of Interdisciplinary Medicine and Biotechnology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
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  • Shu Bian,

    1. Department of Medicine, Gastroenterology/Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
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  • Linglin Li,

    1. Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
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  • Eva Csizmadia,

    1. Department of Medicine, Gastroenterology/Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
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  • Wolfgang G. Junger,

    1. Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
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  • Moritz Schmelzle,

    1. Department of Medicine, Gastroenterology/Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
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  • Anny Usheva,

    1. Division of Endocrinology, Department of Medicine and Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
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  • Elliot B. Tapper,

    1. Department of Medicine, Gastroenterology/Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
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  • Gyorgy Baffy,

    1. Department of Medicine, VA Boston Healthcare System and Brigham and Women's Hospital, Harvard Medical School, Boston, MA
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  • Vikas P. Sukhatme,

    1. Department of Medicine, Division of Interdisciplinary Medicine and Biotechnology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
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  • Yan Wu,

    Corresponding author
    1. Department of Medicine, Gastroenterology/Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
    • 330 Brookline Ave., E/CLS-614, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215
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    • These authors share senior co-authorship

    • fax: 617-735-2924,

  • Simon C. Robson

    Corresponding author
    1. Department of Medicine, Gastroenterology/Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
    • 330 Brookline Ave., E/CLS-614, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215
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    • These authors share senior co-authorship

    • fax: 617-735-2924,


  • Potential conflict of interest: Nothing to report.

  • Supported by National Institutes of Health (NHLBI P01-HL076540 and R01-HL094400).

Abstract

Liver cancer is associated with chronic inflammation, which is linked to immune dysregulation, disordered metabolism, and aberrant cell proliferation. Nucleoside triphosphate diphosphohydrolase-1; (CD39/ENTPD1) is an ectonucleotidase that regulates extracellular nucleotide/nucleoside concentrations by scavenging nucleotides to ultimately generate adenosine. These properties inhibit antitumor immune responses and promote angiogenesis, being permissive for the growth of transplanted tumors. Here we show that Cd39 deletion promotes development of both induced and spontaneous autochthonous liver cancer in mice. Loss of Cd39 results in higher concentrations of extracellular nucleotides, which stimulate proliferation of hepatocytes, abrogate autophagy, and disrupt glycolytic metabolism. Constitutive activation of Ras-mitogen-activated protein kinase (MAPK) and mammalian target of rapamycin (mTOR)-S6K1 pathways occurs in both quiescent Cd39 null hepatocytes in vitro and liver tissues in vivo. Exogenous adenosine 5′-triphosphate (ATP) boosts these signaling pathways, whereas rapamycin inhibits such aberrant responses in hepatocytes. Conclusion: Deletion of Cd39 and resulting changes in disordered purinergic signaling perturb hepatocellular metabolic/proliferative responses, paradoxically resulting in malignant transformation. These findings might impact adjunctive therapies for cancer. Our studies indicate that the biology of autochthonous and transplanted tumors is quite distinct. (HEPATOLOGY 2013)

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