Blockade of CD47-mediated cathepsin S/protease-activated receptor 2 signaling provides a therapeutic target for hepatocellular carcinoma

Authors

  • Terence Kin-Wah Lee,

    1. State Key Laboratory for Liver Research, The University of Hong Kong, Pokfulam, Hong Kong
    2. Departments of Pathology, The University of Hong Kong, Pokfulam, Hong Kong
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    • These authors contributed equally to this work.

  • Vincent Chi-Ho Cheung,

    1. State Key Laboratory for Liver Research, The University of Hong Kong, Pokfulam, Hong Kong
    2. Departments of Pathology, The University of Hong Kong, Pokfulam, Hong Kong
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    • These authors contributed equally to this work.

  • Ping Lu,

    1. State Key Laboratory for Liver Research, The University of Hong Kong, Pokfulam, Hong Kong
    2. Departments of Pathology, The University of Hong Kong, Pokfulam, Hong Kong
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  • Eunice Yuen Ting Lau,

    1. State Key Laboratory for Liver Research, The University of Hong Kong, Pokfulam, Hong Kong
    2. Departments of Pathology, The University of Hong Kong, Pokfulam, Hong Kong
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  • Stephanie Ma,

    1. State Key Laboratory for Liver Research, The University of Hong Kong, Pokfulam, Hong Kong
    2. Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
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  • Kwan Ho Tang,

    1. Departments of Pathology, The University of Hong Kong, Pokfulam, Hong Kong
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  • Man Tong,

    1. Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
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  • Jessica Lo,

    1. State Key Laboratory for Liver Research, The University of Hong Kong, Pokfulam, Hong Kong
    2. Departments of Pathology, The University of Hong Kong, Pokfulam, Hong Kong
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  • Irene Oi Lin Ng

    Corresponding author
    1. State Key Laboratory for Liver Research, The University of Hong Kong, Pokfulam, Hong Kong
    2. Departments of Pathology, The University of Hong Kong, Pokfulam, Hong Kong
    • Address reprint requests to: Irene O.L. Ng, M.D., Ph.D., Room 127B, University Pathology Building, Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong. E-mail: iolng@hku.hk; fax: +852-2872-5197 or Terrence K.W. Lee, Ph.D., Room 704, 7/F, Faculty of Medicine Building, 21 Sassoon Road, Hong Kong. E-mail: tkwlee@hkucc.hku.hk; fax: +852-2819-5375.

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  • Potential conflict of interest: Nothing to report.

  • The study was supported by the Hong Kong Research Grants Council Collaborative Research Fund (HKU 1/06C and HKU 7/CRF/09), Hong Kong Research Grants Council General Research Fund (HKU 771213M; to T.K.W.L.), and the National Natural Science Foundation of China (project no.: 81272440; to T.K.W.L.). I.O.L.N. is Loke Yew Professor in Pathology.

Abstract

Identification of therapeutic targets against tumor-initiating cells (TICs) is a priority in the development of new therapeutic paradigms against cancer. We enriched a TIC population capable of tumor initiation and self-renewal by serial passages of hepatospheres with chemotherapeutic agents. In chemoresistant hepatospheres, CD47 was found to be up-regulated, when compared with differentiated progenies. CD47 is preferentially expressed in liver TICs, which contributed to tumor initiation, self-renewal, and metastasis and significantly affected patients' clinical outcome. Knockdown of CD47 suppressed stem/progenitor cell characteristics. CD47+ hepatocellular carcinoma (HCC) cells preferentially secreted cathepsin S (CTSS), which regulates liver TICs through the CTSS/protease-activated receptor 2 (PAR2) loop. Suppression of CD47 by morpholino approach suppressed growth of HCC in vivo and exerted a chemosensitization effect through blockade of CTSS/PAR2 signaling. Conclusion: These data suggest that CD47 may be an attractive therapeutic target for HCC therapy. (Hepatology 2014;60:179–191)

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