MicroRNA-221 overexpression accelerates hepatocyte proliferation during liver regeneration§

Authors

  • Qinggong Yuan,

    1. Cluster of Excellence REBIRTH, Hannover Medical School, Hannover, Germany
    2. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
    3. TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany
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    • These authors contributed equally to this study.

  • Komal Loya,

    1. Cluster of Excellence REBIRTH, Hannover Medical School, Hannover, Germany
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    • These authors contributed equally to this study.

  • Bhavna Rani,

    1. Cluster of Excellence REBIRTH, Hannover Medical School, Hannover, Germany
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    • These authors contributed equally to this study.

  • Selina Möbus,

    1. Cluster of Excellence REBIRTH, Hannover Medical School, Hannover, Germany
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  • Asha Balakrishnan,

    1. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
    2. TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany
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  • Jutta Lamle,

    1. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
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  • Toni Cathomen,

    1. Department of Experimental Hematology, Hannover Medical School, Hannover, Germany
    2. Laboratory of Cell and Gene Therapy, Center of Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany
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  • Arndt Vogel,

    1. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
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  • Michael P. Manns,

    1. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
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  • Michael Ott,

    1. Cluster of Excellence REBIRTH, Hannover Medical School, Hannover, Germany
    2. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
    3. TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany
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  • Tobias Cantz,

    1. Cluster of Excellence REBIRTH, Hannover Medical School, Hannover, Germany
    2. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
    3. Max Planck Institute for Molecular Biomedicine, Münster, Germany
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  • Amar Deep Sharma

    Corresponding author
    1. Cluster of Excellence REBIRTH, Hannover Medical School, Hannover, Germany
    2. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
    • Ph.D., Stem Cell Biology, Cluster of Excellence REBIRTH, Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hans Borst Zentrum J-11-02-6530, OE 8881, Carl-Neuberg-Str-1, D-30625 Hannover, Germany
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    • fax: 0049 511 532 5234


  • Potential conflict of interest: Nothing to report.

  • Supported by grants from the German Research Foundation (EXC 62/1, SFB 738, SH640/1-1) and HiLF from Hannover Medical School. S.M. and B.R. receive stipends from the Hannover Biomedical Research School (HBRS).

Abstract

The tightly controlled replication of hepatocytes in liver regeneration and uncontrolled proliferation of tumor cells in hepatocellular carcinoma (HCC) are often modulated by common regulatory pathways. Several microRNAs (miRNAs) are involved in HCC progression by modulating posttranscriptional expression of multiple target genes. miR-221, which is frequently up-regulated in HCCs, delays fulminant liver failure in mice by inhibiting apoptosis, indicating a pleiotropic role of miR-221 in hepatocytes. Here, we hypothesize that modulation of miR-221 targets in primary hepatocytes enhances proliferation, providing novel clues for enhanced liver regeneration. We demonstrate that miR-221 enhances proliferation of in vitro cultivated primary hepatocytes. Furthermore, applying two-thirds partial hepatectomy as a surgically induced liver regeneration model we show that adeno-associated virus-mediated overexpression of miR-221 in the mouse liver also accelerates hepatocyte proliferation in vivo. miR-221 overexpression leads to rapid S-phase entry of hepatocytes during liver regeneration. In addition to the known targets p27 and p57, we identify Aryl hydrocarbon nuclear translocator (Arnt) messenger RNA (mRNA) as a novel target of miR-221, which contributes to the pro-proliferative activity of miR-221. Conclusion: miR-221 overexpression accelerates hepatocyte proliferation. Pharmacological intervention targeting miR-221 may thus be therapeutically beneficial in liver failure by preventing apoptosis and by inducing liver regeneration. (HEPATOLOGY 2013;)

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