Liver tumorigenicity promoted by microRNA-221 in a mouse transgenic model

Authors

  • Elisa Callegari,

    1. Dipartimento di Medicina Sperimentale e Diagnostica, Università di Ferrara, Ferrara, Italy
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  • Bahaeldin K. Elamin,

    1. Dipartimento di Medicina Sperimentale e Diagnostica, Università di Ferrara, Ferrara, Italy
    2. Department of Microbiology, Faculty of Medical Laboratory Sciences, University of Khartoum, Khartoum, Sudan
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  • Ferdinando Giannone,

    1. Centro di Ricerca Biomedica Applicata e Dipartimento di Medicina Interna, Policlinico S. Orsola-Malpighi e Università di Bologna, Bologna, Italy
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  • Maddalena Milazzo,

    1. Centro di Ricerca Biomedica Applicata e Dipartimento di Medicina Interna, Policlinico S. Orsola-Malpighi e Università di Bologna, Bologna, Italy
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  • Giuseppe Altavilla,

    1. Dipartimento di Scienze Medico Diagnostiche e Terapie Speciali, Università di Padova, Padova, Italy
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  • Francesca Fornari,

    1. Centro di Ricerca Biomedica Applicata e Dipartimento di Medicina Interna, Policlinico S. Orsola-Malpighi e Università di Bologna, Bologna, Italy
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  • Luciano Giacomelli,

    1. Dipartimento di Scienze Medico Diagnostiche e Terapie Speciali, Università di Padova, Padova, Italy
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  • Lucilla D'Abundo,

    1. Dipartimento di Medicina Sperimentale e Diagnostica, Università di Ferrara, Ferrara, Italy
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  • Manuela Ferracin,

    1. Dipartimento di Medicina Sperimentale e Diagnostica, Università di Ferrara, Ferrara, Italy
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  • Cristian Bassi,

    1. Dipartimento di Medicina Sperimentale e Diagnostica, Università di Ferrara, Ferrara, Italy
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  • Barbara Zagatti,

    1. Dipartimento di Medicina Sperimentale e Diagnostica, Università di Ferrara, Ferrara, Italy
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  • Fabio Corrà,

    1. Dipartimento di Medicina Sperimentale e Diagnostica, Università di Ferrara, Ferrara, Italy
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  • Elena Miotto,

    1. Dipartimento di Medicina Sperimentale e Diagnostica, Università di Ferrara, Ferrara, Italy
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  • Laura Lupini,

    1. Dipartimento di Medicina Sperimentale e Diagnostica, Università di Ferrara, Ferrara, Italy
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  • Luigi Bolondi,

    1. Centro di Ricerca Biomedica Applicata e Dipartimento di Medicina Interna, Policlinico S. Orsola-Malpighi e Università di Bologna, Bologna, Italy
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  • Laura Gramantieri,

    1. Centro di Ricerca Biomedica Applicata e Dipartimento di Medicina Interna, Policlinico S. Orsola-Malpighi e Università di Bologna, Bologna, Italy
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  • Carlo M. Croce,

    1. Dipartimento di Medicina Sperimentale e Diagnostica, Università di Ferrara, Ferrara, Italy
    2. Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University Medical Center, Columbus, OH
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  • Silvia Sabbioni,

    Corresponding author
    1. Dipartimento di Medicina Sperimentale e Diagnostica, Università di Ferrara, Ferrara, Italy
    • Dipartimento di Medicina Sperimentale e Diagnostica, Università di Ferrara, via Luigi Borsari 46, 44121 Ferrara, Italy===

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    • fax: +39-0532-455875

  • Massimo Negrini

    Corresponding author
    1. Dipartimento di Medicina Sperimentale e Diagnostica, Università di Ferrara, Ferrara, Italy
    • Dipartimento di Medicina Sperimentale e Diagnostica, Università di Ferrara, via Luigi Borsari 46, 44121 Ferrara, Italy===

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    • fax: +39 0532 247618


  • Potential conflict of interest: Nothing to report.

Abstract

MicroRNA-221 (miR-221) is one of the most frequently and consistently up-regulated microRNAs (miRNAs) in human cancer. It has been hypothesized that miR-221 may act as a tumor promoter. To demonstrate this, we developed a transgenic (TG) mouse model that exhibits an inappropriate overexpression of miR-221 in the liver. Immunoblotting and immunostaining confirmed a concomitant down-regulation of miR-221 target proteins. This TG model is characterized by the emergence of spontaneous nodular liver lesions in approximately 50% of male mice and by a strong acceleration of tumor development in 100% of mice treated with diethylnitrosamine. Similarly to human hepatocellular carcinoma, tumors are characterized by a further increase in miR-221 expression and a concomitant inhibition of its target protein-coding genes (i.e., cyclin-dependent kinase inhibitor [Cdkn]1b/p27, Cdkn1c/p57, and B-cell lymphoma 2–modifying factor). To validate the tumor-promoting effect of miR-221, we showed that in vivo delivery of anti-miR-221 oligonucleotides leads to a significant reduction of the number and size of tumor nodules. Conclusions: This study not only establishes that miR-221 can promote liver tumorigenicity, but it also establishes a valuable animal model to perform preclinical investigations for the use of anti-miRNA approaches aimed at liver cancer therapy. (HEPATOLOGY 2012;56:1025–1033)

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