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Adenosine triphosphate-binding cassette transporter genes up-regulation in untreated hepatocellular carcinoma is mediated by cellular microRNAs

Authors

  • Florie Borel,

    1. Department of Research & Development, Amsterdam Molecular Therapeutics, Amsterdam; The Netherlands
    2. Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam; The Netherlands
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  • Ruiqi Han,

    1. Department of Research & Development, Amsterdam Molecular Therapeutics, Amsterdam; The Netherlands
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  • Allerdien Visser,

    1. Department of Clinical Chemistry, VU University Medical Center, Amsterdam; The Netherlands
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  • Harald Petry,

    1. Department of Research & Development, Amsterdam Molecular Therapeutics, Amsterdam; The Netherlands
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  • Sander J.H. van Deventer,

    1. Department of Research & Development, Amsterdam Molecular Therapeutics, Amsterdam; The Netherlands
    2. Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden University, Leiden, The Netherlands
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  • Peter L.M. Jansen,

    1. Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam; The Netherlands
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  • Pavlina Konstantinova,

    Corresponding author
    1. Department of Research & Development, Amsterdam Molecular Therapeutics, Amsterdam; The Netherlands
    • Department of Research and Development, Amsterdam Molecular Therapeutics, Meibergdreef 61, 1105 BA Amsterdam, The Netherlands
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    • fax: +31 205669272

  • with collaboration of the Réseau Centre de Ressources Biologiques Foie (French Liver Biobanks Network), France

    1. Department of Research & Development, Amsterdam Molecular Therapeutics, Amsterdam; The Netherlands
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  • Potential conflict of interest: Nothing to report. Amsterdam Molecular Therapeutics declared no commercial interest in the conclusions.

  • Supported by Amsterdam Molecular Therapeutics.

Abstract

Adenosine triphosphate (ATP)-binding cassette (ABC) transporters are drug efflux pumps responsible for the multidrug resistance phenotype causing hepatocellular carcinoma (HCC) treatment failure. Here we studied the expression of 15 ABC transporters relevant for multidrug resistance in 19 paired HCC patient samples (16 untreated, 3 treated by chemotherapeutics). Twelve ABC transporters showed up-regulation in HCC compared with adjacent healthy liver. These include ABCA2, ABCB1, ABCB6, ABCC1, ABCC2, ABCC3, ABCC4, ABCC5, ABCC10, ABCC11, ABCC12, and ABCE1. The expression profile and function of some of these transporters have not been associated with HCC thus far. Because cellular microRNAs (miRNAs) are involved in posttranscriptional gene silencing, we hypothesized that regulation of ABC expression in HCC might be mediated by miRNAs. To study this, miRNAs were profiled and dysregulation of 90 miRNAs was shown in HCC compared with healthy liver, including up-regulation of 11 and down-regulation of 79. miRNA target sites in ABC genes were bioinformatically predicted and experimentally verified in vitro using luciferase reporter assays. In total, 13 cellular miRNAs were confirmed that target ABCA1, ABCC1, ABCC5, ABCC10, and ABCE1 genes and mediate changes in gene expression. Correlation analysis between ABC and miRNA expression in individual patients revealed an inverse relationship, providing an indication for miRNA regulation of ABC genes in HCC. Conclusion: Up-regulation of ABC transporters in HCC occurs prior to chemotherapeutic treatment and is associated with miRNA down-regulation. Up-regulation of five ABC genes appears to be mediated by 13 cellular miRNAs in HCC patient samples. miRNA-based gene therapy may be a novel and promising way to affect the ABC profile and overcome clinical multidrug resistance. (Hepatology 2012)

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