Increased RNA-induced silencing complex (RISC) activity contributes to hepatocellular carcinoma

Authors

  • Byoung Kwon Yoo,

    1. Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA
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    • These authors contributed equally.

  • Prasanna K. Santhekadur,

    1. Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA
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    • These authors contributed equally.

  • Rachel Gredler,

    1. Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA
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  • Dong Chen,

    1. Department of Pathology, Virginia Commonwealth University, School of Medicine, Richmond, VA
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  • Luni Emdad,

    1. Department of Neurosurgery, Mount Sinai Medical Center, New York, NY
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  • Sujit Bhutia,

    1. Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA
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  • Lewis Pannell,

    1. University of South Alabama, Mitchell Cancer Institute, Mobile, AL
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  • Paul B. Fisher,

    1. Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA
    2. VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA
    3. Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA
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  • Devanand Sarkar

    Corresponding author
    1. Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA
    2. Department of Pathology, Virginia Commonwealth University, School of Medicine, Richmond, VA
    3. VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA
    4. Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA
    • 1220 East Broad St., PO Box 980035, Richmond, VA 23298
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    • fax: (804) 628-1176


  • Potential conflict of interest: Nothing to report.

  • D.S. is the Harrison Endowed Scholar in Cancer Research and Blick scholar. P.B.F. holds the Thelma Newmeyer Corman Chair in Cancer Research and is a Samuel Waxman Cancer Research Foundation (SWCRF) Investigator.

Abstract

There is virtually no effective treatment for advanced hepatocellular carcinoma (HCC) and novel targets need to be identified to develop effective treatment. We recently documented that the oncogene Astrocyte elevated gene-1 (AEG-1) plays a seminal role in hepatocarcinogenesis. Employing yeast two-hybrid assay and coimmunoprecipitation followed by mass spectrometry, we identified staphylococcal nuclease domain containing 1 (SND1), a nuclease in the RNA-induced silencing complex (RISC) facilitating RNAi-mediated gene silencing, as an AEG-1 interacting protein. Coimmunoprecipitation and colocalization studies confirmed that AEG-1 is also a component of RISC and both AEG-1 and SND1 are required for optimum RISC activity facilitating small interfering RNA (siRNA) and micro RNA (miRNA)-mediated silencing of luciferase reporter gene. In 109 human HCC samples SND1 was overexpressed in ≈74% cases compared to normal liver. Correspondingly, significantly higher RISC activity was observed in human HCC cells compared to immortal normal hepatocytes. Increased RISC activity, conferred by AEG-1 or SND1, resulted in increased degradation of tumor suppressor messenger RNAs (mRNAs) that are target of oncomiRs. Inhibition of enzymatic activity of SND1 significantly inhibited proliferation of human HCC cells. As a corollary, stable overexpression of SND1 augmented and siRNA-mediated inhibition of SND1 abrogated growth of human HCC cells in vitro and in vivo, thus revealing a potential role of SND1 in hepatocarcinogenesis. Conclusion: We unravel a novel mechanism that overexpression of AEG-1 and SND1 leading to increased RISC activity might contribute to hepatocarcinogenesis. Targeted inhibition of SND1 enzymatic activity might be developed as an effective therapy for HCC. (HEPATOLOGY 2011;)

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