MicroRNA-494 within an oncogenic microRNA megacluster regulates G1/S transition in liver tumorigenesis through suppression of mutated in colorectal cancer

Authors

  • Lionel Lim,

    1. Department of Cell & Tissue Biology, University of California San Francisco, San Francisco, CA
    2. Department of Medicine, University of California San Francisco, San Francisco, CA
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    • These authors contributed equally to this work.

  • Asha Balakrishnan,

    1. Department of Medicine, University of California San Francisco, San Francisco, CA
    2. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
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    • These authors contributed equally to this work.

  • Noelle Huskey,

    1. Department of Cell & Tissue Biology, University of California San Francisco, San Francisco, CA
    2. Department of Medicine, University of California San Francisco, San Francisco, CA
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  • Kirk D. Jones,

    1. Department of Pathology, University of California San Francisco, San Francisco, CA
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  • Mona Jodari,

    1. Department of Cell & Tissue Biology, University of California San Francisco, San Francisco, CA
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  • Raymond Ng,

    1. Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA
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  • Guisheng Song,

    1. Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA
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  • Jesse Riordan,

    1. Anatomy and Cell Biology, University of Iowa, Iowa City, IA
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  • Brittany Anderton,

    1. Department of Cell & Tissue Biology, University of California San Francisco, San Francisco, CA
    2. Department of Medicine, University of California San Francisco, San Francisco, CA
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  • Siu-Tim Cheung,

    1. Department of Surgery, The University of Hong Kong, Hong Kong
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  • Holger Willenbring,

    1. Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA
    2. Liver Center, University of California San Francisco, San Francisco, CA
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  • Adam Dupuy,

    1. Anatomy and Cell Biology, University of Iowa, Iowa City, IA
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  • Xin Chen,

    1. Liver Center, University of California San Francisco, San Francisco, CA
    2. Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA
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  • David Brown,

    1. Mirna Therapeutics, Inc., Austin, TX
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  • Aaron N. Chang,

    1. Baylor Institute for Immunology Research, Dallas, TX
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  • Andrei Goga

    Corresponding author
    1. Department of Cell & Tissue Biology, University of California San Francisco, San Francisco, CA
    2. Department of Medicine, University of California San Francisco, San Francisco, CA
    3. Liver Center, University of California San Francisco, San Francisco, CA
    • Address reprint requests to: Andrei Goga, M.D., Ph.D., Department of Cell & Tissue Biology, University of California San Francisco, 513 Parnassus Avenue, Box 0512, San Francisco, CA 94143-0512. E-mail: andrei.goga@ucsf.edu; fax: 415-476-1128.

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  • Potential conflict of interest: Nothing to report.

  • The work was supported by fellowship supported by A*STAR (to L.L.) and by the Susan G. Komen Foundation (to A.G.), the National Institutes of Health (CA136717 and CA170447; to A.G.), the University of California San Francisco (UCSF) Program for Breakthrough Biological Research and a V-Foundation award (to A.G.), and the UCSF Liver Center (P30 DK026743).

Abstract

Hepatocellular carcinoma (HCC) is associated with poor survival for patients and few effective treatment options, raising the need for novel therapeutic strategies. MicroRNAs (miRNAs) play important roles in tumor development and show deregulated patterns of expression in HCC. Because of the liver's unique affinity for small nucleic acids, miRNA-based therapy has been proposed in the treatment of liver disease. Thus, there is an urgent need to identify and characterize aberrantly expressed miRNAs in HCC. In our study, we profiled miRNA expression changes in de novo liver tumors driven by MYC and/or RAS, two canonical oncogenes activated in a majority of human HCCs. We identified an up-regulated miRNA megacluster comprised of 53 miRNAs on mouse chromosome 12qF1 (human homolog 14q32). This miRNA megacluster is up-regulated in all three transgenic liver models and in a subset of human HCCs. An unbiased functional analysis of all miRNAs within this cluster was performed. We found that miR-494 is overexpressed in human HCC and aids in transformation by regulating the G1/S cell cycle transition through targeting of the Mutated in Colorectal Cancer tumor suppressor. miR-494 inhibition in human HCC cell lines decreases cellular transformation, and anti-miR-494 treatment of primary MYC-driven liver tumor formation significantly diminishes tumor size. Conclusion: Our findings identify a new therapeutic target (miR-494) for the treatment of HCC. (Hepatology 2014;58:202–215)

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