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Retinoblastoma protein potentiates the innate immune response in hepatocytes: Significance for hepatocellular carcinoma

Authors

  • Jack Hutcheson,

    1. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX
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  • Ryan J. Bourgo,

    1. Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA
    2. Ben May Department for Cancer Research, University of Chicago, Chicago, IL
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  • Uthra Balaji,

    1. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX
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  • Adam Ertel,

    1. Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA
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  • Agnieszka K. Witkiewicz,

    1. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX
    2. Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX
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  • Erik S. Knudsen

    Corresponding author
    1. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX
    2. Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX
    • Address reprint requests to: E.S. Knudsen, Ph.D., University of Texas Southwestern Medical Center, Department of Pathology, 5323 Harry Hines Blvd., Dallas, TX 75390-9072. E-mail: erik.knudsen@utsouthwestern.edu; fax: 214-648-4067.

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  • Potential conflict of interest: Nothing to report.

Abstract

Cancers mediated by viral etiology must exhibit deregulated cellular proliferation and evade immune recognition. The role of the retinoblastoma tumor suppressor (RB) pathway, which is lost at relatively high frequency in hepatocellular carcinoma (HCC), has recently been expanded to include the regulation of innate immune responsiveness. In this study we investigated the coordinate impact of RB-loss on cell cycle control and immune function in the liver. We found that RB depletion in hepatoma cells resulted in a compromised immunological response to multiple stimuli and reduced the potential of these cells to recruit myeloid cells. Viral-mediated liver-specific RB deletion in vivo led to the induction of genes associated with proliferation and cell cycle entry as well as the significant attenuation of genes associated with immune function, as evidenced by decreases in cytokine and chemokine expression, leukocyte recruitment, and hepatic inflammation. To determine if these changes in gene expression were instructive in human disease, we compared our liver-specific RB-loss gene signature to existing profiles of HCC and found that this signature was associated with disease progression and confers a worse prognosis. Conclusion: Our data confirm that RB participates in the regulation of innate immunity in liver parenchymal cells both in vitro and in vivo and to our knowledge describes the first gene signature associated with HCC that includes both immunoregulatory and proliferative genes and that can also be attributed to the alteration of a single gene in vitro. (Hepatology 2014;60:1231–1240)

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