Astrocyte elevated gene-1 promotes hepatocarcinogenesis: Novel insights from a mouse model

Authors

  • Jyoti Srivastava,

    1. Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA
    Search for more papers by this author
  • Ayesha Siddiq,

    1. Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA
    Search for more papers by this author
  • Luni Emdad,

    1. Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA
    Search for more papers by this author
  • Prasanna Kumar Santhekadur,

    1. Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA
    Search for more papers by this author
  • Dong Chen,

    1. Department of Pathology, Virginia Commonwealth University, School of Medicine, Richmond, VA
    Search for more papers by this author
  • Rachel Gredler,

    1. Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA
    Search for more papers by this author
  • Xue-Ning Shen,

    1. Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA
    Search for more papers by this author
  • Chadia L. Robertson,

    1. Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA
    Search for more papers by this author
  • Catherine I. Dumur,

    1. Department of Pathology, Virginia Commonwealth University, School of Medicine, Richmond, VA
    2. Virginia Commonwealth University (VCU) Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA
    Search for more papers by this author
  • Phillip B. Hylemon,

    1. Department of Microbiology and Immunology, Virginia Commonwealth University, School of Medicine, Richmond, VA
    2. Virginia Commonwealth University (VCU) Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA
    Search for more papers by this author
  • Nitai D. Mukhopadhyay,

    1. Department of Biostatistics, Virginia Commonwealth University, School of Medicine, Richmond, VA
    Search for more papers by this author
  • Deepak Bhere,

    1. Molecular Neuropathy and Imaging Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
    Search for more papers by this author
  • Khalid Shah,

    1. Molecular Neuropathy and Imaging Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
    Search for more papers by this author
  • Rushdy Ahmad,

    1. Proteomics Group, Broad Institute of Harvard and Massachusetts Institute of Technology, Boston, MA
    Search for more papers by this author
  • Shah Giashuddin,

    1. Department of Pathology, New York Hospital Medical Center, Flushing, NY
    Search for more papers by this author
  • Jillian Stafflinger,

    1. Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA
    Search for more papers by this author
  • Mark A. Subler,

    1. Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA
    Search for more papers by this author
  • Jolene J. Windle,

    1. Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA
    2. Virginia Commonwealth University (VCU) Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA
    3. VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA
    Search for more papers by this author
  • Paul B. Fisher,

    1. Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA
    2. Virginia Commonwealth University (VCU) Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA
    3. VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA
    Search for more papers by this author
  • Devanand Sarkar

    Corresponding author
    1. Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA
    2. Virginia Commonwealth University (VCU) Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA
    3. VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA
    • Virginia Commonwealth University, School of Medicine, 1220 East Broad Street, P.O. Box 980035, Richmond, VA 23298
    Search for more papers by this author
    • fax: 804-628-1176


  • Potential conflict of interest: Nothing to report.

  • The present study was supported, in part, by grants from the James S. McDonnell Foundation and National Cancer Institute (grant no.: R01 CA138540; to D.S.), the Samuel Waxman Cancer Research Foundation (SWCRF; grant to D.S. and P.B.F.), and the National Institutes of Health (grant no.: R01 CA134721; to P.B.F.). D.S. is the Harrison Endowed Scholar in Cancer Research and a Blick scholar. P.B.F. holds the Thelma Newmeyer Corman Chair in Cancer Research and is a SWCRF investigator.

Abstract

Astrocyte elevated gene-1 (AEG-1) is a key contributor to hepatocellular carcinoma (HCC) development and progression. To enhance our understanding of the role of AEG-1 in hepatocarcinogenesis, a transgenic mouse with hepatocyte-specific expression of AEG-1 (Alb/AEG1) was developed. Treating Alb/AEG-1, but not wild-type (WT) mice, with N-nitrosodiethylamine resulted in multinodular HCC with steatotic features and associated modulation of expression of genes regulating invasion, metastasis, angiogenesis, and fatty acid synthesis. Hepatocytes isolated from Alb/AEG-1 mice displayed profound resistance to chemotherapeutics and growth factor deprivation with activation of prosurvival signaling pathways. Alb/AEG-1 hepatocytes also exhibited marked resistance toward senescence, which correlated with abrogation of activation of a DNA damage response. Conditioned media from Alb/AEG-1 hepatocytes induced marked angiogenesis with elevation in several coagulation factors. Among these factors, AEG-1 facilitated the association of factor XII (FXII) messenger RNA with polysomes, resulting in increased translation. Short interfering RNA–mediated knockdown of FXII resulted in profound inhibition of AEG-1-induced angiogenesis. Conclusion: We uncovered novel aspects of AEG-1 functions, including induction of steatosis, inhibition of senescence, and activation of the coagulation pathway to augment aggressive hepatocarcinogenesis. The Alb/AEG-1 mouse provides an appropriate model to scrutinize the molecular mechanism of hepatocarcinogenesis and to evaluate the efficacy of novel therapeutic strategies targeting HCC. (HEPATOLOGY 2012;56:1782–1791)

Ancillary