Hepatic androgen receptor suppresses hepatocellular carcinoma metastasis through modulation of cell migration and anoikis

Authors

  • Wen-Lung Ma,

    1. Sex Hormone Research Centre and Graduate Institute of Clinical Medical Science, China Medical University/Hospital, Taichung, Taiwan
    2. George Whipple Lab for Cancer Research, Departments of Pathology and Urology and the Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York, USA
    Search for more papers by this author
    • These authors contributed equally to this study.

  • Cheng-Lung Hsu,

    1. Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan, ROC
    Search for more papers by this author
    • These authors contributed equally to this study.

  • Chun-Chieh Yeh,

    1. Sex Hormone Research Centre and Graduate Institute of Clinical Medical Science, China Medical University/Hospital, Taichung, Taiwan
    Search for more papers by this author
  • Ming-Heng Wu,

    1. George Whipple Lab for Cancer Research, Departments of Pathology and Urology and the Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York, USA
    Search for more papers by this author
  • Chiung-Kuei Huang,

    1. George Whipple Lab for Cancer Research, Departments of Pathology and Urology and the Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York, USA
    Search for more papers by this author
  • Long-Bin Jeng,

    1. Sex Hormone Research Centre and Graduate Institute of Clinical Medical Science, China Medical University/Hospital, Taichung, Taiwan
    Search for more papers by this author
  • Yao-Ching Hung,

    1. Sex Hormone Research Centre and Graduate Institute of Clinical Medical Science, China Medical University/Hospital, Taichung, Taiwan
    Search for more papers by this author
  • Tze-Yi Lin,

    1. Sex Hormone Research Centre and Graduate Institute of Clinical Medical Science, China Medical University/Hospital, Taichung, Taiwan
    Search for more papers by this author
  • Shuyuan Yeh,

    1. George Whipple Lab for Cancer Research, Departments of Pathology and Urology and the Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York, USA
    Search for more papers by this author
  • Chawnshang Chang

    Corresponding author
    1. Sex Hormone Research Centre and Graduate Institute of Clinical Medical Science, China Medical University/Hospital, Taichung, Taiwan
    2. George Whipple Lab for Cancer Research, Departments of Pathology and Urology and the Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York, USA
    • George Whipple Lab for Cancer Research, Departments of Pathology and Urology and the Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642===

    Search for more papers by this author

  • Potential conflict of interest: Nothing to report.

Abstract

Early reports suggested androgen/androgen receptor (AR) signals promote hepatocarcinogenesis. However, all antiandrogen clinical trials failed in advanced hepatocellular carcinoma (HCC) without reasonable explanations. We examined AR functions in HCC cancer metastasis in this study. We examined hepatic AR roles in HCC metastasis by comparing liver hepatocyte AR knockout and wildtype in a carcinogen-induced HCC mouse model. We examined tumor histology, cancer metastatic risks, and cancer survival in vivo, as well as cell anoikis and migration using primary hepatic tumor culture in vitro. We also examined therapeutic potentials of AR expression combined with the molecular targeting agent sorafenib in an HCC metastasis mouse model. We found a novel cancer phenotype in which mice lacking hepatic AR developed more undifferentiated tumors and larger tumor size at the metastatic stage. These mice also died earlier with increased lung metastasis, suggesting that hepatic AR may play dual yet opposite roles to promote HCC initiation but suppress HCC metastasis. Mechanistic dissection found that hepatic AR could enhance anoikis and suppress migration of HCC cells by way of suppression of p38 phosphorylation/activation and the nuclear factor kappa B (NF-κB)/matrix metallopeptidase 9 (MMP9) pathway, respectively. In addition, the in vivo preclinical trials concluded that a combination therapy of increased AR expression and reduced multiple-kinase inhibitor (sorafenib) exhibited better therapeutic efficacy. Conclusion: Our study demonstrates that AR could orchestrate intrahepatic signaling hierarchies and cellular behaviors, consequently affect HCC progression. Results from combination therapy shed light on developing new therapeutic paradigms for battling HCC at later metastatic stages. (HEPATOLOGY 2012;56:176–185)

Ancillary