Autophagy suppresses tumorigenesis of hepatitis B virus-associated hepatocellular carcinoma through degradation of microRNA-224

Authors

  • Sheng-Hui Lan,

    1. Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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  • Shan-Ying Wu,

    1. Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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  • Roberto Zuchini,

    1. Graduate Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
    2. Department of Internal Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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  • Xi-Zhang Lin,

    1. Department of Internal Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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  • Ih-Jen Su,

    1. National Health Research Institutes, Tainan, Taiwan
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  • Ting-Fen Tsai,

    1. Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan
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  • Yen-Ju Lin,

    1. Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, Hsinchu, Taiwan
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  • Cheng-Tao Wu,

    1. Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, Hsinchu, Taiwan
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  • Hsiao-Sheng Liu

    Corresponding author
    1. Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
    2. Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
    3. Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan
    • Address reprint requests to: Hsiao-Sheng Liu, Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, #1 University road, Tainan, Taiwan; Tel: +1886-6-2353535, ext. 5630; Fax: 1886-6-2082705; E-mail: a713@mail.ncku.edu.tw.

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  • Potential conflict of interest: Nothing to report.

  • Supported by grants from the Headquarters of University Advancement, National Cheng Kung University (D100~101-35001); the National Science Council (NSC-99-2745-B-006-002, NSC100-2320-B-006-022, and NSC101-2320-B006-025-MY3), and from the National Science and Technology Development Fund (No. 97-EC-17-A-31-F1-0695).

Abstract

In hepatocellular carcinoma (HCC), dysregulated expression of microRNA-224 (miR-224) and impaired autophagy have been reported separately. However, the relationship between them has not been explored. In this study we determined that autophagy is down-regulated and inversely correlated with miR-224 expression in hepatitis B virus (HBV)-associated HCC patient specimens. These results were confirmed in liver tumors of HBV X gene transgenic mice. Furthermore, miR-224 was preferentially recruited and degraded during autophagic progression demonstrated by real-time polymerase chain reaction and miRNA in situ hybridization electron microscopy after extraction of autophagosomes. Our in vitro study demonstrated that miR-224 played an oncogenic role in hepatoma cell migration and tumor formation through silencing its target gene Smad4. In HCC patients, the expression of low-Atg5, high-miR-224, and low-Smad4 showed significant correlation with HBV infection and a poor overall survival rate. Autophagy-mediated miR-224 degradation and liver tumor suppression were further confirmed by the autophagy inducer amiodarone and miR-224 antagonist using an orthotopic SD rat model. Conclusion: A noncanonical pathway links autophagy, miR-224, Smad4, and HBV-associated HCC. These findings open a new avenue for the treatment of HCC. (Hepatology 2014;59:505–517)

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