Androgen pathway stimulates MicroRNA-216a transcription to suppress the tumor suppressor in lung cancer-1 gene in early hepatocarcinogenesis

Authors

  • Po-Jen Chen,

    1. Department of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan
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  • Shiou-Hwei Yeh,

    Corresponding author
    1. Department of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan
    2. National Taiwan University Center for Genomic Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
    • Department of Microbiology, National Taiwan University College of Medicine, No. 1, Jen-Ai Road, Section 1, Taipei 100, Taiwan
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    • fax: 886-2-23825962

  • Wan-Hsin Liu,

    1. Department of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan
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  • Chen-Ching Lin,

    1. Institute of Biomedical Informatics and Center for Systems and Synthetic Biology, National Yang-Ming University, Taipei, Taiwan
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  • Hsuan-Cheng Huang,

    1. Institute of Biomedical Informatics and Center for Systems and Synthetic Biology, National Yang-Ming University, Taipei, Taiwan
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  • Chi-Ling Chen,

    1. Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
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  • Ding-Shinn Chen,

    1. National Taiwan University Center for Genomic Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
    2. Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
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  • Pei-Jer Chen

    1. National Taiwan University Center for Genomic Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
    2. Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
    3. Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
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  • Potential conflict of interest: Nothing to report.

Abstract

Deregulation of microRNAs (miRNAs) is common in advanced human hepatocellular carcinoma (HCC); however, the ones involved in early carcinogenesis have not yet been investigated. By examining the expression of 22 HCC-related miRNAs between precancerous and cancerous liver tissues, we found miR-216a and miR-224 were significantly up-regulated, starting from the precancerous stage. Furthermore, the elevation of miR-216a was mainly identified in male patients. To study this gender difference, we demonstrated that pri-miR-216a is activated transcriptionally by the androgen pathway in a ligand-dependent manner and is further enhanced by the hepatitis B virus X protein. The transcription initiation site for pri-miR-216a was delineated, and one putative androgen-responsive element site was identified within its promoter region. Mutation of this site abolished the elevation of pri-miR-216a by the androgen pathway. One target of miR-216a was shown to be the tumor suppressor in lung cancer-1 gene (TSLC1) messenger RNA (mRNA) through the three target sites at its 3′ untranslated region. Finally, the androgen receptor level increased in male liver tissues during hepatocarcinogenesis, starting from the precancerous stage, with a concomitant elevation of miR-216a but a decrease of TSLC1. Conclusion: The current study discovered the up-regulation of miRNA-216a by the androgen pathway and a subsequent suppression of TSLC1 as a new mechanism for the androgen pathway in early hepatocarcinogenesis. (HEPATOLOGY 2012)

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