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SOX1 functions as a tumor suppressor by antagonizing the WNT/β-catenin signaling pathway in hepatocellular carcinoma§

Authors

  • Chun-Ming Tsao,

    1. Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan, Republic of China
    2. Bureau of Investigation, Ministry of Justice, Taiwan, Republic of China
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  • Ming-De Yan,

    1. Division of Gastroenterology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan, Republic of China
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    • Potential conflict of interest: Nothing to report.

  • Yu-Lueng Shih,

    1. Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China
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    • *These authors contributed equally to this work.

  • Pei-Ning Yu,

    1. Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan, Republic of China
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  • Chih-Chi Kuo,

    1. Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan, Republic of China
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  • Wen-Chi Lin,

    1. Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan, Republic of China
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  • Hsin-Jung Li,

    1. Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, Republic of China
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  • Ya-Wen Lin

    Corresponding author
    1. Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan, Republic of China
    • Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, No.161, Section 6, Min-Chuan East Road, Taipei, 114, Taiwan, Republic of China

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    • fax: (886)-2-87917654


  • Supported in part by grants NSC 99-3112-B-016-003, NSC 99-2314-B-016-015-MY2, NSC 100-2320-B-016-011, and NSC 101-2320-B-016-011 from the National Science Council, Taiwan, Republic of China, and by the Liver Disease Prevention and Treatment Research Foundation, Taiwan, Republic of China.

Abstract

Oncogenic activation of the Wnt/β-catenin signaling pathway is common in hepatocellular carcinoma (HCC). Our recent studies have demonstrated that SRY (sex determining region Y)-box 1 (SOX1) and secreted frizzled-related proteins are concomitantly promoter-hypermethylated, and this might lead to abnormal activation of the Wnt signaling pathway in HCC. SOX1 encodes a transcription factor involved in the regulation of embryonic development and cell fate determination. However, the expression and functional role of SOX1 in HCC remains unclear. In this study, we confirmed via quantitative methylation-specific polymerase chain reaction that SOX1 was frequently downregulated through promoter hypermethylation in HCC cells and tissues. Overexpression of SOX1 by a constitutive or inducible approach could suppress cell proliferation, colony formation, and invasion ability in HCC cell lines, as well as tumor growth in nonobese diabetic/severe combined immunodeficiency mice. Conversely, knockdown of SOX1 by withdrawal of doxycycline could partially restore cell proliferation and colony formation in HCC cells. We used a T cell factor (TCF)-responsive luciferase reporter assay and western blot analysis to prove that SOX1 could regulate TCF-responsive transcriptional activity and inhibit the expression of Wnt downstream genes. Furthermore, we used glutathione S-transferase pull-down, co-immunoprecipitation, and confocal microscopy to demonstrate that SOX1 could interact with β-catenin but not with the β-catenin/TCF complex. Moreover, restoration of the expression of SOX1 induces significant cellular senescence in Hep3B cells. Conclusion: Our data show that a developmental gene, SOX1, may function as a tumor suppressor by interfering with Wnt/β-catenin signaling in the development of HCC. (HEPATOLOGY 2012;56:2142–2153)

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