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SIRT2 overexpression in hepatocellular carcinoma mediates epithelial to mesenchymal transition by protein kinase B/glycogen synthase kinase-3β/β-catenin signaling

Authors

  • Juan Chen,

    1. The Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing Medical University, Chongqing, China
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  • Anthony W.H. Chan,

    1. Departments of Anatomical and Cellular Pathology
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  • Ka-Fai To,

    1. Departments of Anatomical and Cellular Pathology
    2. The State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Hong Kong, China
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  • Weixian Chen,

    1. Department of Clinical Laboratory, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
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  • Zhenzhen Zhang,

    1. Department of Infectious Diseases, The Children's Hospital of Chongqing Medical University, Chongqing, China
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  • Jihua Ren,

    1. The Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing Medical University, Chongqing, China
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  • Chunli Song,

    1. The Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing Medical University, Chongqing, China
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  • Yue-Sun Cheung,

    1. Departments of Surgery, The Chinese University of Hong Kong, Hong Kong, China
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  • Paul B.S. Lai,

    1. Departments of Surgery, The Chinese University of Hong Kong, Hong Kong, China
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  • Suk-Hang Cheng,

    1. Departments of Anatomical and Cellular Pathology
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  • Margaret H.L. Ng,

    1. Departments of Anatomical and Cellular Pathology
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  • Ailong Huang,

    Corresponding author
    1. The Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing Medical University, Chongqing, China
    • The Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing Medical University, Chongqing, China
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    • Fax: (86)-02368486780

  • Ben C.B. Ko

    Corresponding author
    1. The Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing Medical University, Chongqing, China
    2. Departments of Anatomical and Cellular Pathology
    3. The State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Hong Kong, China
    • Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Room 38019, Clinical Sciences Building, The Prince of Wales Hospital, Shatin, Hong Kong, China
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    • fax: 852-2637-6274


  • Potential conflict of interest: Nothing to report.

  • This work is supported by the Research Grant Council (grant nos.: CUHK 466109 and 467210) and the National Natural Science Foundation of China (grant no.; 81272764) to B.C.B.K; and National Science and Technology Major Project of China (grant no.:2013ZX10002002, 2012ZX10002005) to A.H.

Abstract

Sirtuin 1 (SIRT1) has been implicated in telomere maintenance and the growth of hepatocellular carcinoma (HCC). Nevertheless, the role of other sirtuins in the pathogenesis of HCC remains elusive. We found that sirtuin 2 (SIRT2), another member of the sirtuin family, also contributes to cell motility and invasiveness of HCC. SIRT2 is up-regulated in HCC cell lines and in a subset of human HCC tissues (23/45). Up-regulations of SIRT2 in primary HCC tumors were significantly correlated with the presence of microscopic vascular invasion (P = 0.001), a more advanced tumor stage (P = 0.004), and shorter overall survival (P = 0.0499). Functional studies by short hairpin RNA–mediated suppression of SIRT2 expression in HCC cell lines revealed significant inhibition of motility and invasiveness. Depletion of SIRT2 also led to the regression of epithelial-mesenchymal transition (EMT) phenotypes, whereas the ectopic expression of SIRT2 in the immortalized hepatocyte cell line L02 promoted cell motility and invasiveness. Mechanistic studies revealed that SIRT2 regulates the deacetylation and activation of protein kinase B, which subsequently impinges on the glycogen synthase kinase-3β/β-catenin signaling pathway to regulate EMT. Conclusions: Our findings have uncovered a novel role for SIRT2 in HCC metastasis, and provide a rationale to explore the use of sirtuin inhibitors in HCC therapy. (HEPATOLOGY 2013;)

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