Lentivirus-mediated RNA interference targeting enhancer of zeste homolog 2 inhibits hepatocellular carcinoma growth through down-regulation of stathmin

Authors

  • Yangchao Chen,

    1. Stanley Ho Center for Emerging Infectious Diseases and Li Ka Shing Institute of Health Sciences, Hong Kong, China
    2. State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Shatin, Hong Kong, China
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  • Marie C. Lin,

    1. Department of Chemistry, The University of Hong Kong, Hong Kong, China
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  • Hong Yao,

    1. Stanley Ho Center for Emerging Infectious Diseases and Li Ka Shing Institute of Health Sciences, Hong Kong, China
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  • Hua Wang,

    1. Stanley Ho Center for Emerging Infectious Diseases and Li Ka Shing Institute of Health Sciences, Hong Kong, China
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  • Ai-Qun Zhang,

    1. Stanley Ho Center for Emerging Infectious Diseases and Li Ka Shing Institute of Health Sciences, Hong Kong, China
    2. Institute of Hepatobiliary Surgery, Chinese People's Liberation Army General Hospital, Beijing, China
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  • Jun Yu,

    1. Stanley Ho Center for Emerging Infectious Diseases and Li Ka Shing Institute of Health Sciences, Hong Kong, China
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  • Chee-kin Hui,

    1. Department of Medicine, The University of Hong Kong, Hong Kong, China
    2. Center for the Study of Liver Disease, The University of Hong Kong, Hong Kong, China
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  • George K. Lau,

    1. Department of Medicine, The University of Hong Kong, Hong Kong, China
    2. Center for the Study of Liver Disease, The University of Hong Kong, Hong Kong, China
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  • Ming-liang He,

    1. Stanley Ho Center for Emerging Infectious Diseases and Li Ka Shing Institute of Health Sciences, Hong Kong, China
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  • Joseph Sung,

    1. Stanley Ho Center for Emerging Infectious Diseases and Li Ka Shing Institute of Health Sciences, Hong Kong, China
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  • Hsiang-fu Kung

    Corresponding author
    1. Stanley Ho Center for Emerging Infectious Diseases and Li Ka Shing Institute of Health Sciences, Hong Kong, China
    2. State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Shatin, Hong Kong, China
    3. State Key Laboratory in Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, China
    • Rm 511A, Basic Medical Sciences Building, The Chinese University of Hong Kong, Shatin, Hong Kong
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    • fax: 852 2994 4988


  • Potential conflict of interest: Nothing to report.

Abstract

Enhancer of zeste homolog 2 (EZH2) has been shown to be overexpressed in hepatocellular (HCC). We investigated the potential role of EZH2 in HCC tumorigenesis and examined the usefulness of RNA interference (RNAi) targeting EZH2 as a form of HCC treatment. Lentivirus-mediated RNAi was employed to knock-down EZH2 expression in human hepatoma cells to study the function of EZH2 in tumorigenesis and evaluate the treatment efficacy. Lentivirus-mediated RNAi effectively reduced EZH2 expression. Suppression of EZH2 in HCC cells significantly reduced their growth rate in vitro and markedly diminished their tumorigenicity in vivo. Moreover, in a mice model of established large-sized HCC, we showed that intratumor injection of lentiviral (Lenti)-shRNA (short hairpin RNA) or siRNA (small interfering RNA) targeting EZH2 produced significant tumor regression. To understand its molecular mechanism of action, we employed proteomic profiling technique and found that stathmin 1 is the downstream target of EZH2, as Lenti-shEZH2 treatment decreased stathmin protein expression, and ectopic overexpression of stathmin prevented Lenti-shEZH2 mediated tumor growth inhibition. Conclusion: Results from our study suggested for the first time that EZH2 plays a key role in HCC tumorigenesis, and is a novel therapeutic target for HCC. (HEPATOLOGY 2007;46:200–208.)

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