Inhibition of tumour angiogenesis and growth by small hairpin HIF-1α and IL-8 in hepatocellular carcinoma

Authors

  • Sung Hoon Choi,

    1. Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
    2. Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
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  • Oh-Joon Kwon,

    1. Department of Biotechnology, College of Engineering, Hanyang University, Seoul, Korea
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  • Jun Yong Park,

    1. Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
    2. Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
    3. Yonsei Liver Cancer Special Clinic, Yonsei University Health System, Seoul, Korea
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  • Do Young Kim,

    1. Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
    2. Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
    3. Yonsei Liver Cancer Special Clinic, Yonsei University Health System, Seoul, Korea
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  • Sang Hoon Ahn,

    1. Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
    2. Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
    3. Yonsei Liver Cancer Special Clinic, Yonsei University Health System, Seoul, Korea
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  • Seung Up Kim,

    1. Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
    2. Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
    3. Yonsei Liver Cancer Special Clinic, Yonsei University Health System, Seoul, Korea
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  • Simon Weonsang Ro,

    1. Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
    2. Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
    3. Yonsei Liver Cancer Special Clinic, Yonsei University Health System, Seoul, Korea
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  • Kyung Sik Kim,

    1. Yonsei Liver Cancer Special Clinic, Yonsei University Health System, Seoul, Korea
    2. Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
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  • Jeon Han Park,

    1. Department of Microbiology and Immunology, Yonsei University College of Medicine, Seoul, Korea
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  • Seungtaek Kim,

    1. Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
    2. Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
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  • Chae-Ok Yun,

    1. Department of Biotechnology, College of Engineering, Hanyang University, Seoul, Korea
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  • Kwang-Hyub Han

    Corresponding author
    1. Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
    2. Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
    3. Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
    4. Yonsei Liver Cancer Special Clinic, Yonsei University Health System, Seoul, Korea
    • Correspondence

      Kwang-Hyub Han, M.D., Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemun-gu, Seoul 120-752, Korea

      Tel: 82 2 2228 1949

      Fax: 82 2 393 6884

      e-mail: gihankhys@yuhs.ac

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Abstract

Background & Aims

Hypoxia-inducible factor-1α (HIF-1α), a key transcription factor in the cellular response to hypoxia, and interleukin 8 (IL-8), a key mediator of angiogenesis, are important in cancerous tumour growth. In this study, we evaluated the effects of HIF-1α and IL-8 knockdown on angiogenesis and tumour growth in hepatocellular carcinoma (HCC).

Methods

Hepatocellular carcinoma cell lines were infected with adenoviruses expressing small-hairpin RNA (shRNA) specific for HIF-1α or IL-8, cultured under hypoxic conditions (1% O2), and examined for their levels of HIF-1α, IL-8, and angiogenesis factors using immunoblot. The effects of adenovirus-mediated shRNA-induced HIF-1α and IL-8 knockdown on tumour growth and angiogenesis were also investigated in a subcutaneous Hep3B-tumour mouse model.

Results

Hypoxia-inducible factor-1α knockdown directly repressed tumour growth, whereas IL-8 knockdown indirectly repressed tumour growth. Combined knockdown of HIF-1α and IL-8 increased survival rates of mice. HIF-1α and IL-8 knockdown also decreased microvessel density and tumour volume in vivo. Similarly, HIF-1α and IL-8 knockdown inhibited the angiogenic effects of HCC cell-conditioned media on tube formation and invasion by endothelial cells in vitro.

Conclusion

These findings indicate that shRNA-induced HIF-1α and IL-8 knockdown inhibit angiogenesis and tumour growth in HCC. Further development of HIF-1α and IL-8 shRNA technologies could lead to effective therapies for HCC.

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