Adeno-associated virus-mediated expression of apolipoprotein (a) kringles suppresses hepatocellular carcinoma growth in mice

Authors

  • Kyuhyun Lee,

    1. Gene Therapy Laboratory, Biomolecular Engineering Division, MOGAM Biotechnology Research Institute, Yongin, Kyonggi-Do, Republic of Korea
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  • Sung-Tae Yun,

    1. Gene Therapy Laboratory, Biomolecular Engineering Division, MOGAM Biotechnology Research Institute, Yongin, Kyonggi-Do, Republic of Korea
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  • Young-Gun Kim,

    1. Gene Therapy Laboratory, Biomolecular Engineering Division, MOGAM Biotechnology Research Institute, Yongin, Kyonggi-Do, Republic of Korea
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  • Yeup Yoon,

    1. New Biologics Division, MOGAM Biotechnology Research Institute, Yongin, Kyonggi-Do, Republic of Korea
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  • Eui-Cheol Jo

    Corresponding author
    1. Gene Therapy Laboratory, Biomolecular Engineering Division, MOGAM Biotechnology Research Institute, Yongin, Kyonggi-Do, Republic of Korea
    • Biomolecular Engineering Division, MOGAM Biotechnology Research Institute, 341 Pojung-Dong Kiheung-Ku, Yongin, Kyonggi-Do 446-799, Republic of Korea
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    • fax: (82) 31 260 9808


  • Presented in part in abstract form at the 8th annual meeting of the American Society for Gene Therapy, St. Louis, MO, 2005.

  • Potential conflict of interest: Nothing to report.

Abstract

Hepatocellular carcinoma (HCC) constitutes more than 90% of all primary liver cancers. HCC is a hypervascular tumor that develops from dedifferentiation of small avascular HCC and is therefore a good target for anti-angiogenic gene therapy. Recent studies have identified apolipoprotein(a) [apo(a)] kringles LK68 and LK8 (LKs) as having a potential anti-angiogenic and anti-tumor activity, and the current study evaluates the therapeutic potential of gene therapy with recombinant adeno-associated virus carrying genes encoding LKs (rAAV-LK) in the treatment of hypervascular HCC. We generated rAAV-LK to obtain persistent transgene expression in vivo, which is essential for anti-angiogenic therapy. The rAAV-produced LKs substantially inhibited proliferation and migration of human umbilical vein endothelial cells (HUVECs) in vitro, validating their anti-angiogenic potential. Intramuscular administration of rAAV-LK gave 60% to 84% suppression (P < .05) of tumor growth in mice bearing subcutaneously transplanted HCC derived from Huh-7 and Hep3B cells, respectively. Histological and immunohistochemical analyses of HCC tumor sections showed that a single administration of rAAV-LK gave rise to persistent expression of LKs that inhibited tumor angiogenesis and triggered tumor apoptosis, and, thus, significantly suppressed tumor growth. The administration of rAAV-LK provided a significant survival benefit (P < .05), and 3 of 10 rAAV-LK–treated mice were still alive without visible tumors and without clinical symptoms 188 days after treatment. In conclusion, rAAV-LK is a potential candidate for anti-angiogenic gene therapy in the treatment of HCC. (HEPATOLOGY 2006;43:1063–1073.)

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