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Short hairpin RNA-expressing oncolytic adenovirus-mediated inhibition of IL-8: effects on antiangiogenesis and tumor growth inhibition

Gene Therapy volume 15, pages 635–651 (2008)Cite this article

Abstract

RNA interference, due to its target specificity, may be highly effective as a novel therapeutic modality, but direct delivery of synthetic small interfering RNA still remains a major obstacle for this approach. To induce long-term expression and specific gene silencing, novel delivery vector system is also required. In this study, we have generated an efficient oncolytic adenovirus (Ad)-based short hairpin (shRNA) expression system (Ad-ΔB7-U6shIL8) against IL-8, a potent proangiogenic factor. To demonstrate IL-8-specificity of this newly engineered Ad-based shRNA, we also manufactured replication-incompetent Ads (Ad-ΔE1-CMVshIL8 and Ad-ΔE1-U6shIL8) under the control of the cytomegalovirus (CMV) and U6 promoters, respectively. Ad-ΔE1-U6shIL8 was highly effective in reducing IL-8 expression, and was much more effective in driving IL-8-specific shRNA than the CMV promoter-driven vector. The reduced IL-8 expression then translated into decreased angiogenesis in vitro as measured by migration, tube formation and rat aortic ring sprouting assays. In addition to its effect on endothelial cells, Ad-ΔE1-U6shIL8 also effectively suppressed the migration and invasion of cancer cells. In vivo, intratumoral injection of Ad-ΔB7-U6shIL8 significantly inhibited the growth of Hep3B and A549 human tumor xenografts. Histopathological analysis of Ad-ΔB7-U6shIL8-treated tumors revealed an increase in apoptotic cells and a reduction in vessel density. Finally, Ad-ΔB7-U6shIL8 was also shown to inhibit the growth of disseminated MDA-MB-231 breast cancer metastases. Taken together, these findings demonstrate the utility and antitumor effectiveness of oncolytic Ad expressing shRNA against IL-8.

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Acknowledgements

This study was supported by grants from the Korea Research Foundation, Republic of Korea (KRF-2005-042-C00148, C-OY), the Korea Biotech R&D Group of MOST (M10416130002-04N1613-00210, C-OY) and KOSEF through National Core Research Center for Nanomedical Technology (R15-2004-024-02001-0, C-OY and J-HK). JYY, JK, J-HH, SNZ and Y-AK are graduate students sponsored by the Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea.

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  1. Brain Korea 21 Project for Medical Sciences, Institute for Cancer Research, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea

    J Y Yoo, J-H Kim, J Kim, J-H Huang, S N Zhang, Y-A Kang & C-O Yun

  2. Department of Pathology, Yonsei University College of Medicine, Seoul, Korea

    H Kim

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Correspondence to C-O Yun.

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Yoo, J., Kim, JH., Kim, J. et al. Short hairpin RNA-expressing oncolytic adenovirus-mediated inhibition of IL-8: effects on antiangiogenesis and tumor growth inhibition. Gene Ther 15, 635–651 (2008). https://doi.org/10.1038/gt.2008.3

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