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

J. Y. Yoo, J. H. Kim, J. Kim, J. H. Huang, S. N. Zhang, Y. A. Kang, H. Kim, Chae Ok Yun

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)635-651
Number of pages17
JournalGene Therapy
Volume15
Issue number9
DOIs
StatePublished - 2008 May 1

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Interleukin-8
Adenoviridae
Small Interfering RNA
Growth
Neoplasms
Cytomegalovirus
Gene Silencing
RNA Interference
Heterografts
Endothelial Cells
Breast Neoplasms
Neoplasm Metastasis
Injections

Cite this

Yoo, J. Y. ; Kim, J. H. ; Kim, J. ; Huang, J. H. ; Zhang, S. N. ; Kang, Y. A. ; Kim, H. ; Yun, Chae Ok. / Short hairpin RNA-expressing oncolytic adenovirus-mediated inhibition of IL-8 : Effects on antiangiogenesis and tumor growth inhibition. In: Gene Therapy. 2008 ; Vol. 15, No. 9. pp. 635-651.
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Short hairpin RNA-expressing oncolytic adenovirus-mediated inhibition of IL-8 : Effects on antiangiogenesis and tumor growth inhibition. / Yoo, J. Y.; Kim, J. H.; Kim, J.; Huang, J. H.; Zhang, S. N.; Kang, Y. A.; Kim, H.; Yun, Chae Ok.

In: Gene Therapy, Vol. 15, No. 9, 01.05.2008, p. 635-651.

Research output: Contribution to journalArticle

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AU - Yoo, J. Y.

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AU - Kim, H.

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