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

 JY Yoo  ;  J-H Kim  ;  J Kim  ;  J-H Huang  ;  SN Zhang  ;  Y-A Kang  ;  H Kim  ;  C-O Yun 
 GENE THERAPY, Vol.15(9) : 635-651, 2008 
Journal Title
Issue Date
Adenoviridae/genetics* ; Animals ; Breast Neoplasms/therapy* ; Cell Line, Tumor ; Endothelial Cells/metabolism ; Female ; Gene Silencing ; Genetic Engineering ; Genetic Therapy/methods* ; Humans ; Interleukin-8/analysis ; Interleukin-8/genetics* ; Interleukin-8/metabolism ; Lung Neoplasms/secondary ; Lung Neoplasms/therapy ; Male ; Matrix Metalloproteinase 2/analysis ; Matrix Metalloproteinase 2/metabolism ; Mice ; Mice, Nude ; Neoplasm Invasiveness ; Neovascularization, Pathologic/genetics ; Oncolytic Virotherapy/methods* ; Promoter Regions, Genetic ; RNA Interference ; RNA, Small Interfering/administration & dosage* ; Transduction, Genetic/methods ; Vascular Endothelial Growth Factor A/analysis ; Vascular Endothelial Growth Factor A/metabolism ; Xenograft Model Antitumor Assays
cancer gene therapy ; IL-8 ; short hairpin RNA (shRNA) ; oncolytic adenovirus
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-DeltaB7-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-DeltaE1-CMVshIL8 and Ad-DeltaE1-U6shIL8) under the control of the cytomegalovirus (CMV) and U6 promoters, respectively. Ad-DeltaE1-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-DeltaE1-U6shIL8 also effectively suppressed the migration and invasion of cancer cells. In vivo, intratumoral injection of Ad-DeltaB7-U6shIL8 significantly inhibited the growth of Hep3B and A549 human tumor xenografts. Histopathological analysis of Ad-DeltaB7-U6shIL8-treated tumors revealed an increase in apoptotic cells and a reduction in vessel density. Finally, Ad-DeltaB7-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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1. College of Medicine (의과대학) > Research Institute (부설연구소) > 1. Journal Papers
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kang, Yoon-A(강윤아)
Kim, Jaesung(김재성)
Kim, Joo Hang(김주항)
Yun, Chae Ok(윤채옥)
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