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Transcriptional silencing of ETS-1 efficiently suppresses angiogenesis of pancreatic cancer

Cancer Gene Therapy volume 16, pages 137–148 (2009)Cite this article

Abstract

In this study, we addressed the hypothesis that transcriptional suppression of erythroblastosis virus E26 oncogene homolog 1 (ETS-1) is an efficient therapeutic approach to pancreatic adenocarcinoma by investigating the effect of ETS-1 suppression in human pancreatic cancer cells. We accomplished this by using an adenoviral vector encoding only the DNA-binding domain of wild-type ETS-1 (ETS-1 dominant negative, ETS-1-DN). ETS-1-DN decreases ETS-1-binding by competing for its binding to DNA. Adenoviral-mediated transfer of ETS-1-DN (adenoviral ETS-1-DN construct, AdETS-1-DN) into pancreatic tumor cell lines did not affect their proliferation rate in vitro but did significantly inhibit their in vivo growth in nude mice. Furthermore, to test the efficacy of ETS-1-DN in vivo, we injected the AdETS-1-DN into established human pancreatic adenocarcinomas grown in nude mice. This treatment significantly reduced tumor size as compared to saline injection, without any detectable side effects. Microvessel density in mouse xenografts displayed significantly lower values in tumors in which ETS-1 was downregulated. In addition, expression of the ETS-1-DN in the pancreatic cancer cells resulted in downregulation of urokinase-type plasminogen activator (u-PA) and metalloproteinase-1 (MMP-1) expression. Taken together, these data suggest that transcriptional inactivation of ETS-1 is able to significantly affect angiogenesis and growth of pancreatic cancer. This effect may be due in part to downregulation of MMP-1 and u-PA expression. Our results suggest that ETS-1-DN is a promising candidate for antiangiogenic gene therapy in pancreatic cancer.

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Abbreviations

AdETS-1-DN:

adenoviral ETS-1-DN construct

EBD:

ETS-1 DNA-binding domain

ETS-1:

erythroblastosis virus E26 oncogene homolog 1

ETS-1-DN:

ETS-1 dominant negative

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Acknowledgements

This work was supported by The Romanian National Authority for Scientific Research—CEEX 62 and 117 research grants—and the Japanese Ministries of Education, Culture, Sport, Science, and Technology.

Author information

Authors and Affiliations

  1. Department of Surgery, University of Medicine, Iasi, Romania

    L P Lefter

  2. Department of Gastroenterological Surgery, Tohoku University School of Medicine, Sendai, Japan

    L P Lefter & M Sunamura

  3. Centre of Surgery and Liver Transplantation, Bucharest, Romania

    S Dima & I Popescu

  4. Department of Molecular Pathology, Tohoku University School of Medicine, Sendai, Japan

    T Furukawa & A Horii

  5. Department of Ageing, Tohoku University School of Medicine, Sendai, Japan

    Y Sato & M Abe

  6. Stefan S Nicolau Institute of Virology, Bucharest, Romania

    M Chivu

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  1. L P Lefter
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Corresponding author

Correspondence to L P Lefter.

Additional information

Some data included in this article were presented at the 17th World Congress of the International Association of Surgeons, Gastroenterologists and Oncologists in Bucharest, Romania, on 5–8 September 2007.

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Lefter, L., Dima, S., Sunamura, M. et al. Transcriptional silencing of ETS-1 efficiently suppresses angiogenesis of pancreatic cancer. Cancer Gene Ther 16, 137–148 (2009). https://doi.org/10.1038/cgt.2008.65

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