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Targeted therapy via oral administration of attenuated Salmonella expression plasmid-vectored Stat3-shRNA cures orthotopically transplanted mouse HCC

Cancer Gene Therapy volume 19, pages 393–401 (2012)Cite this article

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Abstract

The development of RNA interference-based cancer gene therapies has been delayed due to the lack of effective tumor-targeting delivery systems. Attenuated Salmonella enterica serovar Typhimurium (S. Typhimurium) has a natural tropism for solid tumors. We report here the use of attenuated S. Typhimurium as a vector to deliver shRNA directly into tumor cells. Constitutively activated signal transducer and activator of transcription 3 (Stat3) is a key transcription factor involved in both hepatocellular carcinoma (HCC) growth and metastasis. In this study, attenuated S. Typhimurium was capable of delivering shRNA-expressing vectors to the targeted cancer cells and inducing RNA interference in vivo. More importantly, a single oral dose of attenuated S. Typhimurium carrying shRNA-expressing vectors targeting Stat3 induced remarkably delayed and reduced HCC (in 70% of mice). Cancer in these cured mice did not recur over 2 years following treatment. These data demonstrated that RNA interference combined with Salmonella as a delivery system may offer a novel clinical approach for cancer gene therapy.

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Acknowledgements

We thank Dr EL Hohmann (Massachusetts General Hospital, Harvard Medical School, Boston, MA) for supplying the S. Typhimurium strain LH430. This work was funded by the National Natural Science Foundation of China (no. 30801354, no. 30970791), Jilin Provincial Science & Technology Department (no. 20080154), PhD Programs Foundation of Ministry of Education of China (no. 200801831077) and National Cancer Institute Grants CA105005 and CA78282 (DV Kalvakolanu).

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Author notes

  1. Y Tian and B Guo: These authors contributed equally to this work.

Authors and Affiliations

  1. Prostate Diseases Prevention and Treatment Research Centre and Department of Pathophysiology, Norman Bethune College of Medicine, Jilin University, Changchun, People's Republic of China

    Y Tian, H Jia, K Ji, Y Li, T Zhao, L Gao, Y Meng & L Zhang

  2. Department of Emergency Medicine, China-Japan Union Hospital of Jilin University, Changchun, People's Republic of China

    B Guo

  3. The First Hospital of Jilin University, Changchun, People's Republic of China

    Y Sun & X Zhao

  4. Department of Microbiology and Immunology, Greenebaum Cancer Center, Molecular Biology Program, University of Maryland School Medicine, Baltimore, MD, USA

    D V Kalvakolanu

  5. Laboratory of Enteric and Sexually Transmitted Diseases, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD, USA

    D J Kopecko

  6. New Vaccine National Engineering Research Center, Beijing, People's Republic of China

    D Xu

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  1. Y Tian
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Correspondence to L Zhang or D Xu.

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Tian, Y., Guo, B., Jia, H. et al. Targeted therapy via oral administration of attenuated Salmonella expression plasmid-vectored Stat3-shRNA cures orthotopically transplanted mouse HCC. Cancer Gene Ther 19, 393–401 (2012). https://doi.org/10.1038/cgt.2012.12

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  • DOI: https://doi.org/10.1038/cgt.2012.12

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