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Antitumor effects of Stat3-siRNA and endostatin combined therapies, delivered by attenuated Salmonella, on orthotopically implanted hepatocarcinoma

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Abstract

Hepatocellular carcinoma (HCC) is one of the most aggressive carcinomas. Limited therapeutic options, mainly due to a fragmented genetic understanding of HCC, and major HCC resistance to conventional chemotherapy are the key reasons for a poor prognosis. Thus, new effective treatments are urgent and gene therapy may be a novel option. Signal transducer and activator of transcription 3 (Stat3) is a highly studied member of the STAT family. Inhibition of Stat3 signaling has been found to suppress tumor growth and improve survival, providing a molecular target for cancer therapy. Furthermore, HCC is a hypervascular tumor and angiogenesis plays a crucial role in tumor growth and metastasis. Thus, anti-angiogenic therapy, combined with inhibition of Stat3, may be an effective approach to combat HCC. We tested the effect that the combination therapy consisting of endostatin (a powerful angiogenesis inhibitor) and Stat3-specific small interfering RNA, using a DNA vector delivered by attenuated S. typhimurium, on an orthotopic HCC model in C57BL/6 mice. Although antitumor effects were observed with either single therapeutic treatment, the combination therapy provided superior antitumor effects. Correlated with this finding, the combination treatment resulted in significant alteration of Stat3 and endostatin levels and that of the downstream gene VEGF, decreased cell proliferation, induced cell apoptosis and inhibited angiogenesis. Importantly, combined treatment also elicited immune system regulation of various immune cells and cytokines. This study has provided a novel cancer gene therapeutic approach.

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Acknowledgments

This study was supported by grands from the National Natural Science Foundation of China (No. 30801354 and No. 30970791), Specialized Research Fund for the Doctoral Program of Higher Education of China (No.200801831077) and Jilin Provincial Science & Technology Department (No. 20080154). We thank Professor Liying Wang and Professor Yongli Bao for helpful suggestions.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Pathophysiology, Prostate Diseases Prevention and Treatment Research Centre, Norman Bethune College of Medicine, Jilin University, Changchun, 130021, People’s Republic of China

    Huijie Jia, Yang Li, Xin Li, Di Yin, Baofeng Guo, Xuejian Zhao & Ling Zhang

  2. Department of Immunology, Norman Bethune Medical School, Jilin University, Changchun, People’s Republic of China

    Tiesuo Zhao

  3. Department of Oncology and Diagnostic Sciences, School of Dentistry, University of Maryland, Baltimore, MD, USA

    Jiadi Hu

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

    Dennis J. Kopecko

  5. New Vaccine National Engineering Research Center, Beijing three-room South 4 hospital, Chaoyang District, Beijing, 100024, People’s Republic of China

    De Qi Xu

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  1. Huijie Jia
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  2. Yang Li
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  4. Xin Li
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  10. Ling Zhang
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  11. De Qi Xu
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Correspondence to Ling Zhang or De Qi Xu.

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Huijie Jia and Yang Li authors contributed equally to this work.

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Jia, H., Li, Y., Zhao, T. et al. Antitumor effects of Stat3-siRNA and endostatin combined therapies, delivered by attenuated Salmonella, on orthotopically implanted hepatocarcinoma. Cancer Immunol Immunother 61, 1977–1987 (2012). https://doi.org/10.1007/s00262-012-1256-y

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