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Overexpression of von Hippel-Lindau tumor suppressor protein and antisense HIF-1α eradicates gliomas

Cancer Gene Therapy volume 13, pages 428–435 (2006)Cite this article

Abstract

The von Hippel–Lindau tumor suppressor protein (pVHL) suppresses tumor formation by binding the α subunits of hypoxia-inducible-factors responsible for stimulating tumor angiogenesis and glycolysis, and targeting them for ubiquitination and proteasomal destruction. Loss of pVHL leads to tumorigenesis and development of sporadic renal cell carcinomas and central nervous system hemangioblastomas. In the present study, we investigated whether engineered overexpression of pVHL in C6 glioma cells, which already express endogenous pVHL, would suppress the tumorigenicity of this particular tumor cell type. C6 cells overexpressing VHL displayed a reduced growth rate (70% inhibition) compared to the parental cell line when subcutaneously implanted in athymic (nu/nu) mice. Growth inhibition was associated with a 50% reduction in the number of tumor vessels and a 60% increase in tumor cell apoptosis, due in part to downregulation of HIF-1, VEGF, and the antiapoptotic factor Bcl-2, respectively. Gene transfer of VHL suppressed the growth of established C6 gliomas, and synergized with antisense HIF-1 to completely eradicate tumors. The data suggest that VHL gene therapy and/or agents that increase VHL expression could have utility in the treatment of gliomas, particularly when combined with agents that inhibit the expression or function of HIF-1.

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Acknowledgements

This work is supported in part by grants from the National Natural Scientific Foundation of China (30100178, 30471681), the Scientific Research Foundation for the Returned Overseas Chinese Scholars from the State Education Ministry of China, the Wellcome Trust (UK), and the Health Research Council of New Zealand. X Sun and M Liu contributed equally to the work. X Sun is a recipient of a Wellcome Trust Research Leave Fellowship.

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Authors and Affiliations

  1. Department of Molecular Medicine and Pathology, Faculty of Medicine and Health Science, University of Auckland, Auckland, New Zealand

    X Sun & G W Krissansen

  2. Department of Surgery, Qilu Hospital, Shandong University, Jinan, China

    X Sun, M Liu, F Liu & X Zhi

  3. Department of Internal Medicine, Qilu Hospital, Shandong University, Jinan, China

    Y Wei

  4. GeneTherapy Laboratory, Institute of Molecular Biology, University of Hong Kong, Hong Kong

    R Xu

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  1. X Sun
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Correspondence to X Sun.

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Sun, X., Liu, M., Wei, Y. et al. Overexpression of von Hippel-Lindau tumor suppressor protein and antisense HIF-1α eradicates gliomas. Cancer Gene Ther 13, 428–435 (2006). https://doi.org/10.1038/sj.cgt.7700907

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