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Suppression of colorectal tumor growth by regulated survivin targeting

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Abstract

A major goal in cancer gene therapy is to develop efficient gene transfer protocols that allow tissue-specific and tightly regulated expression of therapeutic genes. The ideal vector should efficiently transduce cancer cells with minimal toxicity on normal tissues and persistently express foreign genes. One of the most promising regulatory systems is the mifepristone/RU486-regulated system, which has much lower basal transcriptional activity and high inducibility. In this work, we modified this system by incorporating a cancer-specific promoter, the human telomerase reverse transcriptase (hTERT) promoter. By utilizing hTERT promoter to control the regulator, RU486 could specifically induce the expression of foreign genes in cancer cells but not in normal cells. In the context of this system, a dominant negative mutant of survivin (surDN) was controllably expressed in colorectal tumor cells. The surDN expression induced by RU486 showed a dosage- and time-dependent pattern. Regulated expression of surDN caused caspase-dependent apoptosis in colorectal tumor cells but had little effect on normal cells. Analysis of cell viability showed that RU486-induced expression of surDN suppressed colorectal tumor cell growth and had synergic effect in combination with chemotherapeutic agents. The potential of this system in cancer therapy was evaluated in experimental animals. Tumor xenograft models were established in nude mice with colorectal tumor cells, and RU486 was intraperitoneally administered. The results showed that conditional expression of surDN efficiently inhibited tumor growth in vivo and prolonged the life of tumor-burdened mice. Synergized with the chemotherapeutic drug cisplatin, regulated surDN expression completely suppressed tumor growth. These results indicated that this modified RU486-regulated system could be useful in cancer-targeting therapy.

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Abbreviations

hTERT:

human telomerase reverse transcriptase

SurDN:

survivin dominant negative mutant

GAL4 UAS17-mer :

17-mer GAL4 upstream activation sequence

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Acknowledgments

This work was supported by the Key Project of the Chinese Academy of Sciences (No. KSCX2-3-06), the National Natural Science Foundation of China (No. 30120160823), the Chinese National “863” High-Tech Project Foundation grant (No. 2002AA216021), and the Chinese National “973” Fundamental Research Project (No. 2004CB518804).

We thank Dr. BL Fang for providing us with the hTERT promoter. We also thank Lanying Sun for helping in cell culture, and Dr. Wang Jinhui at the University of Pennsylvania Medical Center and Children’s Hospital of Philadelphia for the critical reading of this manuscript.

Binghua Li and Junkai Fan contributed equally to this work.

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Authors and Affiliations

  1. Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China

    Binghua Li, Junkai Fan, Xinran Liu, Rong Qi, Linan Bo, Jinfa Gu & Xinyuan Liu

  2. Xinyuan Institute of Medicine and Biotechnology, Zhejiang Sci-Tech University, Hangzhou, 310018, China

    Cheng Qian & Xinyuan Liu

  3. Department of Medicine, Medical School, University of Navarra, Pamplona, 31080, Spain

    Cheng Qian

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  1. Binghua Li
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  2. Junkai Fan
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  3. Xinran Liu
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  7. Cheng Qian
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  8. Xinyuan Liu
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Correspondence to Xinyuan Liu.

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Li, B., Fan, J., Liu, X. et al. Suppression of colorectal tumor growth by regulated survivin targeting. J Mol Med 84, 1077–1086 (2006). https://doi.org/10.1007/s00109-006-0106-9

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  • DOI: https://doi.org/10.1007/s00109-006-0106-9

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