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Slug inhibition upregulates radiation-induced PUMA activity leading to apoptosis in cholangiocarcinomas

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Abstract

Resistance of cholangiocarcinoma to irradiation therapy is a major problem in cancer treatment. Slug, a snail family transcription factor, is a suppressor of PUMA (p53 upregulated modulator of apoptosis), which has been shown to be involved in the control of apoptosis. In this study, we investigated whether the modulation of Slug expression, using adeno-associated-virus-mediated transfer of siRNA targeting Slug gene (rAAV2-Slug siRNA), affects cholangiocarcinoma sensitivity to radiation. In the present study, we used rAAV2-Slug siRNA to downregulate the expression of Slug in QBC939 cholangiocarcinoma cell lines in vitro before γ-irradiation. In vivo studies were done with orthotopic cholangiocarcinoma, and radiosensitivity was evaluated both in vitro and in vivo. rAAV2-Slug siRNA transfection resulted in downregulation of the levels of Slug in QBC939 cells. In addition, rAAV2-Slug siRNA, in combination with radiation, increased levels of the PUMA, which contributes to the radiosensitivity of cholangiocarcinomas. Finally, treatment with rAAV2-Slug siRNA plus γ-irradiation completely regressed tumor growth in orthotopic cholangiocarcinomas model. In summary, integrating gene therapy with radiotherapy could have a synergistic effect, thereby improving the survival of patients with cholangiocarcinomas.

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Acknowledgments

We take this opportunity to specifically thank the reviewers and editors for their kind instructions that may be helpful for our further studies.

Conflict of interest

The authors promised there were not any possible conflicts of interest in this research.

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Authors and Affiliations

  1. Department of General Surgery, The Affiliated Hospital of Medical College, QingDao University, 266003, QingDao, Shan Dong Province, People’s Republic of China

    Kejun Zhang, Bingyuan Zhang, Yun Lu, Chuandong Sun, Wei Zhao, Xuelong Jiao & Jilin Hu

  2. Department of Pathology, The Affiliated Hospital of Medical College, QingDao University, 266003, QingDao, Shan Dong Province, People’s Republic of China

    Peng Mu

  3. Department of Molecular Biology, The Affiliated Hospital of Medical College, QingDao University, 266003, QingDao, Shan Dong Province, People’s Republic of China

    Hai Lu

  4. Department of Emercency Medicine, The Affiliated Hospital of Medical College, QingDao University, 266003, QingDao, Shan Dong Province, People’s Republic of China

    Changyong Zhou

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  1. Kejun Zhang
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  2. Bingyuan Zhang
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  3. Yun Lu
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Correspondence to Kejun Zhang.

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Kejun Zhang and Bingyuan Zhang contributed equally to this work.

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Zhang, K., Zhang, B., Lu, Y. et al. Slug inhibition upregulates radiation-induced PUMA activity leading to apoptosis in cholangiocarcinomas. Med Oncol 28 (Suppl 1), 301–309 (2011). https://doi.org/10.1007/s12032-010-9759-x

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  • DOI: https://doi.org/10.1007/s12032-010-9759-x

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