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miRNA-mediated tumor specific delivery of TRAIL reduced glioma growth

  • Laboratory Investigation
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Abstract

As an aggressive cancer with high morbidity, malignant glioma always has a poor prognosis even after surgery, chemotherapy and radiotherapy. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) shows a strong apoptosis-inducing effect on a variety of cancer cells including glioma. However so far, TRAIL delivery mediated by adenoviral vectors lacks tumor specificity and thus has cytotoxicity to normal cells. To improve the tumor-specificity of adenovirus-mediated TRAIL delivery, we utilized miR-124, miR-128, miR-146b and miR-218 to restrict its expression to within glioma cells. qPCR assay showed that expression of these four miRNAs was greatly downregulated in glioma in comparison with normal brain tissue. Luciferase reporter assay confirmed that miR-124, miR-128, miR-146b and miR-218 conferred exogenous gene expression with glioma-specificity. By inserting miRNA response elements (MREs) of these miRNAs into the downstream of TRAIL on adenoviral vectors, TRAIL was highly expressed in glioma cells, but not in normal brain cells. Cell viability and immunoblotting assays and FACS analysis showed that cytotoxicity and apoptosis elicited by TRAIL was only observed in glioma cells, rather than normal brain cells. Animal experiments also showed that MREs-regulated TRAIL delivery reduced the growth of glioma xenograft. In this study, we proved that miRNA-mediated tumor specific delivery of TRAIL was able to inhibit the survival of glioma cells and reduce the growth of glioma in vivo.

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Acknowledgments

We appreciated generous providing of adenoviruses by Dr. Zhao in General Hospital of Chengdu Military Area Command of Chinese PLA, Chengdu, China and plasmids by Dr. Ma, Ocean University of China, Qingdao, China.

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Authors and Affiliations

  1. Department of Neurosurgery, The Affiliated Hospital of Medical College, Qingdao University, Qingdao, 266003, China

    Yongli Bo, Guocai Guo & Weicheng Yao

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  1. Yongli Bo
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  2. Guocai Guo
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  3. Weicheng Yao
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Correspondence to Yongli Bo.

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Bo, Y., Guo, G. & Yao, W. miRNA-mediated tumor specific delivery of TRAIL reduced glioma growth. J Neurooncol 112, 27–37 (2013). https://doi.org/10.1007/s11060-012-1033-y

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  • DOI: https://doi.org/10.1007/s11060-012-1033-y

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