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Evaluation of the Glypican 3 promoter for transcriptional targeting of hepatocellular carcinoma

Gene Therapy volume 25, pages 115–128 (2018)Cite this article

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Abstract

Hepatocellular carcinoma (HCC) is a major health problem as evidenced by its increasing incidence and high morbidity and mortality rates. Most patients with HCC have underlying liver disease and dysfunction which limits the current therapeutic options. Treatments that spare the liver and destroy the HCC are needed. Targeting transcriptional differences between HCC and liver cells may provide this therapeutic window. In this study, we examine the potential of the Glypican 3 (GPC3) promoter as a targeting strategy. GPC3 is an oncofetal protein belonging to the proteoglycan family which is normally only expressed during fetal development. However, in HCC, the expression of this protein is reactivated. Here, we show that GPC3 is expressed primarily in HCC and not in normal liver lines. We show that the GPC3 promoter can be used to drive expression of significantly more luciferase and eYFP in HCC cell lines compared to normal liver cells. Further, we show that vectors containing cytosine deaminase (CD) under GPC3 promotor control induced significantly more killing of HCC cell lines after treatment with 5-FC compared to normal liver cell lines. These data suggest that transcriptionally targeted delivery of transgene in HCC cells can be achieved using the GPC3 promoter and this targeting strategy produces limited toxicity to normal liver cells.

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Acknowledgements

This work was supported by the Gallipoli Medical Research Foundation.

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Authors and Affiliations

  1. Gallipoli Medical Research Institute, Greenslopes Private Hospital, 102 Newdegate Street, Brisbane, QLD 4120, Australia

    Bijay Dhungel, Slawomir Andrzejewski, Aparna Jayachandran, Ritu Shrestha, Charmaine A. Ramlogan-Steel, Christopher J. Layton & Jason C. Steel

  2. Faculty of Medicine, The University of Queensland, 288 Herston Road, Herston, Brisbane, QLD 4006, Australia

    Bijay Dhungel, Slawomir Andrzejewski, Aparna Jayachandran, Charmaine A. Ramlogan-Steel, Christopher J. Layton & Jason C. Steel

  3. University of Queensland Diamantina Institute, Translational Research Institute, 37 Kent Street, Woolloongabba, QLD 4102, Australia

    Bijay Dhungel

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Correspondence to Jason C. Steel.

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Dhungel, B., Andrzejewski, S., Jayachandran, A. et al. Evaluation of the Glypican 3 promoter for transcriptional targeting of hepatocellular carcinoma. Gene Ther 25, 115–128 (2018). https://doi.org/10.1038/s41434-018-0002-2

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