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Modulation of retrovirally driven therapeutic genes by mutant TP53 in anaplastic thyroid carcinoma

Cancer Gene Therapy volume 12, pages 381–388 (2005)Cite this article

A Corrigendum to this article was published on 18 July 2005

Abstract

We previously demonstrated that restoration of TP53 activity in anaplastic thyroid carcinoma inhibits cell growth and induces expression of thyroid differentiation markers. Here, we investigated whether TP53 status may condition the expression of therapeutic genes driven by retroviral LTR or tissue-specific enhancer elements. The TP53-defective ARO anaplastic thyroid carcinoma cells were transfected with TP53Val135, which exhibits wild-type activity at 32°C, and transduced with retroviral vectors, in which therapeutic genes were driven either by wild-type LTR or by a reshuffled LTR containing thyroglobulin (TG) enhancer. Both at 37 and 32°C, expression of transgenes driven by TG enhancer was 10-fold lower than that obtained with wild-type LTR retroviral vector. TP53Val135 transfer into ARO cells repressed transcription from wild-type LTR but increased expression of TG-driven therapeutic genes. This effect was markedly enhanced by cell culture at 32°C and by TSH treatment. Cytotoxic effects shown after ganciclovir treatment paralleled therapeutic gene expression levels. In conclusion, TP53 status in the tumor cell can influence expression of therapeutic genes. When using retroviral-vector-based gene therapy, wild-type LTR vectors should be employed to target TP53-defective tumors, whereas thyroid-specific promoters should be used for transcriptional targeting of thyroid carcinomas carrying wild-type TP53.

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Acknowledgements

This work was supported by Grants from MIUR (Ministero dell'Istruzione, dell'Università e della Ricerca) No. 2001061979 and 2002062741.

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Authors and Affiliations

  1. Department of Histology, Microbiology, and Medical Biotechnologies, University of Padova, I-35121, Padova, Italy

    Luisa Barzon, Elisa Gnatta, Ignazio Castagliuolo, Marta Trevisan & Giorgio Palù

  2. Molecular Oncogenesis Laboratory and Urology Division, Regina Elena Cancer Institute, Experimental Research Center, Rome, Italy

    Fabiola Moretti

  3. Institute of Medical Pathology, Catholic University, Rome, Italy

    Alfredo Pontecorvi

  4. Division of Endocrinology, University of Ancona, Ancona, Italy

    Marco Boscaro

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  1. Luisa Barzon
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  2. Elisa Gnatta
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  8. Giorgio Palù
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Correspondence to Giorgio Palù.

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Barzon, L., Gnatta, E., Castagliuolo, I. et al. Modulation of retrovirally driven therapeutic genes by mutant TP53 in anaplastic thyroid carcinoma. Cancer Gene Ther 12, 381–388 (2005). https://doi.org/10.1038/sj.cgt.7700789

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