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PTTG and PBF repress the human sodium iodide symporter

Oncogene volume 26, pages 4344–4356 (2007)Cite this article

Abstract

The ability of the thyroid to accumulate iodide provides the basis for radioiodine ablation of differentiated thyroid cancers and their metastases. Most thyroid tumours exhibit reduced iodide uptake, although the mechanisms accounting for this remain poorly understood. Pituitary tumour transforming gene (PTTG) is a proto-oncogene implicated in the pathogenesis of thyroid tumours. We now show that PTTG and its binding factor PBF repress expression of sodium iodide symporter (NIS) messenger RNA (mRNA), and inhibit iodide uptake. This process is mediated at least in part through fibroblast growth factor-2. In detailed studies of the NIS promoter in rat FRTL-5 cells, PTTG and PBF demonstrated specific inhibition of promoter activity via the human upstream enhancer element (hNUE). Within this ∼1 kb element, a complex PAX8-upstream stimulating factor 1 (USF1) response element proved critical both to basal promoter activity and to PTTG and PBF repression of NIS. In particular, repression by PTTG was contingent upon the USF1, but not the PAX8, site. Finally, in human primary thyroid cells, PTTG and PBF similarly repressed the NIS promoter via hNUE. Taken together, our data suggest that the reported overexpression of PTTG and PBF in differentiated thyroid cancer has profound implications for activity of the NIS gene, and hence significantly impacts upon the efficacy of radioiodine treatment.

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Acknowledgements

This work was supported by the Wellcome Trust, the Medical Research Council (UK), the Endowment Fund of the Former United Birmingham Hospitals and the Marjorie Robinson Fund. We thank Dr John Morris (Mayo Clinic, Rochester, USA) and Dr Nancy Carrasco (Albert Einstein College of Medicine, New York, USA) for the provision of NIS antibodies, and we acknowledge Roger Holder, Department of Statistics, University of Birmingham, for statistical advice.

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  1. K Boelaert and V E Smith: These two authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine, Division of Medical Sciences, Institute of Biomedical Research, University of Birmingham, Birmingham, UK

    K Boelaert, V E Smith, A L Stratford, L A Tannahill, J C Watkinson, M C Eggo, J A Franklyn & C J McCabe

  2. Department of Medicine, Endocrinology and Diabetes Division, VA Greater Los Angeles Healthcare System, University College Los Angeles, Los Angeles, CA, USA

    T Kogai

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  1. K Boelaert
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Correspondence to C J McCabe.

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Boelaert, K., Smith, V., Stratford, A. et al. PTTG and PBF repress the human sodium iodide symporter. Oncogene 26, 4344–4356 (2007). https://doi.org/10.1038/sj.onc.1210221

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