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This Article IMMEDIATE FREE ACCESS ARTICLE OA Free Full Text Full Text (PDF) OA All Versions of this Article: ERC-08-0251v1 17/1/61    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Burrows, N Articles by Brabant, G Search for Related Content PubMed PubMed Citation Articles by Burrows, N Articles by Brabant, G

¹ School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK
² Department of Endocrinology, Christie Hospital, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK
³ Department of Pathology, Medizinische Hochschule Hannover, FRG, Hannover, Germany
⁴ Experimental and Surgical Oncology, University of Halle-Wittenberg, FRG, Halle, Germany
⁵ Academic Department of Radiation Oncology, University of Manchester, Manchester, UK

(Correspondence should be addressed to G Brabant; Email: georg.brabant{at}manchester.ac.uk)

This is an Open Access article distributed under the terms of the Society for Endocrinology's Re-use Licence which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

^* (K J Williams and G Brabant contributed equally to this work)

Hypoxia-inducible factor 1 (HIF-1) is upregulated by hypoxia and oncogenic signalling in many solid tumours. Its regulation and function in thyroid carcinomas are unknown. We evaluated the regulation of HIF-1 and target gene expression in primary thyroid carcinomas and thyroid carcinoma cell lines (BcPAP, WRO, FTC-133 and 8505c). HIF-1 was not detectable in normal tissue but was expressed in thyroid carcinomas. Dedifferentiated anaplastic tumours (ATCs) exhibited high levels of nuclear HIF-1 staining. The HIF-1 target glucose transporter 1 was expressed to a similar level in all tumour types, whereas carbonic anhydrase-9 was significantly elevated in ATCs. In vitro studies revealed a functionally active HIF-1 pathway in thyroid cells with transcriptional activation observed after graded hypoxia (1% O₂, anoxia) or treatment with a hypoxia mimetic cobalt chloride. High basal and hypoxia-induced expression of HIF-1 in FTC-133 cells that harbour a phosphatase and tensin homologue (PTEN) mutation was reduced by introduction of wild-type PTEN. Similarly, pharmacological inhibition of the phosphoinositide 3-kinase (PI3K) pathway using LY294002 inhibited HIF-1 and HIF-1 targets in all cell lines, including those with B-RAF mutations (BcPAP and 8505c). In contrast, the effects of inhibition of the RAF/MEK/extracellular signal-regulated kinase pathway were restricted by environmental condition and B-RAF mutation status. HIF-1 is functionally expressed in thyroid carcinomas and is regulated not only by hypoxia but also via growth factor signalling pathways and, in particular, the PI3K pathway. Given the strong association of HIF-1 with an aggressive disease phenotype and therapeutic resistance, this pathway may be an attractive target for improved therapy in thyroid carcinomas.