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N Burrows, School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, United Kingdom
J Resch, Dept. of Endocrinology, Christie Hospital, Manchester, United Kingdom
R Cowen, School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, United Kingdom
R von Wasielewski, Dept of Pathology, Medizinische Hochschule Hannover, Hannover, Germany
C Hoang-Vu, AG Experimentelle and Chirurgische Onkologie, Univ.-Klinik und Poliklinik fue Allgemein-, Viszeral- und Gefaesschirurgie Martin Luther Universitat Halle-Wittenberg, Germany
C West, Academic Department of Radiation Oncology, Christie Hospital, Manchester, United Kingdom
K Williams, School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, United Kingdom
G Brabant, Dept. of Endocrinology, Christie Hospital, Manchester, M20 4BX, United Kingdom

Georg Brabant, Email: georg.brabant{at}manchester.ac.uk

Abstract

Hypoxia inducible factor 1 (HIF-1) is upregulated by hypoxia and oncogenic

signalling in many solid tumours. Its regulation and function in thyroid carcinomas is unknown.

We evaluated 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 (GLUT1) was expressed to a similar level in all tumour types, whereas carbonic anhydrase-9 (CA-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 (CoCl2). High basal and hypoxia-induced expression of HIF-1 in FTC-133 cells that harbour a PTEN mutation was reduced by introduction of wtPTEN. Similarly, pharmacological inhibition of the 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/ERK 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 signaling 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.