Journal article
Expression of hypoxia-inducible factor 1α in thyroid carcinomas
Endocrine-related cancer, Vol.17(1), pp.61-72
03/2010
DOI: 10.1677/ERC-08-0251
PMCID: PMC2828807
PMID: 19808899
Abstract
Hypoxia-inducible factor 1α (HIF-1α) 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-1α and target gene expression in primary thyroid carcinomas and thyroid carcinoma cell lines (BcPAP, WRO, FTC-133 and 8505c). HIF-1α was not detectable in normal tissue but was expressed in thyroid carcinomas. Dedifferentiated anaplastic tumours (ATCs) exhibited high levels of nuclear HIF-1α 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.\nIn vitro\nstudies revealed a functionally active HIF-1α pathway in thyroid cells with transcriptional activation observed after graded hypoxia (1% O\n2\n, anoxia) or treatment with a hypoxia mimetic cobalt chloride. High basal and hypoxia-induced expression of HIF-1α 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-1α and HIF-1α 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-1α with an aggressive disease phenotype and therapeutic resistance, this pathway may be an attractive target for improved therapy in thyroid carcinomas.
Details
- Title: Subtitle
- Expression of hypoxia-inducible factor 1α in thyroid carcinomas
- Creators
- N Burrows - School of Pharmacy and Pharmaceutical Sciences, University of ManchesterJ Resch - Department of EndocrinologyR L Cowen - School of Pharmacy and Pharmaceutical Sciences, University of ManchesterR von Wasielewski - Department of PathologyC Hoang-Vu - Experimental and Surgical OncologyC M West - Academic Department of Radiation OncologyK J Williams - School of Pharmacy and Pharmaceutical Sciences, University of ManchesterG Brabant - Department of Endocrinology
- Resource Type
- Journal article
- Publication Details
- Endocrine-related cancer, Vol.17(1), pp.61-72
- DOI
- 10.1677/ERC-08-0251
- PMID
- 19808899
- PMCID
- PMC2828807
- NLM abbreviation
- Endocr Relat Cancer
- ISSN
- 1351-0088
- eISSN
- 1479-6821
- Publisher
- Society for Endocrinology; Bristol
- Grant note
- C1467/A7286 / Experimental Cancer Medicine Centre Funding\nC7820/A8696 / Cancer Research UK\n106294 / Deutsche Krebshilfe\n222741 / Christie Hospital Endowment Fund
- Language
- English
- Date published
- 03/2010
- Academic Unit
- Iowa Neuroscience Institute; Neuroscience and Pharmacology
- Record Identifier
- 9984071984202771
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