Abstract
Hypoxia-inducible factor 1 alpha (HIF-1 alpha) 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 alpha and target gene expression in primary thyroid carcinomas and thyroid carcinoma cell lines (BcPAP, WRO, FTC-133 and 8505c). HIF-1 alpha was not detectable in normal tissue but was expressed in thyroid carcinomas. Dedifferentiated anaplastic tumours (ATCs) exhibited high levels of nuclear HIF-1 alpha 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 alpha pathway in thyroid cells with transcriptional activation observed after graded hypoxia (1% O(2), anoxia) or treatment with a hypoxia mimetic cobalt chloride. High basal and hypoxia-induced expression of HIF-1 alpha 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 alpha and HIF-1 alpha 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 alpha with an aggressive disease phenotype and therapeutic resistance, this pathway may be an attractive target for improved therapy in thyroid carcinomas.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma, Follicular / genetics
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Adenocarcinoma, Follicular / metabolism*
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Adenocarcinoma, Follicular / pathology
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Anaerobiosis
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Antigens, Neoplasm / biosynthesis
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Antigens, Neoplasm / genetics
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Carbonic Anhydrase IX
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Carbonic Anhydrases / biosynthesis
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Carbonic Anhydrases / genetics
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Carcinoma / genetics
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Carcinoma / metabolism*
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Carcinoma / pathology
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Carcinoma, Papillary / genetics
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Carcinoma, Papillary / metabolism*
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Carcinoma, Papillary / pathology
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Cell Hypoxia / physiology
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Cell Line, Tumor / drug effects
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Cell Line, Tumor / metabolism
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Chromones / pharmacology
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Cobalt / pharmacology
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Gene Expression Regulation, Neoplastic* / drug effects
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Glucose Transporter Type 1 / biosynthesis
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Glucose Transporter Type 1 / genetics
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / biosynthesis*
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / physiology
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Morpholines / pharmacology
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / biosynthesis*
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology
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PTEN Phosphohydrolase / genetics
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PTEN Phosphohydrolase / physiology
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Phosphatidylinositol 3-Kinases / physiology
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins B-raf / genetics
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RNA Interference
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RNA, Small Interfering / pharmacology
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Signal Transduction / physiology
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Thyroid Neoplasms / genetics
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Thyroid Neoplasms / metabolism*
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Thyroid Neoplasms / pathology
Substances
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Antigens, Neoplasm
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Chromones
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Glucose Transporter Type 1
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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Morpholines
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Neoplasm Proteins
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Phosphoinositide-3 Kinase Inhibitors
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RNA, Small Interfering
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Cobalt
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BRAF protein, human
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Proto-Oncogene Proteins B-raf
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PTEN Phosphohydrolase
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PTEN protein, human
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CA9 protein, human
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Carbonic Anhydrase IX
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Carbonic Anhydrases
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cobaltous chloride