Expression of hypoxia-inducible factor 1 alpha in thyroid carcinomas.

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.

• Authors: N Burrows, J Resch, R L Cowen, R von Wasielewski, C Hoang-Vu, C M West, K J Williams, G Brabant
• Journal: Endocrine-related cancer (Endocr Relat Cancer) Vol. 17 Issue 1 Pg. 61-72 (Mar 2010) ISSN: 1479-6821 [Electronic] England
• PMID: 19808899 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Neoplasm
• Chromones
• Glucose Transporter Type 1
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Morpholines
• Neoplasm Proteins
• Phosphoinositide-3 Kinase Inhibitors
• RNA, Small Interfering
• 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
• Cobalt
• BRAF protein, human
• Proto-Oncogene Proteins B-raf
• PTEN Phosphohydrolase
• PTEN protein, human
• CA9 protein, human
• Carbonic Anhydrase IX
• Carbonic Anhydrases
• cobaltous chloride

Topics

• Adenocarcinoma, Follicular (genetics, metabolism, pathology)
• Anaerobiosis
• Antigens, Neoplasm (biosynthesis, genetics)
• Carbonic Anhydrase IX
• Carbonic Anhydrases (biosynthesis, genetics)
• Carcinoma (genetics, metabolism, pathology)
• Carcinoma, Papillary (genetics, metabolism, pathology)
• Cell Hypoxia (physiology)
• Cell Line, Tumor (drug effects, metabolism)
• Chromones (pharmacology)
• Cobalt (pharmacology)
• Gene Expression Regulation, Neoplastic (drug effects)
• Glucose Transporter Type 1 (biosynthesis, genetics)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (biosynthesis, genetics, physiology)
• Morpholines (pharmacology)
• Neoplasm Proteins (antagonists & inhibitors, biosynthesis, genetics, physiology)
• PTEN Phosphohydrolase (genetics, physiology)
• Phosphatidylinositol 3-Kinases (physiology)
• Phosphoinositide-3 Kinase Inhibitors
• Proto-Oncogene Proteins B-raf (genetics)
• RNA Interference
• RNA, Small Interfering (pharmacology)
• Signal Transduction (physiology)
• Thyroid Neoplasms (genetics, metabolism, pathology)