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

2.50
Hdl Handle:
http://hdl.handle.net/10541/109399
Title:
Expression of hypoxia-inducible factor 1 alpha in thyroid carcinomas.
Authors:
Burrows, N; Resch, J; Cowen, R L; Von Wasielewski, R; Hoang-Vu, C; West, Catharine M L; Williams, K J; Brabant, Georg E
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.
Affiliation:
School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
Citation:
Expression of hypoxia-inducible factor 1 alpha in thyroid carcinomas. 2010, 17 (1):61-72 Endocr Relat Cancer
Journal:
Endocrine-Related Cancer
Issue Date:
Mar-2010
URI:
http://hdl.handle.net/10541/109399
DOI:
10.1677/ERC-08-0251
PubMed ID:
19808899
Type:
Article
Language:
en
ISSN:
1479-6821
Appears in Collections:
All Christie Publications ; All Paterson Institute for Cancer Research; Endocrinology

Full metadata record

DC FieldValue Language
dc.contributor.authorBurrows, Nen
dc.contributor.authorResch, Jen
dc.contributor.authorCowen, R Len
dc.contributor.authorVon Wasielewski, Ren
dc.contributor.authorHoang-Vu, Cen
dc.contributor.authorWest, Catharine M Len
dc.contributor.authorWilliams, K Jen
dc.contributor.authorBrabant, Georg Een
dc.date.accessioned2010-08-10T12:56:09Z-
dc.date.available2010-08-10T12:56:09Z-
dc.date.issued2010-03-
dc.identifier.citationExpression of hypoxia-inducible factor 1 alpha in thyroid carcinomas. 2010, 17 (1):61-72 Endocr Relat Canceren
dc.identifier.issn1479-6821-
dc.identifier.pmid19808899-
dc.identifier.doi10.1677/ERC-08-0251-
dc.identifier.urihttp://hdl.handle.net/10541/109399-
dc.description.abstractHypoxia-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.en
dc.language.isoenen
dc.subjectCancer Antigensen
dc.subjectTumour Cell Lineen
dc.subjectCancerous Gene Expression Regulationen
dc.subjectCancer Proteinsen
dc.subjectThyroid Canceren
dc.subject.mesh1-Phosphatidylinositol 3-Kinase-
dc.subject.meshAdenocarcinoma, Follicular-
dc.subject.meshAnaerobiosis-
dc.subject.meshAntigens, Neoplasm-
dc.subject.meshCarbonic Anhydrases-
dc.subject.meshCarcinoma-
dc.subject.meshCarcinoma, Papillary-
dc.subject.meshCell Hypoxia-
dc.subject.meshCell Line, Tumor-
dc.subject.meshChromones-
dc.subject.meshCobalt-
dc.subject.meshGene Expression Regulation, Neoplastic-
dc.subject.meshGlucose Transporter Type 1-
dc.subject.meshHumans-
dc.subject.meshHypoxia-Inducible Factor 1, alpha Subunit-
dc.subject.meshMorpholines-
dc.subject.meshNeoplasm Proteins-
dc.subject.meshPTEN Phosphohydrolase-
dc.subject.meshProto-Oncogene Proteins B-raf-
dc.subject.meshRNA Interference-
dc.subject.meshRNA, Small Interfering-
dc.subject.meshSignal Transduction-
dc.subject.meshThyroid Neoplasms-
dc.titleExpression of hypoxia-inducible factor 1 alpha in thyroid carcinomas.en
dc.typeArticleen
dc.contributor.departmentSchool of Pharmacy and Pharmaceutical Sciences, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.en
dc.identifier.journalEndocrine-Related Canceren

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