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http://purl.uniprot.org/citations/22977270http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/22977270http://www.w3.org/2000/01/rdf-schema#comment"

Background

Head and neck paragangliomas (HNPGLs) are rare tumors associated with the parasympathetic nervous system. Most are sporadic, but about one third result from germline mutations in succinate dehydrogenase (SDH) genes (SDHB, SDHC, SDHD, SDHA, or SDHAF2). Although a molecular connection between SDH dysfunction and tumor development is still unclear, the most accepted hypothesis proposes a central role of the pseudohypoxic pathway. SDH dysfunction induces abnormal stabilization of the hypoxia-inducible factors (HIFs) that regulate target genes involved in proliferation, apoptosis, angiogenesis, and metabolism. The involvement of these pathways in the development of sporadic HNPGLs is presently unknown.

Objective

To get some insights into the hypoxic/pseudohypoxic molecular basis of HNPGLs, we attempted to define the gene, microRNA (miRNA), and HIF-1α expression patterns that distinguish tumors from normal paraganglia tissue.

Design

Genome microarray and TaqMan low-density arrays were used to analyze gene and miRNA expression, respectively, in 17 HNPGL tumor tissues and three normal human carotid bodies. Twelve HNPGLs were used for validation of data. HIF-1α, SDHB, and iron-sulfur cluster scaffold protein (ISCU) protein expression was analyzed by immunohistochemistry.

Results

We found activation of a canonical HIF-1α-related gene expression signaling only in a subset of HNPGLs from patients that did not harbor germline or somatic SDH mutations. The pseudohypoxic signature consisted in the overexpression of both HIF-1α-target genes and the HIF-1α-inducible miRNA, miR-210, and down-regulation of the miR-210 target gene, ISCU1/2. A decreased level of the iron-sulfur-containing protein SDHB was found by immunohistochemical analysis performed in two of these tumors.

Conclusions

Collectively, this study unveiled a putative signaling axis of HIF-1α/miRNA-210/ISCU in a subset of HNPGLs that could have an impact on SDHB protein stability by a mechanism independent of SDH mutations, thus providing a foundation to better understand the functional interplay between HIF, miR-210, and mitochondria and its relevance in the pathogenesis of HNPGLs."xsd:string
http://purl.uniprot.org/citations/22977270http://purl.org/dc/terms/identifier"doi:10.1210/jc.2012-2410"xsd:string
http://purl.uniprot.org/citations/22977270http://purl.uniprot.org/core/author"Suarez C."xsd:string
http://purl.uniprot.org/citations/22977270http://purl.uniprot.org/core/author"Secades P."xsd:string
http://purl.uniprot.org/citations/22977270http://purl.uniprot.org/core/author"Balbin M."xsd:string
http://purl.uniprot.org/citations/22977270http://purl.uniprot.org/core/author"Astudillo A."xsd:string
http://purl.uniprot.org/citations/22977270http://purl.uniprot.org/core/author"Merlo A."xsd:string
http://purl.uniprot.org/citations/22977270http://purl.uniprot.org/core/author"Chiara M.D."xsd:string
http://purl.uniprot.org/citations/22977270http://purl.uniprot.org/core/author"de Quiros S.B."xsd:string
http://purl.uniprot.org/citations/22977270http://purl.uniprot.org/core/author"Zambrano I."xsd:string
http://purl.uniprot.org/citations/22977270http://purl.uniprot.org/core/author"Scola B."xsd:string
http://purl.uniprot.org/citations/22977270http://purl.uniprot.org/core/author"Aristegui M."xsd:string
http://purl.uniprot.org/citations/22977270http://purl.uniprot.org/core/date"2012"xsd:gYear
http://purl.uniprot.org/citations/22977270http://purl.uniprot.org/core/name"J Clin Endocrinol Metab"xsd:string
http://purl.uniprot.org/citations/22977270http://purl.uniprot.org/core/pages"E2194-200"xsd:string
http://purl.uniprot.org/citations/22977270http://purl.uniprot.org/core/title"Identification of a signaling axis HIF-1alpha/microRNA-210/ISCU independent of SDH mutation that defines a subgroup of head and neck paragangliomas."xsd:string
http://purl.uniprot.org/citations/22977270http://purl.uniprot.org/core/volume"97"xsd:string
http://purl.uniprot.org/citations/22977270http://www.w3.org/2004/02/skos/core#exactMatchhttp://purl.uniprot.org/pubmed/22977270
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