title: Identification of a signaling axis HIF-1α/microRNA-210/ISCU independent of SDH mutation that defines a subgroup of head and neck paragangliomas.
abstract: 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.
  
  
  METHODS
  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.
authors.affiliation: Hospital Universitario Central de Asturias, Centro General, C/Celestino Villamil s/n, E-33006 Oviedo, Asturias, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Merlo
authors.forename: Sandra Bernaldo
authors.initials: SB
authors.lastname: de Quiros
authors.forename: Pablo
authors.initials: P
authors.lastname: Secades
authors.forename: Iriana
authors.initials: I
authors.lastname: Zambrano
authors.forename: Milagros
authors.initials: M
authors.lastname: Balbín
authors.forename: Aurora
authors.initials: A
authors.lastname: Astudillo
authors.forename: Bartolomé
authors.initials: B
authors.lastname: Scola
authors.forename: Miguel
authors.initials: M
authors.lastname: Arístegui
authors.forename: Carlos
authors.initials: C
authors.lastname: Suarez
authors.forename: María-Dolores
authors.initials: MD
authors.lastname: Chiara
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D007506:Iron-Sulfur Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D010235:Paraganglioma / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D013385:Succinate Dehydrogenase / Q000235:genetics*
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C506160:ISCU protein, human; D007506:Iron-Sulfur Proteins; C543800:MIRN210 microRNA, human; D035683:MicroRNAs; D013385:Succinate Dehydrogenase