title: Identification of somatic VHL gene mutations in sporadic head and neck paragangliomas in association with activation of the HIF-1α/miR-210 signaling pathway.
abstract: BACKGROUND
  Head and neck paragangliomas (HNPGLs) arise from parasympathetic paraganglias and 35% to 45% are hereditary caused by mutations in succinate dehydrogenase (SDH) genes. The connection between SDH and tumor development is unclear. The most accepted hypothesis proposes a central role for the pseudohypoxic (pHx) pathway activated by hypoxia-inducible factor (HIF). Paradoxically, we showed that activation of HIF in HNPGLs is restricted to a subset of HNPGLs lacking SDH mutations. These tumors overexpress HIF-1α protein and target genes and the HIF-inducible microRNA miR-210 (pHx-HNPGLs).
  
  
  OBJECTIVE
  The present study aimed at unraveling the SDH-independent mechanisms involved in the activation of HIF in HNPGLs.
  
  
  METHODS
  The VHL gene was analyzed in 53 tumors by gene sequencing, multiplex-ligation-dependent probe amplification, and quantitative PCR. The miR-210, HIF-1α, and CA9 levels were used as markers of the pHx gene signature. Meta-analysis of the transcriptome of pHx-HNPGLs was performed using the Oncomine platform. Assays in cells lacking functional pVHL and HIF-1α were performed to analyze the role of pVHL/HIF-1α on miR-210 expression.
  
  
  RESULTS
  We identified, for the first time, somatic VHL mutations in HNPGLs. These were found in 2 of 4 pHx-HNPGLs with concomitant loss of heterozygosity in one of them; but not in non-pHx-HNPGLs. Meta-analysis of the transcriptome of pHx-HNPGLs revealed that these tumors are highly related to clear cell renal cell carcinoma. Cell-based assays showed that loss of pVHL lead to upregulation of miR-210 mainly via HIF-1α activation.
  
  
  CONCLUSIONS
  VHL, involved in tumorigenesis of PGLs and clear cell renal cell carcinomas, may be an important player in the pathogenesis of sporadic HNPGLs via activation of an HIF-1α/miR-210 pHx pathway.
authors.affiliation: Hospital Universitario Central de Asturias. Centro General, Laboratory Instituto Universitario de Oncología del Principado de Asturias, no. 2, 1 planta Centro, C/Celestino Villamil s/n, E-33006 Oviedo, Asturias, Spain. mdchiara.uo@uniovi.es.
authors.forename: Anna
authors.initials: A
authors.lastname: Merlo
authors.forename: Sandra Bernaldo
authors.initials: SB
authors.lastname: de Quirós
authors.forename: Inés Sáenz
authors.initials: IS
authors.lastname: de Santa-María
authors.forename: Ana S
authors.initials: AS
authors.lastname: Pitiot
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: Miquel
authors.initials: M
authors.lastname: Quer
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; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D009154:Mutation; D010235:Paraganglioma / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C543800:MIRN210 microRNA, human; D035683:MicroRNAs; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human