title: Role of hypoxia-related proteins in invasion of ameloblastoma cells: crosstalk between NOTCH1, hypoxia-inducible factor 1α, a disintegrin and metalloproteinase 12, and heparin-binding epidermal growth factor.
abstract: OBJECTIVE
  Ameloblastoma AME is a benign tumour characterized by local invasiveness, high recurrence rates, and diverse histological patterns. The oxygen concentration is reduced in specific areas of the tumour microenvironment, which leads to intratumoral hypoxia. Crosstalk between NOTCH1, a disintegrin and metalloproteinase 12 (ADAM-12), hypoxia-inducible factor 1α (HIF-1α) and heparin-binding epidermal growth factor (HB-EGF) under hypoxic conditions has been implicated in invadopodia formation, tumour invasiveness, and metastasis development. The aim of this study was to analyse the expression of these proteins, in order to further elucidate the mechanisms underlying AME invasiveness.
  
  
  RESULTS
  Twenty cases of AME, eight calcifying cystic odontogenic tumours CCOTs and 10 samples of dental follicle were used to investigate the expression of these proteins by immunohistochemistry with the primary antibodies anti-NOTCH1, anti-ADAM-12, anti-HIF-1α, and anti-HB-EGF. Immunostaining results were expressed as the percentage of stained area in images acquired in an AxioScope microscope equipped with an AxioCamHRc camera and a × 40 objective. The results showed that immunoexpression of all proteins was higher in the AME samples than in the CCOT and dental follicle samples (P < 0.05).
  
  
  CONCLUSIONS
  AME showed an increased presence of proteins associated with tumour invasiveness, which indicates a possible role of these proteins in the biological behaviour of this tumour.
authors.affiliation: Cell Culture Laboratory, School of Dentistry, Federal University of Pará, Belém, PA, Brazil.
authors.forename: Natacha Malu Miranda
authors.initials: NM
authors.lastname: da Costa
authors.affiliation: Cell Culture Laboratory, School of Dentistry, Federal University of Pará, Belém, PA, Brazil.
authors.forename: Amanda Dalla Vechia
authors.initials: AD
authors.lastname: Fialho
authors.affiliation: Cell Culture Laboratory, School of Dentistry, Federal University of Pará, Belém, PA, Brazil.
authors.forename: Carolina Carmine
authors.initials: CC
authors.lastname: Proietti
authors.affiliation: Cell Culture Laboratory, School of Dentistry, Federal University of Pará, Belém, PA, Brazil.
authors.forename: Maria Sueli
authors.initials: MS
authors.lastname: da Silva Kataoka
authors.affiliation: Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
authors.forename: Ruy Gastaldoni
authors.initials: RG
authors.lastname: Jaeger
authors.affiliation: Cell Culture Laboratory, School of Dentistry, Federal University of Pará, Belém, PA, Brazil.
authors.forename: Sérgio Melo
authors.initials: SM
authors.lastname: de Alves-Júnior
authors.affiliation: Cell Culture Laboratory, School of Dentistry, Federal University of Pará, Belém, PA, Brazil.
authors.forename: João
authors.initials: J
authors.lastname: de Jesus Viana Pinheiro
mesh_terms: D000072199:ADAM12 Protein / Q000378:metabolism*; D000564:Ameloblastoma / Q000175:diagnosis / Q000378:metabolism*; D015331:Cohort Studies; D003795:Dental Sac / Q000378:metabolism / Q000473:pathology; D005260:Female; D066257:Heparin-binding EGF-like Growth Factor / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D009062:Mouth Neoplasms / Q000175:diagnosis / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D018333:Odontogenic Cyst, Calcifying / Q000175:diagnosis / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000378:metabolism*; D046888:Tissue Array Analysis; D000072258:Tumor Hypoxia; D059016:Tumor Microenvironment
chemical_list: C497442:HIF1A protein, human; D066257:Heparin-binding EGF-like Growth Factor; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D000072199:ADAM12 Protein; C000606480:ADAM12 protein, human
keywords: ADAM-12; HB-EGF; HIF-1α; NOTCH1; ameloblastoma; cellular hypoxia; invadopodia