title: Sonic Hedgehog pathway is upregulated in adamantinomatous craniopharyngiomas.
abstract: OBJECTIVE
  Pituitary stem cells play a role in the oncogenesis of human adamantinomatous craniopharyngiomas (aCPs). We hypothesized that crosstalk between the Wnt/β-catenin and Sonic Hedgehog (SHH) pathways, both of which are important in normal pituitary development, would contribute to the pathogenesis of aCPs.
  
  
  METHODS
  To explore the mRNA and protein expression of components of the SHH signaling pathway in aCPs and their relationship with the identification of CTNNB1/β-catenin mutations and patients outcomes.
  
  
  METHODS
  In 18 aCP samples, CTNNB1 was sequenced, and the mRNA expression levels of SHH pathway members (SHH, PTCH1, SMO, GLI1, GLI2, GLI3, and SUFU) and SMO, GLI1, GLI3, SUFU, β-catenin, and Ki67 proteins were evaluated by quantitative real-time PCR and immunohistochemistry respectively. Anterior normal pituitaries were used as controls. Associations between molecular findings and clinical data were analyzed.
  
  
  RESULTS
  The aCPs presented higher mRNA expression of SHH (+400-fold change (FC); P<0.01), GLI1 (+102-FC; P<0.001), and GLI3 (+5.1-FC; P<0.01) than normal anterior pituitaries. Longer disease-free survival was associated with low SMO and SUFU mRNA expression (P<0.01 and P=0.02 respectively). CTNNB1/β-catenin mutations were found in 47% of the samples. aCPs with identified mutations presented with higher mRNA expression of SMO and GLI1 (+4.3-FC; P=0.02 and +10.2-FC; P=0.03 respectively). SMO, GLI1, GLI3, and SUFU staining was found in 85, 67, 93, and 64% of the samples respectively. Strong GLI1 and GLI3 staining was detected in palisade cells, which also labeled Ki67, a marker of cell proliferation.
  
  
  CONCLUSIONS
  The upregulation of SHH signaling occurs in aCPs. Thus, activation of Wnt/β-catenin and SHH pathways, both of which are important in pituitary embryogenesis, appears to contribute to the pathogenesis of aCP.
authors.affiliation: School of Medicine of Ribeirao PretoUniversity of Sao Paulo, Avenida Bandeirantes, 3900 - Monte Alegre, CEP 14049-900, Ribeirao Preto, Sao Paulo, BrazilFederal University of UberlandiaUberlandia, Minas Gerais, Brazil School of Medicine of Ribeirao PretoUniversity of Sao Paulo, Avenida Bandeirantes, 3900 - Monte Alegre, CEP 14049-900, Ribeirao Preto, Sao Paulo, BrazilFederal University of UberlandiaUberlandia, Minas Gerais, Brazil.
authors.forename: D C
authors.initials: DC
authors.lastname: Gomes
authors.affiliation: School of Medicine of Ribeirao PretoUniversity of Sao Paulo, Avenida Bandeirantes, 3900 - Monte Alegre, CEP 14049-900, Ribeirao Preto, Sao Paulo, BrazilFederal University of UberlandiaUberlandia, Minas Gerais, Brazil.
authors.forename: S A
authors.initials: SA
authors.lastname: Jamra
authors.affiliation: School of Medicine of Ribeirao PretoUniversity of Sao Paulo, Avenida Bandeirantes, 3900 - Monte Alegre, CEP 14049-900, Ribeirao Preto, Sao Paulo, BrazilFederal University of UberlandiaUberlandia, Minas Gerais, Brazil.
authors.forename: L F
authors.initials: LF
authors.lastname: Leal
authors.affiliation: School of Medicine of Ribeirao PretoUniversity of Sao Paulo, Avenida Bandeirantes, 3900 - Monte Alegre, CEP 14049-900, Ribeirao Preto, Sao Paulo, BrazilFederal University of UberlandiaUberlandia, Minas Gerais, Brazil.
authors.forename: L M
authors.initials: LM
authors.lastname: Colli
authors.affiliation: School of Medicine of Ribeirao PretoUniversity of Sao Paulo, Avenida Bandeirantes, 3900 - Monte Alegre, CEP 14049-900, Ribeirao Preto, Sao Paulo, BrazilFederal University of UberlandiaUberlandia, Minas Gerais, Brazil.
authors.forename: M L
authors.initials: ML
authors.lastname: Campanini
authors.affiliation: School of Medicine of Ribeirao PretoUniversity of Sao Paulo, Avenida Bandeirantes, 3900 - Monte Alegre, CEP 14049-900, Ribeirao Preto, Sao Paulo, BrazilFederal University of UberlandiaUberlandia, Minas Gerais, Brazil.
authors.forename: R S
authors.initials: RS
authors.lastname: Oliveira
authors.affiliation: School of Medicine of Ribeirao PretoUniversity of Sao Paulo, Avenida Bandeirantes, 3900 - Monte Alegre, CEP 14049-900, Ribeirao Preto, Sao Paulo, BrazilFederal University of UberlandiaUberlandia, Minas Gerais, Brazil.
authors.forename: C E
authors.initials: CE
authors.lastname: Martinelli
authors.affiliation: School of Medicine of Ribeirao PretoUniversity of Sao Paulo, Avenida Bandeirantes, 3900 - Monte Alegre, CEP 14049-900, Ribeirao Preto, Sao Paulo, BrazilFederal University of UberlandiaUberlandia, Minas Gerais, Brazil.
authors.forename: P C L
authors.initials: PC
authors.lastname: Elias
authors.affiliation: School of Medicine of Ribeirao PretoUniversity of Sao Paulo, Avenida Bandeirantes, 3900 - Monte Alegre, CEP 14049-900, Ribeirao Preto, Sao Paulo, BrazilFederal University of UberlandiaUberlandia, Minas Gerais, Brazil.
authors.forename: A C
authors.initials: AC
authors.lastname: Moreira
authors.affiliation: School of Medicine of Ribeirao PretoUniversity of Sao Paulo, Avenida Bandeirantes, 3900 - Monte Alegre, CEP 14049-900, Ribeirao Preto, Sao Paulo, BrazilFederal University of UberlandiaUberlandia, Minas Gerais, Brazil.
authors.forename: H R
authors.initials: HR
authors.lastname: Machado
authors.affiliation: School of Medicine of Ribeirao PretoUniversity of Sao Paulo, Avenida Bandeirantes, 3900 - Monte Alegre, CEP 14049-900, Ribeirao Preto, Sao Paulo, BrazilFederal University of UberlandiaUberlandia, Minas Gerais, Brazil.
authors.forename: F
authors.initials: F
authors.lastname: Saggioro
authors.affiliation: School of Medicine of Ribeirao PretoUniversity of Sao Paulo, Avenida Bandeirantes, 3900 - Monte Alegre, CEP 14049-900, Ribeirao Preto, Sao Paulo, BrazilFederal University of UberlandiaUberlandia, Minas Gerais, Brazil.
authors.forename: L
authors.initials: L
authors.lastname: Neder
authors.affiliation: School of Medicine of Ribeirao PretoUniversity of Sao Paulo, Avenida Bandeirantes, 3900 - Monte Alegre, CEP 14049-900, Ribeirao Preto, Sao Paulo, BrazilFederal University of UberlandiaUberlandia, Minas Gerais, Brazil.
authors.forename: M
authors.initials: M
authors.lastname: Castro
authors.affiliation: School of Medicine of Ribeirao PretoUniversity of Sao Paulo, Avenida Bandeirantes, 3900 - Monte Alegre, CEP 14049-900, Ribeirao Preto, Sao Paulo, BrazilFederal University of UberlandiaUberlandia, Minas Gerais, Brazil antonini@fmrp.usp.br.
authors.forename: S R
authors.initials: SR
authors.lastname: Antonini
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D003397:Craniopharyngioma / Q000235:genetics / Q000378:metabolism*; D005260:Female; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D009154:Mutation; D010911:Pituitary Neoplasms / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020239:Receptor Cross-Talk; D015398:Signal Transduction / Q000235:genetics; D015854:Up-Regulation; D055815:Young Adult; D051176:beta Catenin / Q000378:metabolism
chemical_list: C495270:CTNNB1 protein, human; D053823:Hedgehog Proteins; D012333:RNA, Messenger; C509239:SHH protein, human; D051176:beta Catenin