title: Unraveling the expression of the oncogene YAP1, a Wnt/beta-catenin target, in adrenocortical tumors and its association with poor outcome in pediatric patients.
abstract: BACKGROUND
  Overexpression of the oncogene yes-associated-protein-1 (YAP1) is associated with increased cell proliferation in human cancers. YAP1 is a potential target of the Wnt/beta-catenin pathway, which plays an important role in adrenocortical tumors (ACT). The role of YAP1 in adrenocortical tumorigenesis has not been assessed.
  
  
  OBJECTIVE
  To evaluate YAP1 expression in normal adrenals and pediatric ACT and its association with disease outcome. To investigate the interaction between YAP1 and the Wnt/beta-catenin pathway in adrenocortical cells.
  
  
  RESULTS
  Strong YAP1 staining was present in fetal adrenals and pediatric ACT but weak in postnatal adrenals. In pediatric ACT, YAP1 mRNA overexpression was associated with death, recurrent/metastatic disease and lower overall survival. The inhibition of the Wnt/beta-catenin pathway increased YAP1 mRNA expression. siYAP1 increased CTNNB1/beta-catenin expression and nuclear staining regardless of DLV2, moreover, it decreased cell growth and impaired cell migration.
  
  
  METHODS
  We assessed in 42 pediatric ACT samples the YAP1 protein expression by immunohistochemistry and mRNA expression by RT-qPCR and analyzed their association with outcome. As controls, we resort 32 fetal and postnatal normal adrenals for IHC and 10 normal adrenal cortices for RT-qPCR. The interaction between YAP1 and the Wnt/beta-catenin pathway was assessed in NCI-H295 adrenocortical cells by inhibiting the TCF/beta-catenin complex and by knocking down YAP1.
  
  
  CONCLUSIONS
  YAP1 overexpression is a marker of poor prognosis for pediatric patients with ACT. In adrenocortical cells, there is a close crosstalk between YAP1 and Wnt/beta-catenin. These data open the possibility of future molecular therapies targeting Hippo/YAP1 signaling to treat advanced ACT.
authors.affiliation: Department of Pediatrics, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.
authors.forename: Rafael H
authors.initials: RH
authors.lastname: Abduch
authors.affiliation: Department of Pediatrics, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.
authors.forename: Ana
authors.initials: A
authors.lastname: Carolina Bueno
authors.affiliation: Department of Pediatrics, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.
authors.forename: Leticia F
authors.initials: LF
authors.lastname: Leal
authors.affiliation: Department of Pediatrics, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.
authors.forename: Marcelo M
authors.initials: MM
authors.lastname: Cavalcanti
authors.affiliation: Federal University of Uberlandia, Brazil.
authors.forename: Débora C
authors.initials: DC
authors.lastname: Gomes
authors.affiliation: Boldrini Children's Center, Campinas, Brazil.
authors.forename: Silvia R
authors.initials: SR
authors.lastname: Brandalise
authors.affiliation: Boldrini Children's Center, Campinas, Brazil.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Masterallo
authors.affiliation: Boldrini Children's Center, Campinas, Brazil.
authors.forename: José A
authors.initials: JA
authors.lastname: Yunes
authors.affiliation: Department of Pediatrics, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.
authors.forename: Carlos E
authors.initials: CE
authors.lastname: Martinelli
authors.affiliation: Department of Pediatrics, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.
authors.forename: Luiz G
authors.initials: LG
authors.lastname: Tone
authors.affiliation: Department of Surgery, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.
authors.forename: Silvio
authors.initials: S
authors.lastname: Tucci
authors.affiliation: Department of Surgery, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.
authors.forename: Carlos A F
authors.initials: CA
authors.lastname: Molina
authors.affiliation: Department of Pathology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.
authors.forename: Fernando S
authors.initials: FS
authors.lastname: Ramalho
authors.affiliation: Department of Internal Medicine, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.
authors.forename: Ayrton C
authors.initials: AC
authors.lastname: Moreira
authors.affiliation: Boldrini Children's Center, Campinas, Brazil.
authors.forename: Izilda A
authors.initials: IA
authors.lastname: Cardinalli
authors.affiliation: Department of Pediatrics, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Scrideli
authors.affiliation: Department of Pathology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.
authors.forename: Leandra N Z
authors.initials: LN
authors.lastname: Ramalho
authors.affiliation: Department of Internal Medicine, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.
authors.forename: Margaret
authors.initials: M
authors.lastname: de Castro
authors.affiliation: Department of Pediatrics, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.
authors.forename: Sonir R
authors.initials: SR
authors.lastname: Antonini
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000293:Adolescent; D000302:Adrenal Cortex / Q000378:metabolism*; D000306:Adrenal Cortex Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007223:Infant; D008297:Male; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016019:Survival Analysis; D014157:Transcription Factors; D051153:Wnt Proteins / Q000378:metabolism; D000091102:YAP-Signaling Proteins; D051176:beta Catenin / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D010750:Phosphoproteins; D014157:Transcription Factors; D051153:Wnt Proteins; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D051176:beta Catenin
keywords: Hippo pathway; Wnt/beta-catenin pathway; YAP1; adrenocortical tumor; outcome