Unraveling the expression of the oncogene YAP1, a Wnt/beta-catenin target, in adrenocortical tumors and its association with poor outcome in pediatric patients
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Rafael H. Abduch1,*, Ana Carolina Bueno1,*, Leticia F. Leal1,#, Marcelo M. Cavalcanti1, Débora C. Gomes6, Silvia R. Brandalise5, Maria J. Masterallo5, José A. Yunes5, Carlos E. Martinelli Jr1, Luiz G. Tone1, Silvio Tucci3, Carlos A.F. Molina3, Fernando S. Ramalho4, Ayrton C. Moreira2, Izilda A. Cardinalli5, Carlos A. Scrideli1, Leandra N.Z. Ramalho4, Margaret de Castro2, Sonir R. Antonini1
1Department of Pediatrics, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
2Department of Internal Medicine, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
3Department of Surgery, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
4Department of Pathology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
5Boldrini Children’s Center, Campinas, Brazil
6Federal University of Uberlandia, Brazil
#Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, SP, Brazil
*These authors have contributed equally to this work
Sonir R. Antonini, email: [email protected]
Keywords: adrenocortical tumor, outcome, YAP1, Hippo pathway, Wnt/beta-catenin pathway
Received: February 12, 2016 Accepted: September 12, 2016 Published: October 1, 2016
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.
Aims: 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.
Materials and 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.
Conclusion: 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.
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