RESUMO
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.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias do Córtex Suprarrenal/metabolismo , Córtex Suprarrenal/metabolismo , Fosfoproteínas/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Adolescente , Neoplasias do Córtex Suprarrenal/genética , Neoplasias do Córtex Suprarrenal/mortalidade , Carcinogênese , Linhagem Celular Tumoral , Proliferação de Células , Criança , Pré-Escolar , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Lactente , Masculino , Metástase Neoplásica , Recidiva Local de Neoplasia , Fosfoproteínas/genética , Transdução de Sinais , Análise de Sobrevida , Fatores de Transcrição , Proteínas Wnt/metabolismo , Proteínas de Sinalização YAP , beta Catenina/metabolismoRESUMO
Adrenocortical tumors (ACTs) may be sporadic or related to inherited genetic syndromes. Uncovering the molecular defects underlying these genetic syndromes has revealed key signaling pathways involved in adrenocortical tumorigenesis. Although the understanding of ACT biology has improved, to date, very few potential prognostic molecular markers of childhood ACTs have been identified. In this review, we summarize the current knowledge of the epidemiology, clinical presentation, diagnosis, prognosis and treatment options for pediatric patients with ACTs. A review of the genetic basis of adrenocortical tumorigenesis is presented, focusing on the main molecular abnormalities involved in the tumorigenic process and potential novel therapy targets that have been generated, or are being generated, with the discovery of these molecular defects.
