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Analysis of Wnt/{beta}-catenin pathway in childhood adrencortical tumors

Grant number: 11/10512-3
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): September 01, 2011
Effective date (End): August 31, 2015
Field of knowledge:Health Sciences - Medicine - Maternal and Child Health
Principal researcher:Sonir Roberto Rauber Antonini
Grantee:Letícia Ferro Leal
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated scholarship(s):13/05337-3 - The interaction between Wnt canonical pathway with PRKAR1A and PDE8B in adrenocortical tumor development and/or progression by using a transgenic mouse model, BE.EP.DR

Abstract

Context: The incidence of adrenocortical tumors (ACTs) in children from Southern Brazil is 10-15 times more frequent than worldwide. The mechanisms involved in the ACT formation and progression are not completely known yet. The Wnt/²-catenin pathway activation is frequent in adult ACTs, commonly due to CTNNB1 mutations. In previous studies, we observed evidence of Wnt/{beta}-catenin pathway activation in childhood ACT, besides low frequency of CTNNB1 mutations. In addition, we also observed reduced expression of Wnt inhibitor genes such as DKK3, SFRP1 and AXIN1 in these tumors. These data led to the hypothesis that the reduced expression of these inhibitor genes could result in Wnt/{beta}-catenin pathway activation in childhood ACT. Therefore, besides CTNNB1 mutations, other genetic events affecting theWnt/{beta}-catenin pathway may be involved in childhood adrenocortical tumorigenesis. Aim: To evaluated the role of Wnt/{beta}-catenin pathway in childhood adrenocortical tumorigenesis. Material e Methods: We will evaluate the expression of Wnt/{beta}-catenin pathway genes in childhood ACT (n=62) and adrenocortical cell lines (Y1, H295 and primary culture from childhood ACT by qPCR, immunohistochemistry, immunocytochemistry and western blot. Using in vitro assays, we will analyze the involvement of CTNNB1 e DKK3 genes in the Wnt/{beta}-catenin pathway activation in childhood ACTs by gene silencing with siRNA. We will evaluate the DKK3 gene methylation pattern and its association with DKK3 gene expression pattern and Wnt pathway activation in these tumors. Additionally, we will investigate the link between microRNA-449 and AXIN1 gene with Wnt/{beta}-catenin pathway activation in childhood ACTs over expressing this microRNA in adrenocortical cell lines. Perspective: This work may contribute to clarify the role of the Wnt/{beta}-catenin pathway in adrenocortical tumorigenesis.

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
LEAL, LETICIA F.; BUENO, ANA CAROLINA; GOMES, DEBORA C.; ABDUCH, RAFAEL; DE CASTRO, MARGARET; ANTONINI, SONIR R.. Inhibition of the Tcf/beta-catenin complex increases apoptosis and impairs adrenocortical tumor cell proliferation and adrenal steroidogenesis. ONCOTARGET, v. 6, n. 40, p. 43016-43032, . (11/13807-4, 11/10512-3)

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