BACKGROUND: Mutations of β-catenin gene (CTNNB1) are frequent in adrenocortical adenomas (AA) and adrenocortical carcinomas (ACC). However, the target genes of β-catenin have not yet been identified in adrenocortical tumors. OBJECTIVE: Our objective was to identify genes deregulated in adrenocortical tumors harboring CTNNB1 genetic alterations and nuclear accumulation of β-catenin. METHODS: Microarray analysis identified a dataset of genes that were differently expressed between AA with CTNNB1 mutations and wild-type (WT) tumors. Within this dataset, the expression profiles of five genes were validated by real time-PCR (RT-PCR) in a cohort of 34 adrenocortical tissues (six AA and one ACC with CTNNB1 mutations, 13 AA and four ACC with WT CTNNB1, and 10 normal adrenal glands) and two human ACC cell lines. We then studied the effects of suppressing β-catenin transcriptional activity with the T-cell factor/β-catenin inhibitors PKF115-584 and PNU74654 on gene expression in H295R and SW13 cells. RESULTS: RT-PCR analysis confirmed the overexpression of ISM1, RALBP1, and PDE2A and the down-regulation of PHYHIP in five of six AA harboring CTNNB1 mutations compared with WT AA (n = 13) and normal adrenal glands (n = 10). RALBP1 and PDE2A overexpression was also confirmed at the protein level by Western blotting analysis in mutated tumors. ENC1 was specifically overexpressed in three of three AA harboring CTNNB1 point mutations. mRNA expression and protein levels of RALBP1, PDE2A, and ENC1 were decreased in a dose-dependent manner in H295R cells after treatment with PKF115-584 or PNU74654. CONCLUSION: This study identified candidate genes deregulated in CTNNB1-mutated adrenocortical tumors that may lead to a better understanding of the role of the Wnt-β-catenin pathway in adrenocortical tumorigenesis.
BACKGROUND: Mutations of β-catenin gene (CTNNB1) are frequent in adrenocortical adenomas (AA) and adrenocortical carcinomas (ACC). However, the target genes of β-catenin have not yet been identified in adrenocortical tumors. OBJECTIVE: Our objective was to identify genes deregulated in adrenocortical tumors harboring CTNNB1 genetic alterations and nuclear accumulation of β-catenin. METHODS: Microarray analysis identified a dataset of genes that were differently expressed between AA with CTNNB1 mutations and wild-type (WT) tumors. Within this dataset, the expression profiles of five genes were validated by real time-PCR (RT-PCR) in a cohort of 34 adrenocortical tissues (six AA and one ACC with CTNNB1 mutations, 13 AA and four ACC with WT CTNNB1, and 10 normal adrenal glands) and two human ACC cell lines. We then studied the effects of suppressing β-catenin transcriptional activity with the T-cell factor/β-catenin inhibitors PKF115-584 and PNU74654 on gene expression in H295R and SW13 cells. RESULTS: RT-PCR analysis confirmed the overexpression of ISM1, RALBP1, and PDE2A and the down-regulation of PHYHIP in five of six AA harboring CTNNB1 mutations compared with WT AA (n = 13) and normal adrenal glands (n = 10). RALBP1 and PDE2A overexpression was also confirmed at the protein level by Western blotting analysis in mutated tumors. ENC1 was specifically overexpressed in three of three AA harboring CTNNB1 point mutations. mRNA expression and protein levels of RALBP1, PDE2A, and ENC1 were decreased in a dose-dependent manner in H295R cells after treatment with PKF115-584 or PNU74654. CONCLUSION: This study identified candidate genes deregulated in CTNNB1-mutated adrenocortical tumors that may lead to a better understanding of the role of the Wnt-β-catenin pathway in adrenocortical tumorigenesis.
Authors: Kei Satoh; Lisa Zhang; Yaqin Zhang; Raju Chelluri; Myriem Boufraqech; Naris Nilubol; Dhaval Patel; Min Shen; Electron Kebebew Journal: Clin Cancer Res Date: 2016-02-12 Impact factor: 12.531
Authors: Alexandra E Kovach; Carmelo Nucera; Quynh T Lam; Ahnthu Nguyen; Dora Dias-Santagata; Peter M Sadow Journal: Discoveries (Craiova) Date: 2015 Apr-Jun
Authors: Chitra Subramanian; Huaping Zhang; Robert Gallagher; Gary Hammer; Barbara Timmermann; Mark Cohen Journal: World J Surg Date: 2014-06 Impact factor: 3.352
Authors: Rodrigo B de Alexandre; Anelia D Horvath; Eva Szarek; Allison D Manning; Leticia F Leal; Fabio Kardauke; Jonathan A Epstein; Dirce M Carraro; Fernando A Soares; Tatiyana V Apanasovich; Constantine A Stratakis; Fabio R Faucz Journal: Endocr Relat Cancer Date: 2015-05-15 Impact factor: 5.678
Authors: Johannes Hofland; Wouter W de Herder; Lieke Derks; Leo J Hofland; Peter M van Koetsveld; Ronald R de Krijger; Francien H van Nederveen; Anelia Horvath; Constantine A Stratakis; Frank H de Jong; Richard A Feelders Journal: Eur J Endocrinol Date: 2012-12-10 Impact factor: 6.664