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Horm Metab Res 2017; 49(08): 631-637
DOI: 10.1055/s-0043-110143
Endocrine Research
© Georg Thieme Verlag KG Stuttgart · New York

Suppression of Forkhead Box Protein O1 (FOXO1) Transcription Factor May Promote Adrenocortical Tumorigenesis

Adam Stenman
1   Yale Endocrine Neoplasia Laboratory, Yale School of Medicine, New Haven, Connecticut, USA
2   Department of Surgery, Yale School of Medicine, New Haven, Connecticut, USA
3   Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
,
Timothy Murtha
1   Yale Endocrine Neoplasia Laboratory, Yale School of Medicine, New Haven, Connecticut, USA
2   Department of Surgery, Yale School of Medicine, New Haven, Connecticut, USA
,
Reju Korah
1   Yale Endocrine Neoplasia Laboratory, Yale School of Medicine, New Haven, Connecticut, USA
2   Department of Surgery, Yale School of Medicine, New Haven, Connecticut, USA
,
Tobias Carling
1   Yale Endocrine Neoplasia Laboratory, Yale School of Medicine, New Haven, Connecticut, USA
2   Department of Surgery, Yale School of Medicine, New Haven, Connecticut, USA
› Author Affiliations
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Publication History

received 31 March 2017

accepted 25 April 2017

Publication Date:
22 June 2017 (online)

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Abstract

Despite recent comprehensive genetic analyses, molecular evidence for a pathophysiological continuum linking benign adrenocortical adenoma (ACA) and highly aggressive adrenocortical carcinoma (ACC) is still elusive. Using human tumor samples and the established ACC cell line SW-13, this study investigated potential regulatory roles for FOXO transcription factors, in modulating adrenocortical tumorigenesis. Adrenocortical tumor specimens (20 ACAs, 10 ACCs, and 9 normal adrenal tissue samples) obtained from 30 patients were analyzed for ubiquitously expressed FOXO transcription factors, FOXO1 and FOXO3 using qRT-PCR and immunohistochemistry. The SW-13 ACC cells were used to study the phenotypic effects of FOXO regulation in vitro. While FOXO3 expression remained unchanged in ACCs, FOXO1 expression was found to be significantly downregulated in 19/20 ACAs and 9/10 ACCs (p<0.0001 and p<0.05, respectively), suggesting a global role for FOXO1 suppression in promoting and maintaining adrenocortical dedifferentiation. Silencing of FOXO1 in SW-13 cells resulted in significant loss of viability (p<0.001) mediated by apoptosis as determined by quantitative Annexin V immunofluorescence analysis (p<0.01). FOXO1 silencing also augmented the migratory behavior of SW-13 cells (p<0.0001), suggesting distinct roles for FOXO1 in promoting viability and controlled motility of adrenocortical cells.

Key words

adrenal cortical adenoma - adrenocortical carcinoma - tumorigenesis - FOXO

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