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Sci Signal. 2017 Mar 7;10(469). pii: eaal2464. doi: 10.1126/scisignal.aal2464.

Dosage-dependent regulation of VAV2 expression by steroidogenic factor-1 drives adrenocortical carcinoma cell invasion.

Author information

1
Université Côte d'Azur, Sophia Antipolis, 06560 Valbonne, France.
2
CNRS UMR7275, Sophia Antipolis, 06560 Valbonne, France.
3
NEOGENEX CNRS International Associated Laboratory, Sophia Antipolis, 06560 Valbonne, France.
4
Institut de Pharmacologie Moléculaire et Cellulaire, Sophia Antipolis, 06560 Valbonne, France.
5
Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital, University of Würzburg, 97080 Würzburg, Germany.
6
Randall Division of Cell and Molecular Biophysics, King's College London, London SE1 1UL, U.K.
7
Inserm, U1016, Institut Cochin, 75014 Paris, France.
8
CNRS UMR8104, 75014 Paris, France.
9
Université Paris Descartes, Sorbonne Paris Cité, 74014 Paris, France.
10
Inserm, UMR970, Paris Cardiovascular Research Centre, 75015 Paris, France.
11
Comprehensive Cancer Center Mainfranken, University of Würzburg, 97080 Würzburg, Germany.
12
Université Côte d'Azur, Sophia Antipolis, 06560 Valbonne, France. ninino@ipmc.cnrs.fr.

Abstract

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a dismal prognosis. Genomic studies have enabled progress in our understanding of the molecular bases of ACC, but factors that influence its prognosis are lacking. Amplification of the gene encoding the transcription factor steroidogenic factor-1 (SF-1; also known as NR5A1) is one of the genetic alterations common in ACC. We identified a transcriptional regulatory mechanism involving increased abundance of VAV2, a guanine nucleotide exchange factor for small GTPases that control the cytoskeleton, driven by increased expression of the gene encoding SF-1 in ACC. Manipulating SF-1 and VAV2 abundance in cultured ACC cells revealed that VAV2 was a critical factor for SF-1-induced cytoskeletal remodeling and invasion in culture (Matrigel) and in vivo (chicken chorioallantoic membrane) models. Analysis of ACC patient cohorts indicated that greater VAV2 abundance robustly correlated with poor prognosis in ACC patients. Because VAV2 is a druggable target, our findings suggest that blocking VAV2 may be a new therapeutic approach to inhibit metastatic progression in ACC patients.

PMID:
28270555
DOI:
10.1126/scisignal.aal2464
[Indexed for MEDLINE]

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