ECE2017 Guided Posters Adrenal 1 (10 abstracts)
Contribution of retinoic acid receptor signalling to adrenal cortex morphology and functional zonation through modulation of WNT/β-catenin pathway
Rami El Zein 1 , Amanda J Rickard 1 , Golib Dzib Jose Felipe 2 , Benoit Samson-Couterie 1 , Angélique Rocha 1 , Marko Poglitsch 3 , Celso E Gomez-Sanchez 4 , Laurence Amar 1, , Fabio Luiz Fernandes-Rosa 1, , Norbert B Ghyselinck 7 , Arndt Benecke 2 , Enzo Lalli 8, , Maria-Christina Zennaro 1, & Sheerazed Boulkroun 1
1INSERM, UMRS_970, Paris Cardiovascular Research Center and Université Paris Descartes, Sorbonne Paris Cité, Paris, France; 2Centre National de la Recherche Scientifique (CNRS), Institut des Hautes Etudes Scientifiques, Bures sur Yvette, France; 3Attoquant Diagnostics GmbH, Vienna, Austria; 4Division of Endocrinology, G.V. (Sonny) Montgomery VA Medical Center and University of Mississippi Medical Center, Jackson, MS 39216, USA; 5Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Unité d’hypertension, Paris, France; 6Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Génétique, Paris, France; 7Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS UMR7104-INSERM U964, Department of Functional Genomics and Cancer, Illkirch, France; 8Institut de Pharmacologie Moléculaire et Cellulaire, Unité Mixte de Recherche 7275, CNRS, Valbonne, France; 9Université de Nice–Sophia Antipolis, Valbonne, France.
Recurrent somatic mutations in KCNJ5, CACNA1D, ATP1A1 and ATP2B3 have been identified in aldosterone producing adenoma (APA). Although the role of these mutations in regulating aldosterone biosynthesis has been clearly established, the mechanisms involved in proliferation and APA formation still remain to be elucidated. The aim of our study was to identify pathways involved in adrenal cortex nodulation and APA formation.
Transcriptomic analysis from 123 APA and 11 control adrenal and correlations of gene expression with genetic, morphological and functional characteristics of the tumors allowed us to identify retinoic acid receptor (RAR) signalling as a central molecular network involved in APA formation independently of the mutation status.
Treatment of H295R cells with all-trans retinoic acid and 9-cis retinoic acid reduced cell viability in a time and dose dependent manner. This effect was due to decreased cell proliferation and increased cell apoptosis. In contrast to the effects observed in vitro, 9-cis retinoic acid did not modify tumor progression in a mouse xenograft model.
Investigation of the adrenal phenotype of rarα−/− mice demonstrated that in young (12 weeks) and old (52 weeks) rarα−/− mice the characteristic cellular arrangement of the adrenal cortex was replaced by an enlarged zona glomerulosa and a disorganized zona fasciculata. This is also associated to dilatation and disorganisation of vessels and increased capsule thickness. Furthermore, young rarα−/− mice displayed lower plasma aldosterone concentration and decreased expression of steroidogenic enzymes. Interestingly, this was associated with the inhibition of WNT/β-catenin pathway.
Our results suggest that RAR signaling contributes to normal adrenal morphology and functional zonation through modulation of WNT/β-catenin pathway and that its disruption could contribute to abnormal cell proliferation in the adrenal cortex, creating a propitious environment for the emergence of specific driver mutations in APA.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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