ECE2015 Guided Posters Pituitary–Basic and IGF-1 (9 abstracts)
Presence and functional actions of In1-ghrelin splicing variant reveals a potentially relevant pathophysiological role in human pituitary adenomas
Alejandro Ibáñez-Costa 1 , Manuel D Gahete 1 , Esther Rivero-Cortés 1 , David Rincón-Fernández 1 , Richard Nelson 2 , Manuel Beltrán 3 , Andrés de la Riva 4 , Miguel A Japón 5 , Eva Venegas-Moreno 6 , María Ángeles Gálvez 7 , Juan A García-Arnés 8 , Alfonso Soto-Moreno 6 , Jennifer Morgan 2 , Natia Tsomaia 2 , Michael D Culler 2 , Carlos Dieguez 9 , Justo P Castaño 1 & Raúl M Luque 1
1Department of Cell Biology, Physiology and Immunology, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofia, University of Cordoba, CIBER Fisiopatolo, Córdoba, Spain; 2IPSEN Bioscience, Cambridge, Massachusetts, USA; 3Department of Pathology, Puerta del Mar University Hospital, Cádiz, Spain; 4Service of Neurosurgery, Hospital Universitario Reina Sofia, Córdoba, Spain; 5Department of Pathology, Hospital Universitario Virgen del Rocío, Sevilla, Spain; 6Metabolism and Nutrition Unit, Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío, Sevilla, Spain; 7Service of Endocrinology and Nutrition, Instituto Maimónides de Investigación Biomédica de Córdoba, Hospital Universitario Reina Sofia, Córdoba, Spain; 8Department of Endocrinology and Nutrition, Carlos Haya Hospital, Málaga, Spain; 9Department of Physiology, University of Santiago de Compostela, CIBER Fisiopatología de la Obesidad y Nutrición, Santiago de Compostela, Spain.
Pituitary adenomas comprise a heterogeneous group of tumours causing serious comorbidities, which would benefit from identification of novel, common molecular/cellular biomarkers and therapeutic targets. The ghrelin system comprises a complex molecular family with multiple functions, and some of its components have been linked to development of various endocrine-related cancers. In this work we aim at better delineating the patho-physiological significance of the ghrelin regulatory system in pituitary tumours, by pursuing two specific objectives: i) to analyse the presence in pituitary tumours of key components of the ghrelin system: native-ghrelin, the recently discovered splicing variant In1-ghrelin, ghrelin receptors GHS-R1a (full-length) and GHS-R1b (truncated variant), and MBOAT4 (GOAT), the enzyme responsible for ghrelin acylation and ii) to compare the direct effects of native-ghrelin and In1-ghrelin variant administration on selected functional parameters in cell cultures derived from the main types of pituitary adenomas. To this end, we studied a large series of 180 pituitary samples: 76 somatotropinomas, 57 non-functioning pituitary adenomas, 29 corticotropinomas, seven prolactinomas, and 11 normal pituitary samples. The results obtained revealed that expression pattern of ghrelin system components undergoes a striking alteration in pituitary adenomas, as compared with normal pituitary, particularly In1-ghrelin, which was consistently overexpressed in all human pituitary adenoma subtypes. Interestingly, similar to that observed for native-ghrelin, In1-ghrelin was functionally active in cultured pituitary adenoma cells, as it increased GH and ACTH secretion, Ca2+ and ERK1/2 signalling, and cell viability, being the effects of In1-ghrelin variants generally greater than those evoked by native-ghrelin. Finally, overexpression of In1-ghrelin (by transfection using an specific expression plasmid) increased cell viability, while the use of a specific siRNA for this ghrelin variant reduced cell viability. Altogether, our results indicate that ghrelin system components are present and markedly altered in human pituitary tumours, where In1-ghrelin variant, particularly, could play a relevant functional role in the regulation of adenoma pathology, this paving the way for using In1-ghrelin variant as a new tool to explore novel diagnostic/prognostic biomarkers and/or therapeutic targets in these human tumours.
Disclosure: This work was supported by Junta de Andalucía (CTS-1406, BIO-0139, PI-0639-2012) Ministerio de Economía y Competitividad, Gobierno de España (BFU2013-43282-R), Instituto de Salud Carlos III (PI13/00651), Centro de Investigación Biomédica en Red de la Fisiopatología de la Obesidad y Nutrición (CIBERobn) and Ayuda Merck Serono 2013. R Nelson, J Morgan, N Tsomaia, and M D Culler are employees of IPSEN.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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