In1-ghrelin, a splice variant of ghrelin gene, is associated with the evolution and aggressiveness of human neuroendocrine tumors: Evidence from clinical, cellular and molecular parameters
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Raul M. Luque1,*,#, Miguel Sampedro-Nuñez2,*, Manuel D. Gahete1, Ana Ramos-Levi2, Alejandro Ibáñez-Costa1, Esther Rivero-Cortés1, Ana Serrano-Somavilla2, Magdalena Adrados3, Michael D. Culler4, Justo P. Castaño1,#, Mónica Marazuela2,#
1Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba Hospital Universitario Reina Sofía, Instituto Maimónides de Investigación Biomèdica de Córdoba (IMIBIC), Campus de Excelencia Internacional Agroalimentario (ceiA3), CIBER Fisiopatología de la Obesidad y Nutricón (CIBERObn), Córdoba, España
2Servicio de Endocrinología y Nutrición, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Instituto de Investigación Sanitaria Princesa, Madrid, España
3Servicio de Patología, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Instituto de Investigación Sanitaria Princesa, Madrid, España
4IPSEN Bioscience, Cambridge, Massachusetts, USA
*These authors have contributed equally to this work
#These authors should be considered co-senior authors
Raúl M. Luque, e-mail: [email protected]
Justo P. Castaño, e-mail: [email protected]
Mónica Marazuela, e-mail: [email protected]
Keywords: ghrelin system, splicing variant, neuroendocrine tumors, aggressiveness, clinical evolution
Received: March 14, 2015 Accepted: June 06, 2015 Published: June 18, 2015
Ghrelin system comprises a complex family of peptides, receptors (GHSRs), and modifying enzymes [e.g. ghrelin-O-acyl-transferase (GOAT)] that control multiple pathophysiological processes. Aberrant alternative splicing is an emerging cancer hallmark that generates altered proteins with tumorigenic capacity. Indeed, In1-ghrelin and truncated-GHSR1b splicing variants can promote development/progression of certain endocrine-related cancers. Here, we determined the expression levels of key ghrelin system components in neuroendocrine tumor (NETs) and explored their potential functional role. Twenty-six patients with NETs were prospectively/retrospectively studied [72 samples from primary and metastatic tissues (30 normal/42 tumors)] and clinical data were obtained. The role of In1-ghrelin in aggressiveness was studied in vitro using NET cell lines (BON-1/QGP-1). In1-ghrelin, GOAT and GHSR1a/1b expression levels were elevated in tumoral compared to normal/adjacent tissues. Moreover, In1-ghrelin, GOAT, and GHSR1b expression levels were positively correlated within tumoral, but not within normal/adjacent samples, and were higher in patients with progressive vs. with stable/cured disease. Finally, In1-ghrelin increased aggressiveness (e.g. proliferation/migration) of NET cells. Altogether, our data strongly suggests a potential implication of ghrelin system in the pathogenesis and/or clinical outcome of NETs, and warrant further studies on their possible value for the future development of molecular biomarkers with diagnostic/prognostic/therapeutic value.
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