title: 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.
abstract: 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.
authors.affiliation: Departamento 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.
authors.forename: Raul M
authors.initials: RM
authors.lastname: Luque
authors.affiliation: Servicio de Endocrinología y Nutrición, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Instituto de Investigación Sanitaria Princesa, Madrid, España.
authors.forename: Miguel
authors.initials: M
authors.lastname: Sampedro-Nuñez
authors.affiliation: Departamento 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.
authors.forename: Manuel D
authors.initials: MD
authors.lastname: Gahete
authors.affiliation: Servicio de Endocrinología y Nutrición, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Instituto de Investigación Sanitaria Princesa, Madrid, España.
authors.forename: Ana
authors.initials: A
authors.lastname: Ramos-Levi
authors.affiliation: Departamento 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.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Ibáñez-Costa
authors.affiliation: Departamento 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.
authors.forename: Esther
authors.initials: E
authors.lastname: Rivero-Cortés
authors.affiliation: Servicio de Endocrinología y Nutrición, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Instituto de Investigación Sanitaria Princesa, Madrid, España.
authors.forename: Ana
authors.initials: A
authors.lastname: Serrano-Somavilla
authors.affiliation: Servicio de Patología, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Instituto de Investigación Sanitaria Princesa, Madrid, España.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Adrados
authors.affiliation: IPSEN Bioscience, Cambridge, Massachusetts, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Culler
authors.affiliation: Departamento 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.
authors.forename: Justo P
authors.initials: JP
authors.lastname: Castaño
authors.affiliation: Servicio de Endocrinología y Nutrición, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Instituto de Investigación Sanitaria Princesa, Madrid, España.
authors.forename: Mónica
authors.initials: M
authors.lastname: Marazuela
mesh_terms: D000217:Acyltransferases / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D018450:Disease Progression; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D054439:Ghrelin / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D018358:Neuroendocrine Tumors / Q000235:genetics / Q000378:metabolism* / Q000556:secondary / Q000628:therapy; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D011237:Predictive Value of Tests; D011446:Prospective Studies; D020033:Protein Isoforms; D054440:Receptors, Ghrelin / Q000235:genetics / Q000378:metabolism; D012074:Remission Induction; D012189:Retrospective Studies; D015398:Signal Transduction; D014162:Transfection; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; C515349:GHRL protein, human; D054439:Ghrelin; D020033:Protein Isoforms; D054440:Receptors, Ghrelin; D000217:Acyltransferases; C542776:MBOAT4 protein, human
keywords: aggressiveness; clinical evolution; ghrelin system; neuroendocrine tumors; splicing variant