Hormaechea-Agulla, DanielGahete, Manuel DJimenez-Vacas, Juan MGomez-Gomez, EnriqueIbañez-Costa, AlejandroL-Lopez, FernandoRivero-Cortes, EstherSarmento-Cabral, AndreValero-Rosa, JoseCarrasco-Valiente, JuliaSanchez-Sanchez, RafaelOrtega-Salas, RosaMoreno, Maria MTsomaia, NatiaSwanson, Steve MCuller, Michael DRequena, Maria JCastaño, Justo PLuque, Raul M2023-01-252023-01-252017-08-15Hormaechea-Agulla D, Gahete MD, Jiménez-Vacas JM, Gómez-Gómez E, Ibáñez-Costa A, L-López F, et al. The oncogenic role of the In1-ghrelin splicing variant in prostate cancer aggressiveness. Mol Cancer. 2017 Aug 29;16(1):146http://hdl.handle.net/10668/11538The Ghrelin-system is a complex, pleiotropic family composed of several peptides, including native-ghrelin and its In1-ghrelin splicing variant, and receptors (GHSR 1a/b), which are dysregulated in various endocrine-related tumors, where they associate to pathophysiological features, but the presence, functional role, and mechanisms of actions of In1-ghrelin splicing variant in prostate-cancer (PCa), is completely unexplored. Herein, we aimed to determine the presence of key ghrelin-system components (native-ghrelin, In1-ghrelin, GHSR1a/1b) and their potential pathophysiological role in prostate cancer (PCa). In1-ghrelin and native-ghrelin expression was evaluated by qPCR in prostate tissues from patients with high PCa-risk (n = 52; fresh-tumoral biopsies), and healthy-prostates (n = 12; from cystoprostatectomies) and correlated with clinical parameters using Spearman-test. In addition, In1-ghrelin and native-ghrelin was measured in plasma from an additional cohort of PCa-patients with different risk levels (n = 30) and control-healthy patients (n = 20). In vivo functional (proliferation/migration) and mechanistic (gene expression/signaling-pathways) assays were performed in PCa-cell lines in response to In1-ghrelin and native-ghrelin treatment, overexpression and/or silencing. Finally, tumor progression was monitored in nude-mice injected with PCa-cells overexpressing In1-ghrelin, native-ghrelin and empty vector (control). In1-ghrelin, but not native-ghrelin, was overexpressed in high-risk PCa-samples compared to normal-prostate (NP), and this expression correlated with that of PSA. Conversely, GHSR1a/1b expression was virtually absent. Remarkably, plasmatic In1-ghrelin, but not native-ghrelin, levels were also higher in PCa-patients compared to healthy-controls. Furthermore, In1-ghrelin treatment/overexpression, and to a much lesser extent native-ghrelin, increased aggressiveness features (cell-proliferation, migration and PSA secretion) of NP and PCa cells. Consistently, nude-mice injected with PC-3-cells stably-transfected with In1-ghrelin, but not native-ghrelin, presented larger tumors. These effects were likely mediated by ERK1/2-signaling activation and involved altered expression of key oncogenes/tumor suppressor genes. Finally, In1-ghrelin silencing reduced cell-proliferation and PSA secretion from PCa cells. Altogether, our results indicate that In1-ghrelin levels (in tissue) and circulating levels (in plasma) are increased in PCa where it can regulate key pathophysiological processes, thus suggesting that In1-ghrelin may represent a novel biomarker and a new therapeutic target in PCa.enAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/AggressivenessGhrelin-systemIn1-ghrelin variantProstate cancerAgedAnimalsBiomarkers, tumorCell line, tumorCell proliferationGhrelinHeterograftsHumansMaleMiceMiddle agedProstateProstatic neoplasmsProtein isoformsResearch article28851363open accessBiomarcadores de tumorGhrelinaIsoformas de proteínasLínea celular tumoralNeoplasias de la próstataProliferación celularPróstata10.1186/s12943-017-0713-91476-4598PMC5576296https://doi.org/10.1186/s12943-017-0713-9https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576296/pdf