RT Journal Article
T1 The oncogenic role of the In1-ghrelin splicing variant in prostate cancer aggressiveness.
A1 Hormaechea-Agulla, Daniel
A1 Gahete, Manuel D
A1 Jimenez-Vacas, Juan M
A1 Gomez-Gomez, Enrique
A1 Ibañez-Costa, Alejandro
A1 L-Lopez, Fernando
A1 Rivero-Cortes, Esther
A1 Sarmento-Cabral, Andre
A1 Valero-Rosa, Jose
A1 Carrasco-Valiente, Julia
A1 Sanchez-Sanchez, Rafael
A1 Ortega-Salas, Rosa
A1 Moreno, Maria M
A1 Tsomaia, Natia
A1 Swanson, Steve M
A1 Culler, Michael D
A1 Requena, Maria J
A1 Castaño, Justo P
A1 Luque, Raul M
K1 Aggressiveness
K1 Ghrelin-system
K1 In1-ghrelin variant
K1 Prostate cancer
AB The 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.
PB BioMed Central
YR 2017
FD 2017-08-15
LK http://hdl.handle.net/10668/11538
UL http://hdl.handle.net/10668/11538
LA en
NO Hormaechea-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):146
DS RISalud
RD Apr 14, 2025