sst5TMD4, a splice variant of the sst5 gene, is overexpressed and associated with aggressiveness in various endocrine-related tumors, but its presence, functional role, and mechanisms of actions in prostate cancer (PCa)-the most common cancer type in males-is completely unexplored. In this study, formalin-fixed, paraffin-embedded prostate pieces from patients with localized PCa, which included tumoral and nontumoral adjacent regions ( = 45), fresh biopsies from patients with high-risk PCa ( = 52), and healthy fresh prostates from cystoprostatectomies ( = 14) were examined. In addition, PCa cell lines and xenograft models were used to determine the presence and functional role of sst5TMD4. Results demonstrated that sst5TMD4 is overexpressed (mRNA/protein) in PCa samples, and this is especially drastic in metastatic and/or high Gleason score tumor samples. Remarkably, sst5TMD4 expression was associated with an altered frequency of 2 single-nucleotide polymorphisms: rs197055 and rs12599155. In addition, PCa cell lines and xenograft models were used to demonstrate that sst5TMD4 overexpression increases cell proliferation and migration in PCa cells and induces larger tumors in nude mice, whereas its silencing decreased proliferation and migration. Remarkably, sst5TMD4 overexpression activated multiple intracellular pathways (ERK/JNK, MYC/MAX, WNT, retinoblastoma), altered oncogenes and tumor suppressor gene expression, and disrupted the normal response to somatostatin analogs in PCa cells. Altogether, we demonstrate that sst5TMD4 is overexpressed in PCa, especially in those patients with a worse prognosis, and plays an important pathophysiologic role in PCa, which suggesting its potential as a biomarker and/or therapeutic target.-Hormaechea-Agulla, D., Jiménez-Vacas, J. M., Gómez-Gómez, E., L.-López, F., Carrasco-Valiente, J., Valero-Rosa, J., Moreno, M. M., Sánchez-Sánchez, R., Ortega-Salas, R., Gracia-Navarro, F., Culler, M. D., Ibáñez-Costa, A., Gahete, M. D., Requena, M. J., Castaño, J. P., Luque, R. M. The oncogenic role of the spliced somatostatin receptor sst5TMD4 variant in prostate cancer.
Early detection of PCa faces severe limitations as PSA displays poor‐specificity/sensitivity. As we recently demonstrated that plasma ghrelin O‐acyltransferase (GOAT)‐enzyme is significantly elevated in PCa‐patients compared with healthy‐controls, using a limited patients‐cohort, we aimed to further explore the potential of GOAT to improve PCa diagnosis using an ample patients‐cohort (n = 312) and defining subgroups (i.e. significant PCa/metastatic patients, etc.) that could benefit from this biomarker. Plasma GOAT‐levels were evaluated by ELISA in patients with (n = 183) and without (n = 129) PCa. Gleason Score ≥ 7 was considered clinically significant PCa. GOAT‐levels were higher in PCa patients vs control patients, and in those with significant PCa vs non‐significant PCa. GOAT‐levels association with the diagnoses of significant PCa was independent from traditional clinical variables (i.e. PSA/age/DRE). Remarkably, GOAT outperformed PSA in patients with PSA‐levels ranging 3‐20 ng/mL for the significant PCa diagnosis [GOAT‐AUC = 0.612 (0.531‐0.693) vs PSA‐AUC = 0.494 (0.407‐0.580)]. A panel of key variables including GOAT/age/DRE/testosterone also outperformed the same panel but with PSA [AUC = 0.720 (0.710‐0.730) vs AUC = 0.705 (0.695‐0.716), respectively]. Notably, GOAT‐levels could also represent a novel predictive biomarker of aggressiveness, as its levels are positively associated with Gleason Score and the presence of metastasis at the time of diagnoses. Altogether, our data reveal that GOAT‐levels can be used as a non‐invasive biomarker for significant PCa diagnosis in patients at risk of PCa (with PSA: 3‐20 ng/mL).
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