The oncogenic role of the spliced somatostatin receptor sst5TMD4 variant in prostate cancer

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 (n = 45), fresh biopsies from patients with high‐risk PCa (n = 52), and healthy fresh prostates from cystoprostatectomies (n = 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. FASEB J. 31, 4682–4696 (2017). www.fasebj.org