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

Abstract

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.

Somatostatin receptor subtype 1 as a potential diagnostic marker and therapeutic target in prostate cancer

“…It has been demonstrated that the expression of some components of the SST system, especially sst variants, are dysregulated in PCa tissue and associated with the aggressiveness of tumor cells, which highlights the putative utility of these components as novel biomarkers and therapeutic targets to develop pharmacologic strategies for this pathology. In this sense, SST receptor subtype 1 (sst1, SSTR1 ) has been described as an important molecule in several types of cancer, such as colon cancer, where it seems to play a significant role and is associated with some aggressiveness features .…”

“…[22][23][24] In fact, somatostatin analogs (eg, the sst2-preferring octreotide and lanreotide, and the pan-sst ligand pasireotide) are currently being used to treat some of these pathologies, such as pituitary adenomas and NETs, highlighting the clinical relevance of this system. [25][26][27] It has been demonstrated that the expression of some components of the SST system, especially sst variants, are dysregulated in PCa tissue and associated with the aggressiveness of tumor cells, [28][29][30] which highlights the putative utility of these components as novel biomarkers and therapeutic targets to develop pharmacologic strategies for this pathology. In this sense, SST receptor subtype 1 (sst1, SSTR1) has been described as an important molecule in several types of cancer, such as colon cancer, where it seems to play a significant role and is associated with some aggressiveness features.…”

Clinical Utility of Ghrelin-O-Acyltransferase (GOAT) Enzyme as a Diagnostic Tool and Potential Therapeutic Target in Prostate Cancer

“…All biopsy specimens were analyzed by experienced urologic pathologists according to the International Society of Urological Pathology 2005 modified criteria [14]. Tumor regions (n = 84) were identified from the Formalin-Fixed Paraffin-Embedded (FFPE) samples by expert urologic pathologists as previously reported [15,16] and used to isolate RNA and perform gene expression analyses. The FFPE pieces were taken from radical prostatectomies (patients belonging to cohort 3).…”

“…DU145 and LNCaP cell lines were obtained from American Type Culture Collection (ATCC; Manassas, VA, USA), cultured according to the manufacturer's instructions, validated by analysis of short tandem repeats sequences using GenePrint 10 System (Promega, Barcelona, Spain) and checked for mycoplasma contamination by PCR as previously reported [8,16]. DU145 cells were selected for functional in vitro and in vivo analyses based on its high expression levels of In1-ghrelin, the main oncogenic element of the ghrelin axis in prostate cancer, which is also a putative target of GOAT [8].…”

“…Cell proliferation was evaluated using Alamar-Blue assay (Bio-Source International, Camarillo, CA, USA) in DU145 cells, as previously reported [16]. Briefly, cells were seeded in 96-well culture plates at a density of 3000-5000 cells/well and serum-starved for 24 h. Then, fluorescence (560 nm) was evaluated using the FlexStation III system (Molecular Devices, Sunnyvale, CA, USA) after 3 h of incubation with Alamar-Blue compound at 10%.…”