Abstract
Glioblastoma (GBM) is the most malignant and lethal brain tumor. Current standard treatment consists of surgery followed by radiotherapy/chemotherapy; however, this is only a palliative approach with a mean post-operative survival of scarcely ~12–15 months. Thus, the identification of novel therapeutic targets to treat this devastating pathology is urgently needed. In this context, the truncated splicing variant of the somatostatin receptor subtype 5 (sst5TMD4), which is produced by aberrant alternative splicing, has been demonstrated to be overexpressed and associated with increased aggressiveness features in several tumors. However, the presence, functional role, and associated molecular mechanisms of sst5TMD4 in GBM have not been yet explored. Therefore, we performed a comprehensive analysis to characterize the expression and pathophysiological role of sst5TMD4 in human GBM. sst5TMD4 was significantly overexpressed (at mRNA and protein levels) in human GBM tissue compared to non-tumor (control) brain tissue. Remarkably, sst5TMD4 expression was significantly associated with poor overall survival and recurrent tumors in GBM patients. Moreover, in vitro sst5TMD4 overexpression (by specific plasmid) increased, whereas sst5TMD4 silencing (by specific siRNA) decreased, key malignant features (i.e., proliferation and migration capacity) of GBM cells (U-87 MG/U-118 MG models). Furthermore, sst5TMD4 overexpression in GBM cells altered the activity of multiple key signaling pathways associated with tumor aggressiveness/progression (AKT/JAK-STAT/NF-κB/TGF-β), and its silencing sensitized GBM cells to the antitumor effect of pasireotide (a somatostatin analog). Altogether, these results demonstrate that sst5TMD4 is overexpressed and associated with enhanced malignancy features in human GBMs and reveal its potential utility as a novel diagnostic/prognostic biomarker and putative therapeutic target in GBMs.
Highlights
Glioblastoma (GBM) is the most prevalent and malignant brain tumor in adults, with the highest mortality among the Central Nervous System (CNS) tumors [1,2]
Sst5TMD4 has been shown to reduce the response to somatostatin analogs (SSAs; e.g., octreotide) [14,17,18,22,23], which are used as valuable drugs to treat different tumor pathologies, including pituitary and neuroendocrine tumors [24,25]
We found that sst5TMD4 could exert its function through the activation of multiple critical mediators of various cancer-relevant signaling pathways closely associated with malignancy progression in different tumor pathologies [8,44,45,46,47,48,49], such as an activation of AKT (i.e., AKT1, BAD, EIF4EBP1, P70S6K, PDK1, GSK3A, CDKN1B, and PRASA40), JAK/STAT (i.e., SRC, STAT1, STAT2, and STAT3), NF-κB (i.e., ATM, EIF2A, HDAC2, TAK1, TBK1, and ZAP70), and TGF-β (i.e., FOS, JUN, ATF2, FOS, JUN, SMAD1, SMAD4, and SMAD5) pathways
Summary
Glioblastoma (GBM) is the most prevalent and malignant brain tumor in adults, with the highest mortality among the Central Nervous System (CNS) tumors [1,2]. We have recently demonstrated that the dysregulation of the alternative splicing process could represent a valuable source for the identification of novel diagnostic, prognostic, and therapeutic targets in different tumor pathologies including GBM [7,8,9,10]. In this context, somatostatin receptors belong to a complex family of different G-protein coupled receptors with seven transmembrane domains (SSTR1-5), which show a similar structure and share common signaling mechanisms [11]. Attempts to use SSAs as medical therapy in brain tumors have rendered controversial results since some of the available studies have not reported a clear therapeutic value for SSAs; the mechanistic reasons underlying those experimental failures remain unknown [26,27,28,29,30]
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