Endocrine Abstracts

Gliomas are derived from glial-cells and are the most common primary brain tumor, characterized by rapid growth and invasion. Astrocytomas are a subset of malignant gliomas which are classified, based on their agresiveness features, in low grades (I and II) to high grades (HGAs; III and IV), being grade-IV (glioblastoma multiforme; GBM) the most malignant and aggressive type. Current standard treatment for GBMs consists on surgery followed by radiotherapy/chemotherapy; however, this is only a palliative approach with an average post-operative survival of ~12–16 months. Therefore, there is a clear need for identification of novel therapeutic targets to treat this devastating pathology. In this context, the truncated splicing variant of the somatostatn receptor subtype-5, named sst5TMD4, which is produced by aberrant alternative splicing process, has been demonstrated to be overexpressed and associated with increased aggressiveness features in several endocrine-related tumours (e.g. pituitary, breast, prostate, thyroid and neuroendocrine tumors). However, the presence, functional role, and associated molecular mechanisms of sst5TMD4 in astrocytomas has not been explored. Therefore, the main objetive of this study was to carried out a comprehensive analysis to characterized the expression of sst5TMD4 in HGA human samples, and to determine its pathophysiological role by using human primary GBM cell cultures and GBM cell-lines (U-87 MG/U-118 MG). Our results revealed that sst5TMD4 splicing variant was significantly overexpressed in human HGA tissues [n = 34, grade III (n = 10) and grade IV (n = 24)] compared to healthy-control brain tissues (n = 4). Remarkably, overexpression of sst5TMD4 variant (with a specific plasmid) increased the proliferation and migration capacity, whereas sst5TMD4 silencing (by specific siRNAs) decreased proliferation and migration rate of GBM cells. Our data also indicate that the modulation of the level of expression of sst5TMD4 significantly altered key signaling pathways associated with tumor aggressiveness in GBM cells, including the decrease in pAKT/AKT ratio, a key pathway robustly associated with tumor progression and aggressiveness. Taken together, our results demonstrate that sst5TMD4 is overexpressed in human HGAs and its presence is associated to enhanced malignancy. Therefore, our data provide an original approach to use sst5TMD4 as novel diagnostic and/or prognostic biomarker and as a new target with therapeutic potential in this poor prognosis type of CNS tumors.

Fundings

MINECO (PID2019–105564RB-I00/FPU16/05059), ISCIII (PI16–00264), Junta de Andalucía (BIO-0139) and CIBERobn.