Endocrine Abstracts

Background: Gliomas are the most common primary brain tumor, being astrocytomas a subset of malignant gliomas graded on a scale of I to IV. Grade-IV astrocytomas (glioblastoma multiforme; GBM) are the most malignant and aggressive type. Current standard treatments are ineffective, being their average postoperative survival of 12-16 months. Therefore, there is a clear need for the identification of novel therapeutic targets to treat this pathology. In this context, the truncated variant of the somatostatin receptor 5, sst5TMD4, is overexpressed and associated with increased aggressiveness in several endocrine-related tumors. However, the presence, functional role and molecular mechanisms of sst5TMD4 in astrocytomas have not been yet explored.

Objectives & Methods: To comprehensively analyse the expression of sst5TMD4 and its pathophysiological role in astrocytomas using human GBM samples and human GBM cell lines (U-87 MG and U-118 MG).

Results: sst5TMD4 variant was significantly overexpressed in astrocytomas (n=63) compared to healthy-control brain tissues (n=15). Remarkably, overexpression of sst5TMD4 increased, whereas its silencing decreased, the proliferation rate and migration capacity of GBM cells in vitro. Our data also indicated that the modulation of the expression of sst5TMD4 in GBM cells altered key signaling pathways associated with tumor aggressiveness and progression such as the AKT pathway. Moreover, the silencing of sst5TMD4 sensitized GBM cells to the treatment with somatostatin analog pasireotide.

Conclusion: Our results demonstrate that the sst5TMD4 splicing variant is overexpressed in astrocytomas and associated with enhanced malignancy, supporting its possible utility as a tool to develop new molecular biomarkers and drug therapies for GBMs.

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