ECE2017 Eposter Presentations: Adrenal and Neuroendocrine Tumours Endocrine tumours and neoplasia (50 abstracts)
Dysregulation of the components of the splicing machinery in neuroendocrine tumors and its association with malignancy and aggressiveness
Sergio Pedraza-Arévalo 1 , Emilia Alors-Pérez 1 , Aura D. Herrera-Martínez 2 , Mercedes del Río-Moreno 1 , Rafael Sánchez-Sánchez 3 , Rosa Ortega-Salas 3 , Raquel Serrano-Blanch 4 , María A. Gálvez-Moreno 2 , Manuel D. Gahete 1 , Raúl M. Luque 1 & Justo P. Castaño 1
1Department of Cell Biology, Physiology and Immunology, Maimonides Institute of Biomedical Research of Cordoba (IMIBIC), Reina Sofia University Hospital (HURS), University of Cordoba (UCO), CIBER Physi, Cordoba, Spain; 2Service of Endocrinology and Nutrition, HURS/IMIBIC, Cordoba, Spain; 3Service of Anatomical Pathology, HURS/IMIBIC, Cordoba, Spain; 4Service of Medical Oncology, HURS/IMIBIC, Cordoba, Spain.
Dysregulation of the splicing machinery is emerging as a novel cancer hallmark due to its association with multiple dysfunctions in tumor cells. An inappropriate function of the components of this machinery (spliceosome) could be primarily linked with the generation of tumor-associated aberrant splicing variants. In line with this, we have previously reported that overexpression of aberrantly spliced variants of somatostatin receptor 5 (sst5TMD4) and ghrelin (In1-ghrelin) is directly associated to malignancy features in gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Therefore, in this study we aimed to characterize, for the first time, the pattern of expression of a selected set of components of the splicing machinery in GEP-NETs samples, compared to adjacent non-tumoral control-tissues, and to determine its relationship with the aggressiveness of these tumors. Accordingly, we designed a PCR-based array to determine the expression levels of components of the major (n=13) and minor spliceosome (n=4) and associated splicing factors (n=28) using a microfluidic technology in 20 pancreatic NET-samples (47% G1, 47% G2 and 6% G3) and control-tissues. The results showed that the expression of several splicing factors and spliceosome components was altered in tumor tissues compared to non-tumoral adjacent tissues. Remarkably, important splicing factors (e.g. CELF4, NOVA1, SNW1, and RAVER1) and components of spliceosome (e.g. PRP8) were clearly overexpressed in NET-samples, wherein they were correlated with some malignancy features. Furthermore, in vitro assays using NETs cellular models (i.e. BON-I/QGP-I-cells) demonstrated that CELF4 and NOVA1 overexpression induced an increase on cell-proliferation, while their silencing (using specific siRNAs) caused a marked decrease on cell-proliferation, suggesting a role in the aggressiveness of these tumors and their putative suitability as therapeutic targets in pancreatic NETs. Hence, our results demonstrate an alteration of splicing machinery in pancreatic NETs and unveil its putative relevance in NETs development/progression, where it could provide novel diagnostic biomarkers and therapeutic tools for this pathology.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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