ECE2024 Poster Presentations Endocrine-Related Cancer (40 abstracts)
Alteration in the molecular components of machinery that regulate gene expression mechanisms and genomic stability in thyroid cancer and their association with tumour behaviour and/or clinical features
Andrea Martínez Vara 1,2 , Francisco Porcel Pastrana 1,2,3,4 , Isidoro Di-Caro 1,2,3 , André Sarmento-Cabral 1,2,3,4 , Rafael Sánchez Sánchez 2,3 , Ana Romero Lluch 5 , Pilar Santisteban 6 , Elena Navarro González 5 , María A Gávez Moreno 1,2,3 , Raúl M Luque 1,2,3,4 & Antonio J Martínez Fuentes 1,2,3,4
1Maimónides Institute for Biomedical Research of Córdoba (IMIBIC), Córdoba, Spain; 2Universidad de Córdoba, Biología Celular, Fisiología e Inmunología, Córdoba, Spain; 3Reina Sofía University Hospital (HURS), Córdoba, Spain; 4CIBER Physiopathology of Obesity and Nutrition (CIBERobn), Córdoba, Spain; 5Servicio de Endocrinología y Nutrición, Hospital Virgen del Rocío, Sevilla, Spain; 6Instituto de Investigaciones Biomédicas “Alberto Sols”, Consejo Superior de Investigaciones Científicas; Universidad Autónoma de Madrid (CSIC-UAM) and Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
Emerging evidence indicates that the cellular machineries controlling gene expression mechanisms and genomic stability are altered in several endocrine-related cancers (ERCs), leading to some oncogenic events associated with tumour progression/aggressiveness. However, whether this phenomenon also occurs in thyroid cancer has not been yet explored. Therefore, this study was focused on: 1) investigating the potential alteration in the levels of components of the molecular machineries that control either RNA metabolism [Splicing machinerie, RNA-Exosome complex, Non-sense Mediated Decay (NMD)] or genomic stability (shelterin-telomerase) in clinically well-characterized human papillary and medullary thyroid cancer samples compared to its adjacent non-tumour tissue; and, 2) whether these alterations might be associated with relevant clinical parameters. Results revealed a clear dysregulation of several components of these machineries in papillary and medullary thyroid cancer samples, wherein the expression of specific components was associated with key clinical parameters. Based on these results, we explored different functional (e.g. proliferation, migration, and tumour-spheres and colonies formation) and mechanistic (gene expression/signalling pathways) assays in human thyroid cancer cell models (TCP1 and Cal62). In general, these in vitrostudies revealed that different molecular components of splicing, RNA-exosome, NSMD and telomerase machineries significantly modulated cell aggressiveness features in thyroid cancer cells. Moreover, we targeted the key splicing-factor-3B-subunit-1 component (SF3B1; a core component of the splicing machinery) with the specific inhibitor pladienolide B as well as with a specific siRNA to carry out the silencing of SF3B1 expression. Results revealed that both pladienolide-B treatment and the silencing of SF3B1 significantly decreased different aggressiveness parameters (proliferation, migration, tumour-spheres and colonies formation) in thyroid cancer cells, thus confirming the critical role of SF3B1 and consequently, of the splicing machinery, in thyroid pathophysiology. Altogether, our data demonstrate a drastic dysregulation of the key components of the molecular machineries controlling gene expression mechanisms and genomic stability (particularly splicing) in papillary and medullary thyroid cancer samples that might be associated to the tumorigenesis of this ERC. In particular, the genetic and/or pharmacological inhibition of SF3B1 may represent a promising novel therapeutic strategy worth to be explored through randomized controlled trials that could improve the outcome of patients affected by clinically aggressive thyroid cancer.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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