ECE2023 Poster Presentations Endocrine-related Cancer (62 abstracts)
Characterization of splicing machinery components in thyroid cancer and their correlation/association with tumour behaviour and clinical features
Isidoro Di Caro 1,2,3,4 , André Sarmento-Cabral 1,2,3,4 , Miguel E. G-Garcia 1,2,3,4 , Andrea Martínez Vara 1,2 , Ana María Moyano-Sánchez 2,3 , Rafael Sánchez-Sánchez 2,3 , Ana Romero Lluch 5 , Pilar Santisteban Sanz 6 , Elena Navarro Gonzalez 5 , Maria Angeles Galvez Moreno 2,3 , Raul M. Luque 1,2,3,4 & Antonio Jesús Martínez-Fuentes 1,2,3,4
1Maimónides Institute for Biomedical Research of Córdoba (IMIBIC), 14004 Córdoba, Spain, Córdoba, Spain; 2University of Córdoba, Department of Cellular Biology, Physiology and Immunology, Córdoba, Spain; 3Reina Sofía University Hospital (HURS), Córdoba, Spain; 4CIBER Physiopathology of Obesity and Nutrition (CIBERobn), Spain; 5Hospital Virgen del Rocío, Servicio de Endocrinología y Nutrición, Seville, Spain; 6Instituto de Investigaciones Biomédicas “Alberto Sols”, Consejo Superior de Investigaciones Científicas, Madrid, Spain
Emerging evidence indicates that the cellular machinery controlling the splicing process (spliceosome) is altered in several tumour types, leading to oncogenic splicing events associated with tumour progression and aggressiveness. However, whether this molecular phenomenon also occurs in thyroid cancer has not been yet explored. Therefore, our main aim was to explore the potential dysregulation of the expression of relevant spliceosome components and splicing factors in clinically well-characterized human thyroid cancer samples (papillar, follicular and medullary), compared to its adjacent non-tumour tissue, and whether these alterations might be associated with relevant clinical parameters. Results revealed a clear dysregulation of several components of the splicing-machinery in thyroid cancer samples compared to its adjacent non-tumoral tissue, wherein the expression of specific components was associated with key clinical parameters. Based on these results, we next 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 response to the inhibition of the splicing machinery activity [i.e. using the splicing-factor-3B-subunit-1 (SF3B1; a core component of this machinery) inhibitor pladienolide B] and SF3B1 silencing (using an specific siRNA). These in vitro studies revealed that pladienolide-B significantly decreased cell aggressiveness parameters (proliferation, migration, formation of tumour-spheres and colonies) in thyroid cancer cells through the modulation of the expression levels of different component of key oncogenic signalling routes. Similarly, SF3B1 silencing also reduced the above-mentioned tumour-related features, 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 splicing-machinery in thyroid cancer tissues that might be associated to its tumorigenesis, paving the way to explore the use of specific splicing-machinery components as novel diagnostic/prognostic and therapeutic targets in this pathology. 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 improves 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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