EYES2019 7th ESE Young Endocrinologists and Scientists (EYES) Meeting Oral Presentations (67 abstracts)
Splicing machinery is dysregulated in pituitary neuroendocrine tumors (PitNETs) and associated with aggressiveness features
Juan M Jiménez-Vacas 1, , Mari C Vázquez-Borrego 1, , Antonio C Fuentes-Fayos 1, , Eva Venegas-Moreno 5 , Mônica R Gadelha 6, , María A Gálvez-Moreno 1, , Alfonso Soto-Moreno 5 , Manuel D Gahete 1, , Justo P Castaño 1, & Raúl M Luque 1,
1Maimonides Institute of Biomedical Research of Cordoba (IMIBIC), Cordoba, Spain; 2Department of Cell Biology, Physiology and Immunology, University of Cordoba, Spain; 3Reina Sofia University Hospital (HURS), Cordoba, Spain; 4CIBER Physiopathology of Obesity and Nutrition (CIBERobn), Cordoba, Spain; 5Metabolism and Nutrition Unit, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS), Sevilla, Spain; 6Neuroendocrinology Research Center/Endocrinology Division, Medical School and Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; 7Neuroendocrinology Division, Instituto Estadual do Cérebro Paulo Niemeyer, Rio de Janeiro, Brazil; 8Service of Endocrinology and Nutrition, IMIBIC, HURS, Cordoba, Spain.
Objective and methods: Recent studies suggest that altered alternative splicing and, consequently, appearance of an abnormal splicing pattern and even of aberrant/oncogenic splicing-variants, represent a common molecular feature of most tumor pathologies, including Pituitary Neuroendocrine Tumors (PitNETs). However, the putative alteration, pathophysiological role and potential therapeutic utility of splicing machinery components [i.e. spliceosome-components (SCs) and splicing-factors (SFs)] remain unknown in PitNETs. Therefore, we aimed to: 1) Analyze the expression levels of selected splicing machinery components, and their association with relevant clinical parameters, in PitNETs [n=261: somatotropinomas (n=138)/Non-Functioning PitNETS (NFPTs; n=90)/ corticotropinomas (n=24)/Prolactinomas (n=9)]; and, 2) evaluate the potential antitumor actions (cell-proliferation/viability/hormone-secretion) of a spliceosome-inhibitor (pladienolide-B) in PitNET-cells.
Results: A severe dysregulation of the expression levels of SCs and SFs was found in all the PitNET-subtypes compared to normal-pituitaries, which provided unique molecular fingerprints that accurately discriminate between normal and tumor tissue in each of the PitNET-subtypes analyzed. Results also identified several SCs commonly dysregulated in all PitNET-subtypes. Interestingly, the expression-levels of several SCs and SFs were associated to key clinical features. Notably, pladienolide-B markedly reduced cell-proliferation/viability/hormone secretion in PitNET cell-cultures/cell-lines.
Conclusions: The splicing machinery is severely and distinctly dysregulated in the main PitNET-subtypes which opens a new window to investigate the plausible contribution of splicing dysregulation and its subsequent outcomes to pituitary tumorigenesis, and to assess the potential value of specific splicing machinery components as novel diagnostic/prognostic tools in these pathologies. Furthermore, our study unveils that the spliceosome could be novel actionable therapeutic target to combat PitNETs.
Funding: This work has been funded by the following grants: Instituto de Salud Carlos III [co-funded by European Union (ERDF/ESF), ‘Investing in your future’: PI16/00264], Ministerio de Ciencia, Innovación y Universidades (BFU2016-80360-R); Junta de Andalucía (BIO-0139); CIBERobn; and Sociedad Andaluza de Endocrinología, Diabetes y Nutrición (SAEDYN).
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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