Spliceosomic dysregulation unveils NOVA1 as a candidate actionable therapeutic target in pancreatic neuroendocrine tumors.

Autor: Pedraza-Arevalo S; Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain; Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Córdoba, Spain; Reina Sofia University Hospital, Córdoba, Spain., Alors-Pérez E; Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain; Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Córdoba, Spain; Reina Sofia University Hospital, Córdoba, Spain., Blázquez-Encinas R; Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain; Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Córdoba, Spain; Reina Sofia University Hospital, Córdoba, Spain., Herrera-Martínez AD; Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain; Endocrinology and Nutrition Service, Reina Sofia University Hospital, Córdoba, Spain., Jiménez-Vacas JM; Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain; Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Córdoba, Spain; Reina Sofia University Hospital, Córdoba, Spain., Fuentes-Fayos AC; Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain; Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Córdoba, Spain; Reina Sofia University Hospital, Córdoba, Spain., Reyes Ó; Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain; Department of Computer Sciences, University of Córdoba, Córdoba, Spain., Ventura S; Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain; Department of Computer Sciences, University of Córdoba, Córdoba, Spain., Sánchez-Sánchez R; Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain; Pathology Service, Reina Sofia University Hospital, Córdoba, Spain., Ortega-Salas R; Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain; Pathology Service, Reina Sofia University Hospital, Córdoba, Spain., Serrano-Blanch R; Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain; Medical Oncology Service, Reina Sofia University Hospital, Córdoba, Spain., Gálvez-Moreno MA; Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain; Endocrinology and Nutrition Service, Reina Sofia University Hospital, Córdoba, Spain., Gahete MD; Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain; Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Córdoba, Spain; Reina Sofia University Hospital, Córdoba, Spain., Ibáñez-Costa A; Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain; Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Córdoba, Spain; Reina Sofia University Hospital, Córdoba, Spain. Electronic address: b12ibcoa@uco.es., Luque RM; Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain; Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Córdoba, Spain; Reina Sofia University Hospital, Córdoba, Spain. Electronic address: raul.luque@uco.es., Castaño JP; Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain; Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Córdoba, Spain; Reina Sofia University Hospital, Córdoba, Spain. Electronic address: justo@uco.es.
Jazyk: angličtina
Zdroj: Translational research : the journal of laboratory and clinical medicine [Transl Res] 2023 Jan; Vol. 251, pp. 63-73. Date of Electronic Publication: 2022 Jul 24.
DOI: 10.1016/j.trsl.2022.07.005
Abstrakt: Dysregulation of the splicing machinery is emerging as a hallmark in cancer due to its association with multiple dysfunctions in tumor cells. Inappropriate function of this machinery can generate tumor-driving splicing variants and trigger oncogenic actions. However, its role in pancreatic neuroendocrine tumors (PanNETs) is poorly defined. In this study we aimed to characterize the expression pattern of a set of splicing machinery components in PanNETs, and their relationship with aggressiveness features. A qPCR-based array was first deployed to determine the expression levels of components of the major (n = 13) and minor spliceosome (n = 4) and associated splicing factors (n = 27), using a microfluidic technology in 20 PanNETs and non-tumoral adjacent samples. Subsequently, in vivo and in vitro models were applied to explore the pathophysiological role of NOVA1. Expression analysis revealed that a substantial proportion of splicing machinery components was altered in tumors. Notably, key splicing factors were overexpressed in PanNETs samples, wherein their levels correlated with clinical and malignancy features. Using in vivo and in vitro assays, we demonstrate that one of those altered factors, NOVA1, is tightly related to cell proliferation, alters pivotal signaling pathways and interferes with responsiveness to drug treatment in PanNETs, suggesting a role for this factor in the aggressiveness of these tumors and its suitability as therapeutic target. Altogether, our results unveil a severe alteration of the splicing machinery in PanNETs and identify the putative relevance of NOVA1 in tumor development/progression, which could provide novel avenues to develop diagnostic biomarkers and therapeutic tools for this pathology.
(Copyright © 2022 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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