Tumor suppressor role of RBM22 in prostate cancer acting as a dual-factor regulating alternative splicing and transcription of key oncogenic genes.

Autor: Jiménez-Vacas JM; Maimonides Institute for Biomedical Research of Córdoba (IMIBIC), Cordoba, Spain; Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Cordoba, Spain; Hospital Universitario Reina Sofía (HURS), Cordoba, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, (CIBERobn), Cordoba, Spain. Electronic address: b12jivaj@uco.es., Montero-Hidalgo AJ; Maimonides Institute for Biomedical Research of Córdoba (IMIBIC), Cordoba, Spain; Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Cordoba, Spain; Hospital Universitario Reina Sofía (HURS), Cordoba, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, (CIBERobn), Cordoba, Spain., Gómez-Gómez E; Maimonides Institute for Biomedical Research of Córdoba (IMIBIC), Cordoba, Spain; Hospital Universitario Reina Sofía (HURS), Cordoba, Spain; Urology Service, HURS/IMIBIC, Cordoba, Spain., Sáez-Martínez P; Maimonides Institute for Biomedical Research of Córdoba (IMIBIC), Cordoba, Spain; Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Cordoba, Spain; Hospital Universitario Reina Sofía (HURS), Cordoba, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, (CIBERobn), Cordoba, Spain., Fuentes-Fayos AC; Maimonides Institute for Biomedical Research of Córdoba (IMIBIC), Cordoba, Spain; Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Cordoba, Spain; Hospital Universitario Reina Sofía (HURS), Cordoba, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, (CIBERobn), Cordoba, Spain., Closa A; The John Curtin School of Medical Research, Australian National University, Canberra, Australia; EMBL Australia Partner Laboratory Network at the Australian National University, Canberra, Australia., González-Serrano T; Maimonides Institute for Biomedical Research of Córdoba (IMIBIC), Cordoba, Spain; Hospital Universitario Reina Sofía (HURS), Cordoba, Spain; Anatomical Pathology Service, HURS, Cordoba, Spain., Martínez-López A; Hospital Universitario Reina Sofía (HURS), Cordoba, Spain; Anatomical Pathology Service, HURS, Cordoba, Spain., Sánchez-Sánchez R; Maimonides Institute for Biomedical Research of Córdoba (IMIBIC), Cordoba, Spain; Hospital Universitario Reina Sofía (HURS), Cordoba, Spain; Anatomical Pathology Service, HURS, Cordoba, Spain., López-Casas PP; Prostate Cancer Clinical Research Unit, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain., Sarmento-Cabral A; Maimonides Institute for Biomedical Research of Córdoba (IMIBIC), Cordoba, Spain; Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Cordoba, Spain; Hospital Universitario Reina Sofía (HURS), Cordoba, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, (CIBERobn), Cordoba, Spain., Olmos D; Prostate Cancer Clinical Research Unit, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain., Eyras E; The John Curtin School of Medical Research, Australian National University, Canberra, Australia; EMBL Australia Partner Laboratory Network at the Australian National University, Canberra, Australia; Catalan Institution for Research and Advanced Studies. Barcelona, Spain; Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain., Castaño JP; Maimonides Institute for Biomedical Research of Córdoba (IMIBIC), Cordoba, Spain; Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Cordoba, Spain; Hospital Universitario Reina Sofía (HURS), Cordoba, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, (CIBERobn), Cordoba, Spain., Gahete MD; Maimonides Institute for Biomedical Research of Córdoba (IMIBIC), Cordoba, Spain; Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Cordoba, Spain; Hospital Universitario Reina Sofía (HURS), Cordoba, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, (CIBERobn), Cordoba, Spain., Luque RM; Maimonides Institute for Biomedical Research of Córdoba (IMIBIC), Cordoba, Spain; Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Cordoba, Spain; Hospital Universitario Reina Sofía (HURS), Cordoba, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, (CIBERobn), Cordoba, Spain. Electronic address: raul.luque@uco.es.
Jazyk: angličtina
Zdroj: Translational research : the journal of laboratory and clinical medicine [Transl Res] 2023 Mar; Vol. 253, pp. 68-79. Date of Electronic Publication: 2022 Sep 09.
DOI: 10.1016/j.trsl.2022.08.016
Abstrakt: Prostate cancer (PCa) is one of the leading causes of cancer-related deaths among men. Consequently, the identification of novel molecular targets for treatment is urgently needed to improve patients' outcomes. Our group recently reported that some elements of the cellular machinery controlling alternative-splicing might be useful as potential novel therapeutic tools against advanced PCa. However, the presence and functional role of RBM22, a key spliceosome component, in PCa remains unknown. Therefore, RBM22 levels were firstly interrogated in 3 human cohorts and 2 preclinical mouse models (TRAMP/Pbsn-Myc). Results were validated in in silico using 2 additional cohorts. Then, functional effects in response to RBM22 overexpression (proliferation, migration, tumorspheres/colonies formation) were tested in PCa models in vitro (LNCaP, 22Rv1, and PC-3 cell-lines) and in vivo (xenograft). High throughput methods (ie, RNA-seq, nCounter PanCancer Pathways Panel) were performed in RBM22 overexpressing cells and xenograft tumors. We found that RBM22 levels were down-regulated (mRNA and protein) in PCa samples, and were inversely associated with key clinical aggressiveness features. Consistently, a gradual reduction of RBM22 from non-tumor to poorly differentiated PCa samples was observed in transgenic models (TRAMP/Pbsn-Myc). Notably, RBM22 overexpression decreased aggressiveness features in vitro, and in vivo. These actions were associated with the splicing dysregulation of numerous genes and to the downregulation of critical upstream regulators of cell-cycle (i.e., CDK1/CCND1/EPAS1). Altogether, our data demonstrate that RBM22 plays a critical pathophysiological role in PCa and invites to suggest that targeting negative regulators of RBM22 expression/activity could represent a novel therapeutic strategy to tackle this disease.
(Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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