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This study aimed to comprehensively characterize the spliceosomal profile and explore its role in HCC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Expression levels of 70 selected spliceosome components and splicing factors and clinical implications were evaluated in two retrospective and six in silico HCC cohorts. Functional, molecular and mechanistic studies were implemented in three cell lines (HepG2, Hep3B and SNU\u2010387) and preclinical Hep3B\u2010induced xenograft tumours.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Spliceosomal dysregulations were consistently found in retrospective and in silico cohorts.\n                      <jats:italic>EIF4A3<\/jats:italic>\n                      ,\n                      <jats:italic>RBM3<\/jats:italic>\n                      ,\n                      <jats:italic>ESRP2<\/jats:italic>\n                      and\n                      <jats:italic>SRPK1<\/jats:italic>\n                      were the most dysregulated spliceosome elements in HCC.\n                      <jats:italic>EIF4A3<\/jats:italic>\n                      expression was associated with decreased survival and greater recurrence. Plasma EIF4A3 levels were significantly elevated in HCC patients. In vitro EIF4A3\u2010silencing (or pharmacological inhibition) resulted in reduced aggressiveness, and hindered xenograft\u2010tumours growth in vivo, whereas EIF4A3 overexpression increased tumour aggressiveness. EIF4A3\u2010silencing altered the expression and splicing of key HCC\u2010related genes, specially FGFR4.\n                      <jats:italic>EIF4A3<\/jats:italic>\n                      \u2010silencing blocked the cellular response to the natural ligand of FGFR4, FGF19. Functional consequences of\n                      <jats:italic>EIF4A3<\/jats:italic>\n                      \u2010silencing were mediated by FGFR4 splicing as the restoration of non\u2010spliced FGFR4 full\u2010length version blunted these effects, and FGFR4 inhibition did not exert further effects in\n                      <jats:italic>EIF4A3<\/jats:italic>\n                      \u2010silenced cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Splicing machinery is strongly dysregulated in HCC, providing a source of new diagnostic, prognostic and therapeutic options in HCC. EIF4A3 is consistently elevated in HCC patients and associated with tumour aggressiveness and mortality, through the modulation of FGFR4 splicing.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ctm2.1102","type":"journal-article","created":{"date-parts":[[2022,11,24]],"date-time":"2022-11-24T08:03:38Z","timestamp":1669277018000},"source":"Crossref","is-referenced-by-count":29,"title":["Spliceosomal profiling identifies EIF4A3 as a novel oncogene in hepatocellular carcinoma acting through the modulation of FGFR4 splicing"],"prefix":"10.1002","volume":"12","author":[{"given":"Juan L.","family":"L\u00f3pez\u2010C\u00e1novas","sequence":"first","affiliation":[{"name":"Maimonides Biomedical Research Institute of Cordoba (IMIBIC)  Cordoba Spain"},{"name":"Department of Cell Biology Physiology and Immunology University of C\u00f3rdoba  Cordoba Spain"},{"name":"Reina Sof\u00eda University Hospital  Cordoba Spain"},{"name":"CIBER Pathophysiology of Obesity and Nutrition (CIBERobn)  Cordoba Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Herm\u00e1n\u2010S\u00e1nchez","sequence":"additional","affiliation":[{"name":"Maimonides Biomedical Research Institute of Cordoba (IMIBIC)  Cordoba Spain"},{"name":"Department of Cell Biology Physiology and Immunology University of C\u00f3rdoba  Cordoba Spain"},{"name":"Reina Sof\u00eda University Hospital  Cordoba Spain"},{"name":"CIBER Pathophysiology of Obesity and Nutrition (CIBERobn)  Cordoba Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Trinidad","family":"Moreno\u2010Montilla","sequence":"additional","affiliation":[{"name":"Maimonides Biomedical Research Institute of Cordoba (IMIBIC)  Cordoba Spain"},{"name":"Department of Cell Biology Physiology and Immunology University of C\u00f3rdoba  Cordoba Spain"},{"name":"Reina Sof\u00eda University Hospital  Cordoba Spain"},{"name":"CIBER Pathophysiology of Obesity and Nutrition (CIBERobn)  Cordoba 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