title: Deletion of serine/arginine-rich splicing factor 3 in hepatocytes predisposes to hepatocellular carcinoma in mice.
abstract: Alterations in RNA splicing are associated with cancer, but it is not clear whether they result from malignant transformation or have a causative role. We show here that hepatocyte-specific deletion of serine/arginine-rich splicing factor 3 (SRSF3) impairs hepatocyte maturation and metabolism in early adult life, and mice develop spontaneous hepatocellular carcinoma (HCC) with aging. Tumor development is preceded by chronic liver disease with progressive steatosis and fibrosis. SRSF3 protects mice against CCl4 -induced fibrosis and carcinogenesis and suppresses inclusion of the profibrogenic EDA exon in fibronectin 1. Loss of SRSF3 increases expression of insulin-like growth factor 2 and the A-isoform of the insulin receptor, allowing aberrant activation of mitogenic signaling, promotes aberrant splicing and expression of epithelial to mesenchymal transition (EMT) genes, and activates Wnt/β-catenin signaling leading to c-Myc induction. Finally, SRSF3 expression is either decreased or the protein mislocalized in human HCC.
  
  
  CONCLUSIONS
  Our data suggest a potential role for SRSF3 in preventing hepatic carcinogenesis by regulating splicing to suppress fibrosis, mitogenic splicing, and EMT. Thus, these mice may provide an attractive model to discover the pathogenic mechanisms linking aberrant pre-messenger RNA splicing with liver damage, fibrosis, and HCC.
authors.affiliation: Medical Research Service, VA San Diego Healthcare System, San Diego, CA; Department of Medicine, Division of Endocrinology and Metabolism, University of California San Diego, La Jolla, CA.
authors.forename: Supriya
authors.initials: S
authors.lastname: Sen
authors.forename: Magda
authors.initials: M
authors.lastname: Langiewicz
authors.forename: Hassan
authors.initials: H
authors.lastname: Jumaa
authors.forename: Nicholas J G
authors.initials: NJ
authors.lastname: Webster
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D005234:Fatty Liver / Q000235:genetics; D005260:Female; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008060:Lipodystrophy / Q000235:genetics; D008103:Liver Cirrhosis / Q000235:genetics; D008113:Liver Neoplasms / Q000235:genetics*; D008297:Male; D018345:Mice, Knockout; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D012326:RNA Splicing; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D000068103:Serine-Arginine Splicing Factors; D013002:Somatomedins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D015415:Biomarkers; D016271:Proto-Oncogene Proteins c-myc; D016601:RNA-Binding Proteins; C491388:SRSF3 protein, human; D013002:Somatomedins; C106161:Srsf3 protein, mouse; D051176:beta Catenin; D000068103:Serine-Arginine Splicing Factors