Hualin Wang1,2, Bouchra Lekbaby1,2, Nadim Fares3, Jeremy Augustin1,2, Tarik Attout1,2, Aurelie Schnuriger1,2,4, Anne-Marie Cassard5, Ganna Panasyuk6,7, Gabriel Perlemuter5,8, Ivan Bieche9, Sophie Vacher9, Janick Selves10, Jean-Marie Péron10, Brigitte Bancel3, Philippe Merle3, Dina Kremsdorf1,2, Janet Hall3, Isabelle Chemin3, Patrick Soussan11,12,13. 1. INSERM U1135, Centre d'immunologie et de maladie infectieuse, 91 boulevard de l'Hôpital, 75013, Paris, France. 2. Sorbonne Université, Paris, France. 3. Centre de Recherche en Cancérologie de Lyon, UMR INSERM 1052, CNRS 5286, Lyon Cedex 03, France. 4. Département de Virologie, Hôpitaux Est Parisien, Paris, France. 5. Faculté de médecine Paris-Sud, Université Paris-Sud, 94270, Kremlin-Bicêtre, France. 6. Institut Necker-Enfants Malades, Université Paris Descartes, Paris, France. 7. INSERM U1151/CNRS Unité Mixte de Recherche (UMR) 8253, Paris, France. 8. AP-HP, Hôpital Antoine Béclère, Service d'hépato-gastroentérologie, 92140, Clamart, France. 9. Institut Curie-Hôpital, Paris, France. 10. Institut Universitaire de Cancérologie de Toulouse Oncopole, Université Paul Sabatier, Toulouse, France. 11. INSERM U1135, Centre d'immunologie et de maladie infectieuse, 91 boulevard de l'Hôpital, 75013, Paris, France. patrick.soussan@inserm.fr. 12. Sorbonne Université, Paris, France. patrick.soussan@inserm.fr. 13. Département de Virologie, Hôpitaux Est Parisien, Paris, France. patrick.soussan@inserm.fr.
Abstract
PURPOSE: Trans-acting splicing factors (SF) shape the eukaryotic transcriptome by regulating alternative splicing (AS). This process is recurrently modulated in liver cancer suggesting its direct contribution to the course of liver disease. The aim of our study was to investigate the relationship between the regulation of SFs expression and liver damage. METHODS: The expression profile of 10 liver-specific SF and the AS events of 7 genes associated with liver disorders was assessed by western-blotting in 6 murine models representing different stages of liver damage, from inflammation to hepatocellular carcinoma (HCC). Relevant SFs (PSF, SRSF3, and SRSF6) and target genes (INSR, SRSF3, and SLK) modulated in mice were investigated in a cohort of 179 HCC patients. RESULTS: Each murine model of liver disease was characterized by a unique SF expression profile. Changes in the SF profile did not affect AS events of the selected genes despite the presence of corresponding splicing sites. In human HCC expression of SFs, including the tumor-suppressor SRSF3, and AS regulation of genes studied were frequently upregulated in tumor versus non-tumor tissues. Risk of tumor recurrence positively correlated with AS isoform of the INSR gene. In contrast, increased levels of SFs expression correlated with an extended overall survival of patients. CONCLUSIONS: Dysregulation of SF expression is an early event occurring during liver injury and not just at the stage of HCC. Besides impacting on AS regulation, overexpression of SF may contribute to preserving hepatocyte homeostasis during liver pathogenesis.
PURPOSE: Trans-acting splicing factors (SF) shape the eukaryotic transcriptome by regulating alternative splicing (AS). This process is recurrently modulated in liver cancer suggesting its direct contribution to the course of liver disease. The aim of our study was to investigate the relationship between the regulation of SFs expression and liver damage. METHODS: The expression profile of 10 liver-specific SF and the AS events of 7 genes associated with liver disorders was assessed by western-blotting in 6 murine models representing different stages of liver damage, from inflammation to hepatocellular carcinoma (HCC). Relevant SFs (PSF, SRSF3, and SRSF6) and target genes (INSR, SRSF3, and SLK) modulated in mice were investigated in a cohort of 179 HCC patients. RESULTS: Each murine model of liver disease was characterized by a unique SF expression profile. Changes in the SF profile did not affect AS events of the selected genes despite the presence of corresponding splicing sites. In human HCC expression of SFs, including the tumor-suppressor SRSF3, and AS regulation of genes studied were frequently upregulated in tumor versus non-tumor tissues. Risk of tumor recurrence positively correlated with AS isoform of the INSR gene. In contrast, increased levels of SFs expression correlated with an extended overall survival of patients. CONCLUSIONS: Dysregulation of SF expression is an early event occurring during liver injury and not just at the stage of HCC. Besides impacting on AS regulation, overexpression of SF may contribute to preserving hepatocyte homeostasis during liver pathogenesis.
Entities:
Keywords:
Alternative splicing; Hepatocellular carcinoma; Liver disease; Splicing factors