Alteration of splicing factors’ expression during liver disease progression: impact on hepatocellular carcinoma outcome
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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.
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.
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.
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.
KeywordsAlternative splicing Splicing factors Liver disease Hepatocellular carcinoma
Serine/arginine-rich splicing factor
Heterogeneous nuclear ribonucleoprotein
Proline-rich splicing factor
Splicing factor 1
Non-alcoholic fatty liver disease
Alcohol liver disease
Diacylglycerol kinase, delta
TNF receptor superfamily member 6
Collagen, type XVIII, alpha 1
Serine/arginine-rich splicing factor 3
Ubiquitin specific peptidase 4
We thank Drs J. Pol, P. De La Grange, G. Wang and M. Dutertre for helpful scientific discussion. We thank animal facilities platform from Pitié and Broussais Universities. We thank P3S platform of Pitié University. We also thank the TCGA Research Network (http://cancergenome.nih.gov/) for HCC data.
Experimental conception and design of these experiments HW, JH, IC, and PS. Conduction the experiments: HW, BL, NF, ACS, GP, JA, IB, SV, and PS. Analysis of the data: HW, NF, TA, AS, GP, DK, JH, IC and PS. Provide biological samples: JS, JMP, BB, PM. Wrote the manuscript: HW, JH, DK and PS.
This work was supported by grants from INSERM, Sorbonne Université, Fondation ARC (Grant number M17JRAS009) and ANRS (Grant number ECTZ22204). HW was supported by the China Scholarship Council.
Compliance with ethical standards
Conflicts of interest
Hualin Wang, Bouchra Lekbaby, Nadim Fares, Jeremy Augustin, Tarik Attout, Aurelie Schnuriger, Anne-Marie Cassard, Ganna Panasyuk, Gabriel Perlemute, Ivan Bieche, Sophie Vacher, Janick Selves, Jean-Marie Péron, Brigitte Bancel, Philippe, Dina Kremsdorf, Janet Hall, Isabelle Chemin, Patrick Soussan have no conflict of interest to declare.
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