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Hepatology International
Published in: Hepatology International 4/2019

01-07-2019 | Hepatocellular Carcinoma | Original Article

Alteration of splicing factors’ expression during liver disease progression: impact on hepatocellular carcinoma outcome

Authors: Hualin Wang, Bouchra Lekbaby, Nadim Fares, Jeremy Augustin, Tarik Attout, Aurelie Schnuriger, Anne-Marie Cassard, Ganna Panasyuk, Gabriel Perlemuter, Ivan Bieche, Sophie Vacher, Janick Selves, Jean-Marie Péron, Brigitte Bancel, Philippe Merle, Dina Kremsdorf, Janet Hall, Isabelle Chemin, Patrick Soussan

Published in: Hepatology International | Issue 4/2019

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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.
Appendix
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Metadata
Title
Alteration of splicing factors’ expression during liver disease progression: impact on hepatocellular carcinoma outcome
Authors
Hualin Wang
Bouchra Lekbaby
Nadim Fares
Jeremy Augustin
Tarik Attout
Aurelie Schnuriger
Anne-Marie Cassard
Ganna Panasyuk
Gabriel Perlemuter
Ivan Bieche
Sophie Vacher
Janick Selves
Jean-Marie Péron
Brigitte Bancel
Philippe Merle
Dina Kremsdorf
Janet Hall
Isabelle Chemin
Patrick Soussan
Publication date
01-07-2019
Publisher
Springer India
Published in
Hepatology International / Issue 4/2019
Print ISSN: 1936-0533
Electronic ISSN: 1936-0541
DOI
https://doi.org/10.1007/s12072-019-09950-7

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