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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Med. | doi: 10.3389/fmed.2019.00179

IGF2 mRNA binding protein 2 transgenic mice are more prone to develop a ductular reaction and to progress towards cirrhosis

 Beate Czepukojc1, Ahmad Barghash2, Sascha Tierling1, Yvette Simon1, Christina Körbel3, Cristina Cadenas4,  Noemi van Hul5,  Agapios Sachinidis6,  Jan G G. Hengstler4, Volkhard Helms1, Matthias W. Laschke3, Jörn Walter1, Johannes Haybaeck7, Isabelle Leclercq8,  Alexandra K. Kiemer1 and  Sonja M. Kessler1, 8, 9*
  • 1Saarland University, Germany
  • 2German jordanian university, Jordan
  • 3Saarland University Hospital, Germany
  • 4Leibniz Research Centre for Working Environment and Human Factors (IfADo), Germany
  • 5Karolinska Institute (KI), Sweden
  • 6University of Cologne, Germany
  • 7Otto von Guericke University Magdeburg, Germany
  • 8Catholic University of Louvain, Belgium
  • 9Medical University of Graz, Austria

The insulin-like growth factor 2 (IGF2) mRNA binding proteins (IMPs/IGF2BPs) IMP1 and 3 are regarded as oncofetal proteins, whereas the hepatic IMP2 expression in adults is controversially discussed. The splice variant IMP2-2/p62 promotes steatohepatitis and hepatocellular carcinoma. Aim of this study was to clarify whether IMP2 is expressed in the adult liver and influences progression toward cirrhosis.
IMP2 was expressed at higher levels in embryonic compared to adult tissues as quantified in embryonic, newborn, and adult C57BL/6J mouse livers and suggested by analysis of publicly available human data. In an IMP2-2 transgenic mouse model microarray and qPCR analyses revealed increased expression of liver progenitor cell (LPC) markers Bex1, Prom1, Spp1, and Cdh1 indicating a de-differentiated liver cell phenotype. Induction of these LPC markers was confirmed in human cirrhotic tissue datasets. The LPC marker Spp1 has been described to play a major role in fibrogenesis. Thus, DNA methylation was investigated in order to decipher the regulatory mechanism of Spp1 induction. In IMP2-2 transgenic mouse livers single CpG sites were differentially methylated, as quantified by amplicon sequencing, whereas human HCC samples of a human publicly available dataset showed promoter hypomethylation. In order to study the impact of IMP2 on fibrogenesis in the context of steatohepatitis wild-type or IMP2-2 transgenic mice were fed either a methionine-choline deficient (MCD) or a control diet for 2-12 weeks. MCD-fed IMP2-2 transgenic mice showed a higher incidence of ductular reaction (DR), accompanied by hepatic stellate cell activation, extracellular matrix (ECM) deposition, and induction of the LPC markers Spp1, Cdh1, and Afp suggesting the occurrence of de-differentiated cells in transgenic livers. In human cirrhotic samples IMP2 overexpression correlated with LPC marker and ECM component expression. Progression of liver disease was induced by combined MCD and diethylnitrosamine (DEN) treatment. Combined MCD-DEN treatment resulted in shorter survival of IMP2-2 transgenic compared to wild-type mice. Only IMP2-2 transgenic livers progressed to cirrhosis, which was accompanied by a strong DR.
In conclusion, IMP2 is an oncofetal protein in the liver that promotes DR characterized by de-differentiated cells towards steatohepatitis-associated cirrhosis development with poor survival.

Keywords: Liver cancer (LC), stem cell, de-differentiation, Oval cell, HCC, Fibrosis

Received: 17 Jan 2019; Accepted: 23 Jul 2019.

Edited by:

Salvatore Piscuoglio, University Hospital of Basel, Switzerland

Reviewed by:

Laurent G. Dollé, Biothèque wallonie bruxelles, Belgium
Caner Ercan, Faculty of Medicine, Gazi University, Turkey  

Copyright: © 2019 Czepukojc, Barghash, Tierling, Simon, Körbel, Cadenas, van Hul, Sachinidis, Hengstler, Helms, Laschke, Walter, Haybaeck, Leclercq, Kiemer and Kessler. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Sonja M. Kessler, Saarland University, Saarbrücken, 66123, Saarland, Germany, s.kessler@mx.uni-saarland.de