Please use this identifier to cite or link to this item: doi:10.22028/D291-30772
Title: IGF2 mRNA Binding Protein 2 Transgenic Mice Are More Prone to Develop a Ductular Reaction and to Progress Toward Cirrhosis
Author(s): Czepukojc, Beate
Abuhaliema, Ali
Barghash, Ahmad
Tierling, Sascha
Naß, Norbert
Simon, Yvette
Körbel, Christina
Cadenas, Cristina
van Hul, Noemi
Sachinidis, Agapios
Hengstler, Jan G
Helms, Volkhard
Laschke, Matthias W.
Walter, Jörn
Haybaeck, Johannes
Leclercq, Isabelle
Kiemer, Alexandra
Kessler, Sonja M.
Language: English
Title: Frontiers in Medicine
Volume: 6
Publisher/Platform: Frontiers
Year of Publication: 2019
Free key words: liver cancer
stem cell
de-differentiation
oval cell
HCC
fibrosis
DDC notations: 500 Science
610 Medicine and health
Publikation type: Journal Article
Abstract: 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 strong DR. In conclusion, IMP2 is an oncofetal protein in the liver that promotes DR characterized by de-differentiated cells toward steatohepatitis-associated cirrhosis development with poor survival.
DOI of the first publication: 10.3389/fmed.2019.00179
Link to this record: urn:nbn:de:bsz:291--ds-307723
hdl:20.500.11880/29040
http://dx.doi.org/10.22028/D291-30772
ISSN: 2296-858X
Date of registration: 22-Apr-2020
Description of the related object: Supplementary Material
Related object: https://www.frontiersin.org/articles/10.3389/fmed.2019.00179/full#supplementary-material
Faculty: NT - Naturwissenschaftlich- Technische Fakultät
M - Medizinische Fakultät
Department: NT - Biowissenschaften
NT - Pharmazie
M - Chirurgie
Professorship: NT - Prof. Dr. Volkhard Helms
NT - Prof. Dr. Alexandra K. Kiemer
NT - Prof. Dr. Jörn Walter
M - Prof. Dr. Michael D. Menger
Collections:SciDok - Der Wissenschaftsserver der Universität des Saarlandes

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