Oncotarget

Research Papers:

Increased liver carcinogenesis and enrichment of stem cell properties in livers of Dickkopf 2 (Dkk2) deleted mice

Thorsten Maass _, Jens Marquardt, Ju-Seog Lee, Markus Krupp, Peter Scholz-Kreisel, Carolin Mogler, Peter Schirmacher, Martina Müller, Heiner Westphal, Peter R. Galle and Andreas Teufel

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Oncotarget. 2016; 7:28903-28913. https://doi.org/10.18632/oncotarget.3293

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Abstract

Thorsten Maass1, Jens Marquardt2, Ju-Seog Lee3, Markus Krupp4, Peter Scholz-Kreisel2, Carolin Mogler5, Peter Schirmacher5, Martina Müller1, Heiner Westphal6, Peter R. Galle2, Andreas Teufel1

1Department of Internal Medicine I, University of Regensburg, Regensburg, Germany

2I. Department of Medicine, University Medical Center Mainz, Mainz, Germany

3Cancer Biology Program, MD Anderson Cancer Center, Houston, TX, USA

4Department of Informatics, Johannes Gutenberg University Mainz, Mainz, Germany

5Institute of Pathology, University of Heidelberg, Heidelberg, Germany

6Laboratory of Mammalian Genes and Development, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA

Correspondence to:

Andreas Teufel, email: andreas.teufel@ukr.de

Keywords: transcriptomics profiling, prognostic signature, genetic signature, Dkk2, stem cells

Received: January 13, 2015     Accepted: February 08, 2015     Published: March 16, 2015

ABSTRACT

Dkk2 a antagonist of the Wnt/β-catenin-signaling pathway was shown to be silenced in diverse cancers. More recent data indicate that Dkk family members may also possess functions independent of Wnt-signaling during carcinogenesis. The detailed biological function of Dkks and its relevance for liver cancer is unknown. We analyzed the effects of a genetic deletion of Dkk2 (Dkk2−/−) in a hepatocarcinogenesis model using DEN/Phenobarbital. Untreated Dkk2−/− animals, showed considerable atypia with variation of hepatocyte size and chromatin density. In livers of Dkk2−/− mice nodule formation was seen at 9 months of age with focal loss of trabecular architecture and atypical hepatocytes and after DEN induction Dkk2−/− mice developed significantly more liver tumors compared to controls. Whole transcriptome analysis of untreated Dkk2−/− liver tissue revealed a Dkk2-dependent genetic network involving Wnt/β-Catenin but also multiple additional oncogenic factors, such as e.g. Pdgf-b, Gdf-15 and Hnf4a. Dkk2−/− tumor cells showed a significant deregulation of stemness genes associated with enhanced colony forming properties. Integration of the Dkk2−/− signature into human data was strongly associated with patients survival. Dkk2 deletion results in alterations of liver morphology leading to an increased frequency of liver cancer. The associated genetic changes included factors not primarily related to Wnt/β-Catenin-signaling and correlated with the clinical outcome of HCC-patients.


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