title: Increased liver carcinogenesis and enrichment of stem cell properties in livers of Dickkopf 2 (Dkk2) deleted mice.
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.
authors.affiliation: Department of Internal Medicine I, University of Regensburg, Regensburg, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Maass
authors.affiliation: I. Department of Medicine, University Medical Center Mainz, Mainz, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Marquardt
authors.affiliation: Cancer Biology Program, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Ju-Seog
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Department of Informatics, Johannes Gutenberg University Mainz, Mainz, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Krupp
authors.affiliation: I. Department of Medicine, University Medical Center Mainz, Mainz, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Scholz-Kreisel
authors.affiliation: Institute of Pathology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Carolin
authors.initials: C
authors.lastname: Mogler
authors.affiliation: Institute of Pathology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.affiliation: Department of Internal Medicine I, University of Regensburg, Regensburg, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Müller
authors.affiliation: Laboratory of Mammalian Genes and Development, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Heiner
authors.initials: H
authors.lastname: Westphal
authors.affiliation: I. Department of Medicine, University Medical Center Mainz, Mainz, Germany.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Galle
authors.affiliation: Department of Internal Medicine I, University of Regensburg, Regensburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Teufel
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics* / Q000473:pathology; D053263:Gene Regulatory Networks / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014411:Neoplastic Stem Cells / Q000473:pathology*; D060449:Wnt Signaling Pathway / Q000235:genetics
chemical_list: C498622:DKK2 protein, human; C405060:Dkk2 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins
keywords: Dkk2; genetic signature; prognostic signature; stem cells; transcriptomics profiling
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