title: IMP2/p62 induces genomic instability and an aggressive hepatocellular carcinoma phenotype.
abstract: Hepatocellular carcinoma (HCC) represents the third leading cause of cancer-related deaths and commonly develops in inflammatory environments. The IGF2 mRNA-binding protein IMP2-2/IGF2BP2-2/p62 was originally identified as an autoantigen in HCC. Aim of this study was to investigate a potential pathophysiological role of p62 in hepatocarcinogenesis. Human HCC tissue showed overexpression of IMP2, which strongly correlated with the fetal markers AFP and DLK1/Pref-1/FA-1 and was particularly elevated in tumors with stem-like features and hypervascularization. Molecular classification of IMP2-overexpressing tumors revealed an aggressive phenotype. Livers of mice overexpressing the IMP2 splice variant p62 highly expressed the stem cell marker DLK1 and secreted DLK1 into the blood. p62 was oncogenic: diethylnitrosamine (DEN)-treated p62 transgenic mice exhibited a higher tumor incidence and multiplicity than wild types. Tumors of transgenics showed a more aggressive and stem-like phenotype and displayed more oncogenic chromosomal aberrations determined with aCGH analysis. DEN-treated p62 transgenic mice exhibited distinct signs of inflammation, such as inflammatory cytokine expression and oxidative stress markers, that is, thiobarbituric acid-reactive substance (TBARS) levels. Reactive oxygen species (ROS) production was elevated in HepG2 cells, which either overexpressed p62 or were treated with DLK1. p62 induced this ROS production by a DLK1-dependent induction and activation of the small Rho-GTPase RAC1, activating NADPH oxidase and being overexpressed in human HCC. Our data indicate that p62/IMP2 promotes hepatocarcinogenesis by an amplification of inflammation.
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Saarland University, Saarbruecken, Germany.|Institute of Pathology, Medical University of Graz, Graz, Austria.
authors.forename: S M
authors.initials: SM
authors.lastname: Kessler
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Saarland University, Saarbruecken, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Laggai
authors.affiliation: Center for Bioinformatics, Saarland University, Saarbruecken, Germany.|Saarbruecken Graduate School of Computer Science, Saarbruecken, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Barghash
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Saarland University, Saarbruecken, Germany.
authors.forename: C S
authors.initials: CS
authors.lastname: Schultheiss
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria.
authors.forename: E
authors.initials: E
authors.lastname: Lederer
authors.affiliation: Institute of Human Genetics, Medical University of Graz, Graz, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Artl
authors.affiliation: Center for Bioinformatics, Saarland University, Saarbruecken, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Helms
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria.
authors.forename: J
authors.identifier: http://orcid.org/0000-0001-5518-3359
authors.initials: J
authors.lastname: Haybaeck
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Saarland University, Saarbruecken, Germany.
authors.forename: A K
authors.initials: AK
authors.lastname: Kiemer
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000556:secondary; D042822:Genomic Instability; D056945:Hep G2 Cells; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology; D008114:Liver Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics* / Q000556:secondary; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000502:physiology; D009479:Neuropeptides / Q000378:metabolism; D018384:Oxidative Stress; D010641:Phenotype; D016601:RNA-Binding Proteins / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D002135:Calcium-Binding Proteins; C512925:Dlk1 protein, mouse; C559768:IGF2BP2 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D009479:Neuropeptides; D016601:RNA-Binding Proteins; C484602:Rac1 protein, mouse; D017382:Reactive Oxygen Species; D020830:rac1 GTP-Binding Protein