title: Tumor promotion and inhibition by phenobarbital in livers of conditional Apc-deficient mice.
abstract: Activation of Wnt/β-catenin signaling is important for human and rodent hepatocarcinogenesis. In mice, the tumor promoter phenobarbital (PB) selects for hepatocellular tumors with activating β-catenin mutations via constitutive androstane receptor activation. PB-dependent tumor promotion was studied in mice with genetic inactivation of Apc, a negative regulator of β-catenin, to circumvent the problem of randomly induced mutations by chemical initiators and to allow monitoring of PB- and Wnt/β-catenin-dependent tumorigenesis in the absence of unknown genomic alterations. Moreover, the study was designed to investigate PB-induced proliferation of liver cells with activated β-catenin. PB treatment provided Apc-deficient hepatocytes with only a minor proliferative advantage, and additional connexin 32 deficiency did not affect the proliferative response. PB significantly promoted the outgrowth of Apc-deficient hepatocellular adenoma (HCA), but simultaneously inhibited the formation of Apc-deficient hepatocellular carcinoma (HCC). The probability of tumor promotion by PB was calculated to be much lower for hepatocytes with loss of Apc, as compared to mutational β-catenin activation. Comprehensive transcriptomic and phosphoproteomic characterization of HCA and HCC revealed molecular details of the two tumor types. HCC were characterized by a loss of differentiated hepatocellular gene expression, enhanced proliferative signaling, and massive over-activation of Wnt/β-catenin signaling. In conclusion, PB exerts a dual role in liver tumor formation by promoting the growth of HCA but inhibiting the growth of HCC. Data demonstrate that one and the same compound can produce opposite effects on hepatocarcinogenesis, depending on context, highlighting the necessity to develop a more differentiated view on the tumorigenicity of this model compound.
authors.affiliation: Department of Food Safety, Federal Institute for Risk Assessment, Max-Dohrn-Str. 8-10, 10589, Berlin, Germany. Albert.Braeuning@bfr.bund.de.|Department of Toxicology, University of Tuebingen, Wilhelmstr. 56, 72074, Tuebingen, Germany. Albert.Braeuning@bfr.bund.de.
authors.forename: Albert
authors.initials: A
authors.lastname: Braeuning
authors.affiliation: Department of Toxicology, University of Tuebingen, Wilhelmstr. 56, 72074, Tuebingen, Germany.
authors.forename: Alina
authors.initials: A
authors.lastname: Gavrilov
authors.affiliation: Department of Toxicology, University of Tuebingen, Wilhelmstr. 56, 72074, Tuebingen, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Geissler
authors.affiliation: Department of Toxicology, University of Tuebingen, Wilhelmstr. 56, 72074, Tuebingen, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Wenz
authors.affiliation: INSERM U1016, Institut Cochin, Paris, France.
authors.forename: Sabine
authors.initials: S
authors.lastname: Colnot
authors.affiliation: Natural and Medical Sciences Institute, Markwiesenstr. 55, 72770, Reutlingen, Germany.
authors.forename: Markus F
authors.initials: MF
authors.lastname: Templin
authors.affiliation: Natural and Medical Sciences Institute, Markwiesenstr. 55, 72770, Reutlingen, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Metzger
authors.affiliation: Department of Computer Science, University of Tuebingen, Sand 1, 72076, Tuebingen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Römer
authors.affiliation: Department of Computer Science, University of Tuebingen, Sand 1, 72076, Tuebingen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Zell
authors.affiliation: Department of Toxicology, University of Tuebingen, Wilhelmstr. 56, 72074, Tuebingen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Schwarz
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology; D007150:Immunohistochemistry; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D010634:Phenobarbital / Q000633:toxicity*; D059467:Transcriptome / Q000187:drug effects*; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D051176:beta Catenin / Q000235:genetics
chemical_list: D025601:Adenomatous Polyposis Coli Protein; C495267:CTNNB1 protein, mouse; C000613192:adenomatous polyposis coli protein, mouse; D051176:beta Catenin; D010634:Phenobarbital
keywords: Beta-catenin; CAR activation; HCC; Hepatocarcinogenesis; Non-genotoxic carcinogen