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Tumor promotion and inhibition by phenobarbital in livers of conditional Apc-deficient mice

Content Provider	Springer Nature Link
Author	Braeuning, Albert Gavrilov, Alina Geissler, Miriam Wenz, Christine Colt, Sabine Templin, Markus F. Metzger, Ute Römer, Michael Zell, Andreas Schwarz, Michael
Copyright Year	2016
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.
Starting Page	1481
Ending Page	1494
Page Count	14
File Format	PDF
ISSN	03405761
Journal	Archives of Toxicology
Volume Number	90
Issue Number	6
e-ISSN	14320738
Language	English
Publisher	Springer Berlin Heidelberg
Publisher Date	2016-02-02
Publisher Place	Berlin, Heidelberg
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	CAR activation Beta-catenin Hepatocarcinogenesis HCC Non-genotoxic carcinogen Pharmacology/Toxicology Occupational Medicine/Industrial Medicine Environmental Health Biomedicine general
Content Type	Text
Resource Type	Article
Subject	Health, Toxicology and Mutagenesis Medicine Toxicology

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