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β-Catenin loss in hepatocytes promotes hepatocellular cancer after diethylnitrosamine and phenobarbital administration to mice

UNSPECIFIED (2012) β-Catenin loss in hepatocytes promotes hepatocellular cancer after diethylnitrosamine and phenobarbital administration to mice. PLoS ONE, 7 (6).

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Abstract

Hepatocellular Carcinoma (HCC) is the fifth most common cancer worldwide. β-Catenin, the central orchestrator of the canonical Wnt pathway and a known oncogene is paramount in HCC pathogenesis. Administration of phenobarbital (PB) containing water (0.05% w/v) as tumor promoter following initial injected intraperitoneal (IP) diethylnitrosamine (DEN) injection (5 μg/gm body weight) as a tumor inducer is commonly used model to study HCC in mice. Herein, nine fifteen-day male β-catenin knockout mice (KO) and fifteen wild-type littermate controls (WT) underwent DEN/PB treatment and were examined for hepatic tumorigenesis at eight months. Paradoxically, a significantly higher tumor burden was observed in KO (p<0.05). Tumors in KO were β-catenin and glutamine synthetase negative and HGF/Met, EGFR & IGFR signaling was unremarkable. A significant increase in PDGFRα and its ligand PDGF-CC leading to increased phosphotyrosine-720-PDGFRα was observed in tumor-bearing KO mice (p<0.05). Simultaneously, these livers displayed increased cell death, stellate cell activation, hepatic fibrosis and cell proliferation. Further, PDGF-CC significantly induced hepatoma cell proliferation especially following β-catenin suppression. Our studies also demonstrate that the utilized DEN/PB protocol in the WT C57BL/6 mice did not select for β-catenin gene mutations during hepatocarcinogenesis. Thus, DEN/PB enhanced HCC in mice lacking β-catenin in the liver may be due to their ineptness at regulating cell survival, leading to enhanced fibrosis and regeneration through PDGFRα activation. β-Catenin downregulation also made hepatoma cells more sensitive to receptor tyrosine kinases and thus may be exploited for therapeutics. © 2012 Awuah et al.


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Details

Item Type: Article
Status: Published
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorColeman, William B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Date: 25 June 2012
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 7
Number: 6
DOI or Unique Handle: 10.1371/journal.pone.0039771
Schools and Programs: School of Medicine > Cellular and Molecular Pathology
School of Medicine > Critical Care Medicine
Refereed: Yes
PubMed Central ID: PMC3382575
PubMed ID: 22761897
Date Deposited: 11 Jul 2012 18:13
Last Modified: 12 Jan 2019 10:55
URI: http://d-scholarship.pitt.edu/id/eprint/12693

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