title: β-Catenin loss in hepatocytes promotes hepatocellular cancer after diethylnitrosamine and phenobarbital administration to mice.
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.
authors: Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors: Prince Kwaku
authors: PK
authors: Awuah
authors: Byung Han
authors: BH
authors: Rhieu
authors: Sucha
authors: S
authors: Singh
authors: Amalea
authors: A
authors: Misse
authors: Satdarshan P S
authors: SP
authors: Monga
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D004052:Diethylnitrosamine / Q000633:toxicity*; D022781:Hepatocytes / Q000378:metabolism*; D007150:Immunohistochemistry; D008024:Ligands; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010634:Phenobarbital / Q000633:toxicity*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000502:physiology*
chemical_list: D002273:Carcinogens; D008024:Ligands; D051176:beta Catenin; D004052:Diethylnitrosamine; D020796:Receptor, Platelet-Derived Growth Factor alpha; D010634:Phenobarbital