β-catenin loss in hepatocytes promotes hepatocellular cancer after diethylnitrosamine and phenobarbital administration to miceβ-catenin损失肝细胞促进肝细胞癌diethylnitrosamine和苯巴比妥后政府老鼠.pdfVIP

b-Catenin Loss in Hepatocytes Promotes Hepatocellular Cancer after Diethylnitrosamine and Phenobarbital Administration to Mice 1 1 1 1 1,2 Prince Kwaku Awuah , Byung Han Rhieu , Sucha Singh , Amalea Misse , Satdarshan P. S. Monga * 1 Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America, 2 Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America Abstract Hepatocellular Carcinoma (HCC) is the fifth most common cancer worldwide. b-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 mg/gm body weight) as a tumor inducer is commonly used model to study HCC in mice. Herein, nine fifteen-day male b-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 b-catenin and glutamine synthetase negative and HGF/Met, EGFR IGFR signaling was unremarkable. A significant increase in PDGFRa and its ligand PDGF-CC leading to increased phosphotyrosine-720-PDGFRa 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 espe