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.
Highlights
Hepatocellular Carcinoma (HCC) is the fifth most common cancer and the third cause of cancer death worldwide [1]
The mice lacking b-catenin in hepatocytes displayed significantly enhanced tumorigenesis than wild-type littermate controls (WT) mice that was grossly appreciable as larger and greater numbers of tumors (Fig. 1B)
We identify higher numbers of TUNEL-positive hepatocytes in knockout mice (KO) at 8 months after DEN/PB as compared to treated WT, suggesting greater cell death (Fig. 2A)
Summary
Hepatocellular Carcinoma (HCC) is the fifth most common cancer and the third cause of cancer death worldwide [1]. One pathway of critical importance in HCC is the Wnt/bcatenin signaling. B-Catenin is the central effector of the canonical Wnt signaling, which is a highly conserved pathway regulating critical cellular processes such as proliferation, differentiation, survival and self-renewal [2,3,4,5]. Upon binding of Wnt protein to its cell surface receptor Frizzled and co-receptor lowdensity lipoprotein– related protein 5/6 (LRP5/6), a signal is transduced through disheveled that allows for inactivation of degradation complex comprised of glycogen synthase kinase 3b (GSK3b), adenomatous polyposis coli gene product (APC) and casein kinase Ia, which allows b-catenin to dissociate and translocate to the nucleus to bind to lymphoid enhancer-binding factor/T cell factor (LEF/TCF) family of proteins to transactivate target genes. B-catenin is a well-recognized oncogene and considered a valuable therapeutic target
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