Hepatitis B virus promotes β-catenin-signalling and disassembly of adherens junctions in a Src kinase dependent fashion
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Gesa von Olshausen1, Maria Quasdorff2,3, Romina Bester4, Silke Arzberger2,4, Chunkyu Ko4, Maarten van de Klundert4, Ke Zhang4, Margarete Odenthal5,6, Marc Ringelhan4,7, Carien M. Niessen6,8,9 and Ulrike Protzer4,10
1Department of Internal Medicine I, University Hospital rechts der Isar, Technical University of Munich, Munich, Germany
2Molecular Infectiology, Institute for Medical Micro biology, Immunology and Hygiene, University Hospital Cologne, Cologne, Germany
3Department of Gastroenterology and Hepatology, University Hospital Cologne, Cologne, Germany
4Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Munich, Germany
5Institute of Pathology, University Hospital Cologne, Cologne, Germany
6Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany
7Department of Internal Medicine II, University Hospital rechts der Isar, Technical University of Munich, Munich, Germany
8Department of Dermatology, University Hospital of Cologne, Cologne, Germany
9Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
10German Center for Infection Research (DZIF), Munich Partner Site, Munich, Germany
Ulrike Protzer, email: firstname.lastname@example.org
Carien M. Niessen, email: email@example.com
Keywords: hepatitis B virus (HBV); hepatocellular carcinoma (HCC); β-catenin; Src kinase; E-cadherin
Received: April 10, 2018 Accepted: August 27, 2018 Published: September 21, 2018
Hepatitis B virus (HBV) infection is a prominent cause of hepatocellular carcinoma (HCC) but the underlying molecular mechanisms are complex and multiple pathways have been proposed such as the activation of the Wnt-/β-catenin-signalling and dysregulation of E-cadherin/β-catenin adherens junctions. This study aimed to identify mechanisms of how HBV infection and replication as well as HBV X protein (HBx) gene expression in the context of an HBV genome influence Wnt-/β-catenin-signalling and formation of adherens junctions and to which extent HBx contributes to this.
Regulation of E-cadherin/β-catenin junctions and β-catenin-signalling as well as the role of HBx were investigated using constructs transiently or stably inducing replication of HBV+/-HBx in hepatoma cell lines. In addition, HCC and adjacent non-tumorous tissue samples from HBV-infected HCC patients and drug interference in HBV-infected cells were studied.
Although HBV did not alter overall expression levels of E-cadherin or β-catenin, it diminished their cell surface localization resulting in nuclear translocation of β-catenin and activation of its target genes. In addition, HBV gene expression increased the amount of phosphorylated c-Src kinase. Treatment with Src kinase inhibitor Dasatinib reduced HBV replication, prevented adherens junction disassembly and reduced β-catenin-signalling, while Sorafenib only did so in cells with mutated β-catenin. Interestingly, none of the HBV induced alterations required HBx.
Thus, HBV stimulated β-catenin-signalling and induced disassembly of adherens junctions independently of HBx through Src kinase activation. These pathways may contribute to hepatocellular carcinogenesis and seem to be more efficiently inhibited by Dasatinib than by Sorafenib.
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