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von Olshausen G, Quasdorff M, Bester R, et al. Hepatitis B virus promotes β-catenin-signalling and disassembly of adherens junctions in a Src kinase dependent fashion. Oncotarget. 2018;9(74):33947-33960doi: 10.18632/oncotarget.26103.
von Olshausen, G., Quasdorff, M., Bester, R., Arzberger, S., Ko, C., van de Klundert, M., Zhang, K., Odenthal, M., Ringelhan, M., Niessen, C. M., & Protzer, U. (2018). Hepatitis B virus promotes β-catenin-signalling and disassembly of adherens junctions in a Src kinase dependent fashion. Oncotarget, 9(74), 33947-33960. https://doi.org/10.18632/oncotarget.26103
von Olshausen, Gesa, et al. "Hepatitis B virus promotes β-catenin-signalling and disassembly of adherens junctions in a Src kinase dependent fashion." Oncotarget vol. 9,74 (2018): 33947-33960. doi: https://doi.org/10.18632/oncotarget.26103
von Olshausen G, Quasdorff M, Bester R, Arzberger S, Ko C, van de Klundert M, Zhang K, Odenthal M, Ringelhan M, Niessen CM, Protzer U. Hepatitis B virus promotes β-catenin-signalling and disassembly of adherens junctions in a Src kinase dependent fashion. Oncotarget. 2018 Sep 21;9(74):33947-33960. doi: 10.18632/oncotarget.26103. eCollection 2018 Sep 21. PMID: 30338037; PMCID: PMC6188061.
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Oncotarget. 2018 Sep 21;9(74):33947-33960. doi: 10.18632/oncotarget.26103. eCollection 2018 Sep 21.

Hepatitis B virus promotes β-catenin-signalling and disassembly of adherens junctions in a Src kinase dependent fashion.

Oncotarget

Gesa von Olshausen, Maria Quasdorff, Romina Bester, Silke Arzberger, Chunkyu Ko, Maarten van de Klundert, Ke Zhang, Margarete Odenthal, Marc Ringelhan, Carien M Niessen, Ulrike Protzer

Affiliations

  1. Department of Internal Medicine I, University Hospital rechts der Isar, Technical University of Munich, Munich, Germany.
  2. Molecular Infectiology, Institute for Medical Micro biology, Immunology and Hygiene, University Hospital Cologne, Cologne, Germany.
  3. Department of Gastroenterology and Hepatology, University Hospital Cologne, Cologne, Germany.
  4. Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Munich, Germany.
  5. Institute of Pathology, University Hospital Cologne, Cologne, Germany.
  6. Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany.
  7. Department of Internal Medicine II, University Hospital rechts der Isar, Technical University of Munich, Munich, Germany.
  8. Department of Dermatology, University Hospital of Cologne, Cologne, Germany.
  9. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
  10. German Center for Infection Research (DZIF), Munich Partner Site, Munich, Germany.

PMID: 30338037 PMCID: PMC6188061 DOI: 10.18632/oncotarget.26103

Abstract

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.

Keywords: E-cadherin; Src kinase; hepatitis B virus (HBV); hepatocellular carcinoma (HCC); β-catenin

Conflict of interest statement

CONFLICTS OF INTEREST The authors declare no conflicts of interest.

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