Research Papers:

Exogenous hepatitis B virus envelope proteins induce endoplasmic reticulum stress: involvement of cannabinoid axis in liver cancer cells

Roberta Montalbano, Birgit Honrath, Thaddeus Till Wissniowski, Moritz Elxnat, Silvia Roth, Matthias Ocker, Karl Quint, Yuri Churin, Martin Roederfeld, Dirk Schroeder, Dieter Glebe, Elke Roeb and Pietro Di Fazio _

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Oncotarget. 2016; 7:20312-20323. https://doi.org/10.18632/oncotarget.7950

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Roberta Montalbano1, Birgit Honrath1, Thaddeus Till Wissniowski2, Moritz Elxnat1, Silvia Roth1, Matthias Ocker3,6, Karl Quint3, Yuri Churin4, Martin Roederfeld4, Dirk Schroeder4, Dieter Glebe5, Elke Roeb4, Pietro Di Fazio1

1Department of Visceral, Thoracic and Vascular Surgery, Philipps University of Marburg, Marburg, Germany

2Division of Gastroenterology, Philipps University of Marburg, Marburg, Germany

3Institute for Surgical Research, Philipps University of Marburg, Marburg, Germany

4Department of Gastroenterology, Justus Liebig University, Giessen, Germany

5Institute of Medical Virology, National Reference Centre for Hepatitis B and D Viruses, Justus Liebig University, Giessen, Germany

6Present address: Department of Gastroenterology CBF, Charité University Medicine Berlin and Bayer Pharma AG, Experimental Medicine Oncology, Berlin, Germany

Correspondence to:

Pietro Di Fazio, e-mail: [email protected]

Roberta Montalbano, e-mail: [email protected]

Keywords: hepatitis B virus, endoplasmic reticulum stress, endocannabinoid system

Received: April 27, 2015     Accepted: February 13, 2016     Published: March 07, 2016


HBV represents the most common chronic viral infection and major cause of hepatocellular carcinoma (HCC), although its exact role in liver tumorigenesis is unclear. Massive storage of the small (SHBs), middle (MHBs) and large surface (LHBs) HBV envelope proteins leads to cell stress and sustained inflammatory responses. Cannabinoid (CB) system is involved in the pathogenesis of liver diseases, stimulating acute and chronic inflammation, liver damage and fibrogenesis; it triggers endoplasmic reticulum (ER) stress response. The aim of our work was to investigate the activation of ER stress pathway after ectopic HBV envelope proteins expression, in liver cancer cells, and the role exerted by CB receptors. PCR, immunofluorescence and western blotting showed that exogenous LHBs and MHBs induce a clear ER stress response in Huh-7 cells expressing CB1 receptor. Up-regulation of the chaperone BiP/GRP78 (Binding Immunoglobulin Protein/Glucose-Regulated Protein 78) and of the transcription factor CHOP/GADD153 (C/EBP Homologous Protein/Growth Arrest and DNA Damage inducible gene 153), phosphorylation of PERK (PKR-like ER Kinase) and eIF2α (Eukaryotic Initiation Factor 2α) and splicing of XBP1 (X-box binding protein 1) was observed. CB1–/– HepG2 cells did not show any ER stress activation. Inhibition of CB1 receptor counteracted BiP expression in transfected Huh-7 and in HBV+ PLC/PRF/5 cells; whereas no effect was observed in HBV HLF cells. These results suggest that HBV envelope proteins are able to induce the ER stress pathway. CB1 expression is directly correlated with ER stress function. Further investigations are needed to clarify the involvement of cannabinoid in HCC progression after HBV infection.

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