Hepatitis B virus surface proteins accelerate cholestatic injury and tumor progression in Abcb4-knockout mice
Metrics: PDF 1581 views | HTML 2328 views | ?
Daniel Zahner1,*, Hannah Glimm2,*, Tomomitsu Matono2,*, Yuri Churin2, Diran Herebian3, Ertan Mayatepek3, Kernt Köhler4, Stefan Gattenlöhner5, Anne Stinn2, Annette Tschuschner2, Martin Roderfeld2, Elke Roeb2
1Central Laboratory Animal Facility, Justus Liebig University, Giessen, Germany
2Department of Gastroenterology, Justus Liebig University, Giessen, Germany
3Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, Heinrich-Heine-University, Duesseldorf, Germany
4Institute of Veterinary Pathology, Justus-Liebig-University, Giessen, Germany
5Department of Pathology, Justus-Liebig-University, Giessen, Germany
*These authors have contributed equally to this work
Elke Roeb, email: firstname.lastname@example.org
Keywords: HBsAg, ER-stress, carcinogenesis, cholangitis, fibrosis
Received: May 30, 2016 Accepted: January 03, 2017 Published: February 02, 2017
Understanding of the pathophysiology of cholestasis associated carcinogenesis could challenge the development of new personalized therapeutic approaches and thus improve prognosis. Simultaneous damage might aggravate hepatic injury, induce chronic liver disease and even promote carcinogenesis. We aimed to study the effect of Hepatitis B virus surface protein (HBsAg) on cholestatic liver disease and associated carcinogenesis in a mouse model combining both impairments. Hybrids of Abcb4-/- and HBsAg transgenic mice were bred on fibrosis susceptible background BALB/c. Liver injury, serum bile acid concentration, hepatic fibrosis, and carcinogenesis were enhanced by the combination of simultaneous damage in line with activation of c-Jun N-terminal kinase (JNK), proto-oncogene c-Jun, and Signal transducer and activator of transcription 3 (STAT3). Activation of Protein Kinase RNA-like Endoplasmic Reticulum Kinase (PERK) and Eukaryotic translation initiation factor 2A (eIF2α) indicated unfolded protein response (UPR) in HBsAg-expressing mice and even in Abcb4-/- without HBsAg-expression. CONCLUSION: Cholestasis-induced STAT3- and JNK-pathways may predispose HBsAg-associated tumorigenesis. Since STAT3- and JNK-activation are well characterized critical regulators for tumor promotion, the potentiation of their activation in hybrids suggests an additive mechanism enhancing tumor incidence.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.