Hoesel, Marianna, Quasdorff, Maria, Ringelhan, Marc ORCID: 0000-0003-3131-5657, Kashkar, Hamid, Debey-Pascher, Svenja, Sprinzl, Martin F., Bockmann, Jan-Hendrik, Arzberger, Silke, Webb, Dennis, von Olshausen, Gesa ORCID: 0000-0001-8145-0414, Weber, Achim ORCID: 0000-0003-0073-3637, Schultze, Joachim L., Buening, Hildegard, Heikenwalder, Mathias and Protzer, Ulrike ORCID: 0000-0002-9421-1911 (2017). Hepatitis B Virus Activates Signal Transducer and Activator of Transcription 3 Supporting Hepatocyte Survival and Virus Replication. Cell. Mol. Gastroenterol. Hepatol., 4 (3). S. 339 - 364. SAN DIEGO: ELSEVIER INC. ISSN 2352-345X

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Abstract

BACKGROUND & AIMS: The human hepatitis B virus (HBV) is a major cause of chronic hepatitis and hepatocellular carcinoma, but molecular mechanisms driving liver disease and carcinogenesis are largely unknown. We therefore studied cellular pathways altered by HBV infection. METHODS: We performed gene expression profiling of primary human hepatocytes infected with HBV and proved the results in HBV-replicating cell lines and human liver tissue using real-time polymerase chain reaction and Western blotting. Activation of signal transducer and activator of transcription (STAT3) was examined in HBV-replicating human hepatocytes, HBV-replicating mice, and liver tissue from HBV-infected individuals using Western blotting, STAT3-luciferase reporter assay, and immunohistochemistry. The consequences of STAT3 activation on HBV infection and cell survival were studied by chemical inhibition of STAT3 phosphorylation and small interfering RNA-mediated knockdown of STAT3. RESULTS: Gene expression profiling of HBV-infected primary human hepatocytes detected no interferon response, while genes encoding for acute phase and antiapoptotic proteins were up-regulated. This gene regulation was confirmed in liver tissue samples of patients with chronic HBV infection and in HBV- related hepatocellular carcinoma. Pathway analysis revealed activation of STAT3 to be the major regulator. Interleukin-6-dependent and - independent activation of STAT3 was detected in HBV-replicating hepatocytes in cell culture and in vivo. Prevention of STAT3 activation by inhibition of Janus tyrosine kinases as well as small interfering RNA-mediated knockdown of STAT3-induced apoptosis and reduced HBV replication and gene expression. CONCLUSIONS: HBV activates STAT3 signaling in hepatocytes to foster its own replication but also to prevent apoptosis of infected cells. This very likely supports HBV-related carcinogenesis.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Hoesel, MariannaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Quasdorff, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ringelhan, MarcUNSPECIFIEDorcid.org/0000-0003-3131-5657UNSPECIFIED
Kashkar, HamidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Debey-Pascher, SvenjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sprinzl, Martin F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bockmann, Jan-HendrikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Arzberger, SilkeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Webb, DennisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
von Olshausen, GesaUNSPECIFIEDorcid.org/0000-0001-8145-0414UNSPECIFIED
Weber, AchimUNSPECIFIEDorcid.org/0000-0003-0073-3637UNSPECIFIED
Schultze, Joachim L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buening, HildegardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heikenwalder, MathiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Protzer, UlrikeUNSPECIFIEDorcid.org/0000-0002-9421-1911UNSPECIFIED
URN: urn:nbn:de:hbz:38-213361
DOI: 10.1016/j.jcmgh.2017.07.003
Journal or Publication Title: Cell. Mol. Gastroenterol. Hepatol.
Volume: 4
Number: 3
Page Range: S. 339 - 364
Date: 2017
Publisher: ELSEVIER INC
Place of Publication: SAN DIEGO
ISSN: 2352-345X
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
GENE-EXPRESSION PROFILES; NF-KAPPA-B; HEPATOCELLULAR-CARCINOMA CELLS; CDNA MICROARRAY ANALYSIS; TRANSGENIC MOUSE-LIVER; X PROTEIN; OXIDATIVE STRESS; ADENOVIRUS VECTORS; STAT3 ACTIVATION; IMMUNE-RESPONSESMultiple languages
Gastroenterology & HepatologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/21336

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