Universität zu Köln

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

Full text not available from this repository.

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:	Creators Email ORCID ORCID Put Code Hoesel, Marianna UNSPECIFIED UNSPECIFIED UNSPECIFIED Quasdorff, Maria UNSPECIFIED UNSPECIFIED UNSPECIFIED Ringelhan, Marc UNSPECIFIED orcid.org/0000-0003-3131-5657 UNSPECIFIED Kashkar, Hamid UNSPECIFIED UNSPECIFIED UNSPECIFIED Debey-Pascher, Svenja UNSPECIFIED UNSPECIFIED UNSPECIFIED Sprinzl, Martin F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bockmann, Jan-Hendrik UNSPECIFIED UNSPECIFIED UNSPECIFIED Arzberger, Silke UNSPECIFIED UNSPECIFIED UNSPECIFIED Webb, Dennis UNSPECIFIED UNSPECIFIED UNSPECIFIED von Olshausen, Gesa UNSPECIFIED orcid.org/0000-0001-8145-0414 UNSPECIFIED Weber, Achim UNSPECIFIED orcid.org/0000-0003-0073-3637 UNSPECIFIED Schultze, Joachim L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Buening, Hildegard UNSPECIFIED UNSPECIFIED UNSPECIFIED Heikenwalder, Mathias UNSPECIFIED UNSPECIFIED UNSPECIFIED Protzer, Ulrike UNSPECIFIED orcid.org/0000-0002-9421-1911 UNSPECIFIED
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:	Keywords Language GENE-EXPRESSION PROFILES; NF-KAPPA-B; HEPATOCELLULAR-CARCINOMA CELLS; CDNA MICROARRAY ANALYSIS; TRANSGENIC MOUSE-LIVER; X PROTEIN; OXIDATIVE STRESS; ADENOVIRUS VECTORS; STAT3 ACTIVATION; IMMUNE-RESPONSES Multiple languages Gastroenterology & Hepatology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/21336