Page 132 - ebook HCC

GENEV
PROGRAMME AND ABSTRACTSAND ABSTRACTS
EASL
130 PROGRAMME GENEVA, SWITZERLANDA, SWITZERLAND EASL HCC SUMMITHCC SUMMIT 131
130
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FEBRUAR
FEBRUARY 13 - 16, 2014Y 13 - 16, 2014
Poster Board Number B26 Poster Board Number B27
B-CELL LYMPHOMA 3 PROTEIN MODULATES ASOCCIATION BETWEEN ANGIOPOEITIN-1
LIVER INJURY AND REGENRATION IN VIVO AND ANGIOPOEITIN-2 WITH STAGES OF LIVER
FIBROSIS AND GRADES OF INFLAMMATION IN
Michael Nagel , Amrit Mann , Nadine Gehrke , Ari Weisman , Peter R. Galle , CHRONIC HEPATITIS C PATIENTS
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Marcus A. Wörns , Jörn M. Schattenberg 1
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1 I. Medizinische Klinik, Institute for Molecular Medicine Mainz ,
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University Medical Center Mainz, 55131 Mainz, Germany Ángel Hernández-Bartolomé , Rosario Lopez-Muñoz , Yolanda Rodriguez-Muñoz ,
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Maria Jesus Borque , Paloma Sanz-Cameno , Ricardo Moreno-Otero , Luisa Garcia-Buey 1
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Corresponding author’s e-mail: namic.de.vu@freenet.de 1 Unit liver, Hospital Universitario de La Princesa, Madrid, Spain,
2 Biology Molecular Unit, Hospital Universitario de La Princesa, Madrid, Spain
Introduction: The present study aims at delineating the role of Bcl-3 (B-Cell Lymphoma)
in liver injury and regeneration. The proto-oncogene Bcl-3 has been reported to play a role Corresponding author’s e-mail: angel.nandez@hotmail.com
in hepatic cell-proliferation and -survival. Bcl-3 is an atypical member of IkB (Inhibitor of
Kappa B) family as it does not bind RelA or cRel-containing dimers. In nucleus, it seems
to regulate NF-kB (Nuclear Factor Kappa B) targets in association with p50 or p52. Bcl-3 Introduction: Hepatitis C virus (HCV) infection often progresses to chronic hepatitis
has been shown to activate or suppress the NF-kB in vitro although the exact mechanisms C (CHC), one of the leading causes of cirrhosis and hepatocellular carcinoma (HCC).
are not understood. HCC arises in the setting of chronic inflammation, a setting in which Angiogenesis is closely related to the pathogenesis of chronic liver disease and its
NF-kB may play a significant role. Aberrant expression of Bcl-3 has been associated with progression to HCC.
many cancers including HCC. Nuclear localization of p50 and p52, but not p65 in human Aims: The purpose of this study was to analyze the expression of Angiopoietin-1 (Ang-1)
BASIC POSTER ABSTRACTS Results: Hepatocyte-specific overexpression of Bcl-3 (Bcl-3 Hepar ) was achieved by cre- Methodology: The study included liver biopsies of 47 CHC patients and 8 healthy BASIC POSTER ABSTRACTS
HCCs may be of significance and Bcl-3 could be a downstream target in modulation of the
NF-kB signaling.
and Angiopoietin-2 (Ang-2) in liver tissue of CHC patients and uninfected subject
individuals. Biopsies were classified according to the Metavir system and stored in
mediated deletion (Alfp-cre) of a lox-P-site flanked-Neo-Stop cassette switched before
Bcl-3 cDNA. Wildtype and Bcl-3
mice were treated with GalactosamineN (GalN)
biological embedding medium (OCT) at -80°C until analysis. After thawing, biopsies were
Hepar
and lipopolysaccaride (LPS), a model of TNF-mediated acute liver injury. Liver injury -
assessed by serum ALT levels, histology, and caspase 8 activation - was less pronounced
Ang-1 and Ang-2 by western blotting and ELISA assays. Groups were compared using
Mann-Whitney non parametric test and data were analyzed by using Pearson correlation
in Bcl-3 Hepar mice. Also, Bcl-3 Hepar mice exhibited significantly elevated proliferation indices homogenized in RIPA buffer with protease inhibitors and analyzed the expression of
(Ki67) as compared to the control animals hinting towards a role in the liver regeneration. coefficient.
Significantly enhanced expression levels of NF-kB members RelA and cRel, NF-kB targets
IL-1beta and IL-6 as well as TLR4 (Toll-like receptor) were ascertained. Activation of the Results: Ang-2 levels were significantly higher in CHC patients compared with uninfected
p50 subunit of NFkB was significantly reduced. Interestingly, expression of RIP1 (receptor controls. Furthermore, we observed that Ang-2 levels were significantly higher (p <0.05) in
interacting protein) an adaptor that mediates TNF- and TLR3/4-induced NF-kB activation patients with elevated inflammation (A3) and advanced liver fibrosis (F3-F4). Interestingly,
was significantly reduced, and that of RIP3, a key downstream regulator of TNF-mediated the expression of Ang-2 was significantly and positively correlated with inflammation and
necroptosis was significantly enhanced. fibrosis in group of CHC patients (p <0.03 and 0.02, respectively), but Ang-1 expression
was not related to the progression of disease.
Conclusions: Bcl-3 mitigates TNF-mediated acute liver injury in mice. This is partially
mediated by enhanced proliferation and compromised activation the caspase8-dependent Conclusions: The relationship between expression Ang-2 and the progression disease
apoptotic signaling pathway. Our preliminary results hint towards activation of an alternate to HCC development may reflect the alteration of hepatic vascular homeostasis of these
RIP3-dependent signalling pathway which may contribute to the equilibrium between patients and constitute an important target for therapeutic intervention.
cell death and hepatocyte regeneration. These findings imply that Bcl-3 is an important
modulator of liver homeostasis.