TY  - GEN
UR  - https://archiv.ub.uni-heidelberg.de/volltextserver/27596/
A1  - Elßner, Christin
N2  - Chronic liver diseases such as viral hepatitis and alcoholic liver disease are a major health burden
affecting millions of people worldwide. Chronic liver damage can cause fibrosis, which might
ultimately progress to cirrhosis as the major risk factor for the development of hepatocellular
carcinoma (HCC). HCC is the most common type of primary liver cancers (accounting for ~ 80 %)
and originates from hepatocytes, whereas intrahepatic cholangiocarcinoma (ICC, accounting for
~ 15 %) is a malignant liver tumor arising from biliary epithelial cells. Together, they are among the
most frequently diagnosed cancers and a leading cause of cancer-related deaths.
NF-kB comprises a family of transcription factors, which regulate the expression of target genes
involved in different functions such as inflammation, immunity, cell proliferation, differentiation, and
survival. Two major signaling pathways termed as the canonical and non-canonical NF-?B pathway
have been described leading to receptor-mediated NF-kB activation. Both pathways are dependent on
different signaling components and activate distinct target genes. While activation of canonical NFkB
signaling and its key player RELA have been reported to play a crucial role in chronic liver
diseases, the role of non-canonical NF-kB signaling with RELB as its key transcriptional factor
remains largely elusive. Therefore, the main objective of this work was to investigate the functional
importance of RELB for the liver, chronic liver diseases, and hepatocarcinogenesis.
For this purpose, an established mouse model with a specific disruption of the cylindromatosis gene
(Cyld) in liver parenchymal cells (LPC) was used. CYLD is a deubiquitinase and acts as a negative
regulator of NF-kB signaling. Mice lacking liver-specific full-length CYLD (Cyld?LPC) exhibit a severe
biliary phenotype consisting of ductular reaction and biliary fibrosis, accompanied by highly
upregulated RELB expression. To determine whether RELB overexpression contributes to this biliary
phenotype, a double knockout mouse containing an additional deletion of RELB (Cyld/Relb?LPC mice)
was generated. Analysis of Cyld/Relb?LPC mice revealed that nuclear translocation of RELB is essential
for the ductular reaction, activation of the oval cell compartment and development of biliary fibrosis
in Cyld?LPC mice, as the spontaneous phenotype of Cyld?LPC mice is completely reverted in
Cyld/Relb?LPC mice. Moreover, sustained RELB activation induced a specific cytokine response
without significant increased immune cell infiltration. The finding that cholangiocytes of Cyld?LPC
mice acquire a reactive phenotype with the ability to express proinflammatory cytokines such as LT?
points to a perpetuating feedback mechanism of constitutive RELB upregulation ultimately promoting
ductular reaction in Cyld?LPC mice. RELB deficiency also affected the protein expression of NF-kB
signaling molecules involved in the canonical and non-canonical signaling pathway. Whereas liver
lysates of Cyld?LPC mice showed elevated NF-kB activation, protein levels of Cyld/Relb?LPC livers were
similar to control mice.
To assess the role of RELB in the injured liver, different chemically induced chronic liver damage
models were used. While both RELB and CYLD had no impact on the fibrotic response induced by
direct hepatocyte damage, Cyld?LPC mice showed in a cholangiopathy mouse model the most severe
biliary phenotype with cholestasis and biliary fibrosis compared to treated control mice. This
pronounced biliary injury was RELB driven, as additional RELB deletion was able to revert this
phenotype. Interestingly, Cyld/Relb?LPC mice were protected against cholestatic damage, maintained
body weight, and displayed normal bilirubin levels.
In the second part of this thesis, the importance of RELB for human chronic liver diseases and
hepatocarcinogenesis was investigated. In liver parenchymal cells from patients with chronic infection
with hepatitis B or C viruses, autoimmune hepatitis, alcoholic liver disease, early stage primary biliary
cholangitis (PBC) and primary sclerosing cholangitis (PSC), an increased nuclear translocation of
RELB was observable. Especially in cholangiocytes of early disease stage of PBC and PSC, LT? acts
as a possible upstream trigger leading to sustained RELB activation. In liver tissues from patients with
HCC or ICC, nuclear translocation of RELB was significantly increased. Nuclear RELB expression
was significantly associated with poor overall survival of HCC patients identifying RELB as a novel
prognostic factor to predict the outcome of HCC patients.
Taken together, the results of the present study uncover for the first time a crucial role of non-canonical
NF-kB signaling for ductular reaction, progenitor cell activation and biliary driven fibrosis in a mouse
model. The finding, that RELB is activated in human diseased liver, HCC, and ICC could harbor broad
implications for basic research and clinical application.
Y1  - 2020///
TI  - The role of non-canonical NF-kB for liver
homeostasis, chronic liver injury and
hepatocarcinogenesis
CY  - Heidelberg
AV  - public
ID  - heidok27596
ER  -