Therapeutic approaches to the prevention of liver fibrosis and cancer progression
Author(s)
Advisor
Date
2015-08Publisher
Bilkent University
Language
English
Type
ThesisItem Usage Stats
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Abstract
In our previous studies on liver regeneration, we demonstrated that following partial
hepatectomy (PH) FLT3 contributes cellular proliferation that provides a basis for
liver regeneration. Moreover, we were able to suggest a potential role for FLT3 in
hepatocarcinogenesis for the first time. Therefore, we further investigated the effect of
FLT3 inhibition on the invasiveness and aggressiveness of hepatocarcinogenesis. Our
findings were parallel to our previous results supporting the contribution of FLT3 in
hepatocarcinogenesis. Thus, we are presenting FLT3 as a novel candidate for the
diagnosis and treatment of HCC. We also focused on liver fibrosis since it is the initial
wound healing response generated by the liver against damaging insults. Liver fibrosis
is a reversible process, but if its progression is not prevented it might turn into
cirrhosis and end up with HCC. Toll-like receptors (TLRs) have been reported to
contribute to this fibrotic response generated in the liver resulting from the activating
effects of various danger ligands. We show that using suppressive
oligodeoxynucleotide (ODN) A151 might control TLR dependent immune activation
that takes place after the induction of liver fibrosis. Our results show that suppressive
ODN A151 administration has a negative effect on αSMA expression and collagen
accumulation, which are the major events taking place during liver fibrogenesis.
Additionally, this suppressive effect of suppressive ODN A151 was revealed to be
systemic. Splenocytes of suppressive ODN A151 administered mice showed different cytokine secretion patterns and antigen presenting cell (APC) function after being
stimulated with various TLR ligands. These findings suggested us that using
suppressive ODN might be a rational and novel approach to control the liver
fibrogenesis and even prevent its progression into cirrhosis reducing the number of
liver transplantations needed by the patients. Finally, we focused on HSPs, some of
which are also known to activate TLR signaling. Additionally, HSP27 has a role in
actin cytoskeleton organization and controlling cellular motility, which are among the
events that take place in liver fibrogenesis. Therefore, for the first time we present
preliminary data on the potential role of HSP27 in liver fibrosis and quercetin
treatment as a therapeutic approach due to its HSP27 and αSMA expression changing
effects.
Keywords
LiverLiver cancer
Hepatocellular carcinoma
Liver fibrosis
FLT3
TLRs
Suppressive ODN A151
HSPs
HSP27
Quercetin