Page 93 - ebook HCC

GENEVA, SWITZERLANDA, SWITZERLAND
PROGRAMME
EASL
90 PROGRAMME AND ABSTRACTSAND ABSTRACTS GENEV EASL HCC SUMMITHCC SUMMIT 91
90
91
FEBRUARY 13 - 16, 2014Y 13 - 16, 2014
FEBRUAR
Poster Board Number B1 Poster Board Number B2
CONNECTING METABOLISM AND HCC EFFECT OF EXTRACELLULAR MATRIX PROTEINS
DEVELOPMENT THROUGH THYROID HORMONE ON PROGENITOR CELL DIFFERENTIATION
INTERACTING PROTEIN (TRIP) FUNCTION
Femke Heindryckx , Eliene Bogaerts , Hans Van Vlierberghe , Pär Gerwins 1
2
2
1
1 Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala,
Bettina Meissburger , Mauricio Berriel Diaz , Ashley Eheim , Stephan Herzig 1 2 3 Sweden, Gastroenterology & Hepatology, Ghent University Hospital, Ghent, Belgium
1
1
1
2
2
1 Molecular Metabolic Control, German Cancer Research Center (DKFZ), Heidelberg
University Hospital, Heidelberg, Center for Molecular Biology (ZMBH), Corresponding author’s e-mail: Femke.Heindryckx@imbim.uu.se
3
69120 Heidelberg, Germany
Corresponding author’s e-mail: m.berrieldiaz@dkfz.de Introduction: Activated hepatic stellate cells cause an excessive deposition of extracellular
matrix (ECM) in chronically damaged livers. ECM proteins as well as their proteolytic
fragments have been implicated in playing a crucial role in tumor growth, metastasis, and
Introduction: Obesity and associated metabolic disorders are recognized risk factors for tumor neo-angiogenesis. Whereas some of the molecules in the tumor microenvironment
the development of liver cancer. Many chronically obese people develop non-alcoholic have an effect on vasculature, others have a direct effect on the tumor cells, altering
fatty liver disease (NAFLD), which can progress to steatohepatitis (NASH) and liver their behavior and phenotypic properties. While the effect of ECM on angiogenesis has
cirrhosis, which may promote malignant transformation of liver cells. However, detailed been investigated extensively, fewer research focuses on the direct effect of ECM proteins
molecular mechanisms linking metabolic disorders to hepatocellular carcinoma (HCC) are and their degradation products on tumor growth. An interesting feature is that there is
largely unknown. increasing evidence that the ECM is an essential component of the stem cell niche and
that it can directly regulate stem cell differentiation, although the molecular details of how
BASIC POSTER ABSTRACTS complexes in the metabolic etiology of HCC. Aims: We aim to investigate the direct effect of ECM proteins on hepatocellular carcinoma BASIC POSTER ABSTRACTS
Aims: We aimed to identify and functionally characterize distinct transcriptional regulator
this is achieved have only just started to emerge.
Methodology: To characterize oncogenic pathways in HCC, which specifically arise in
(HCC), mainly focusing on progenitor cell differentiation.
the setting of metabolic dysfunction, we employed DEN-induced liver carcinogenesis in a
model of diet-induced obesity/NAFLD. Expression profiling of tumor and non-tumor tissue
Methodology: Human immortalized hepatic stellate cells (LX2) were stimulated with
from mice fed low-fat diet (LFD) or high-fat diet (HFD) was performed. This data-set was
compared to hepatic gene expression from both genetic and diet-induced obesity as well
these cells was collected and used for subsequent stimulation of the human hepatoma
as models of NASH. Upon confirmation in human data-sets, selected candidates were TGF-beta and/or the fibrin degradation product Fragment E (FnE) for 48hrs. Medium from
cell line HepG2. HepG2 cells were also grown on plates coated with ECM proteins,
functionally characterized in vitro, utilizing proliferation assays and analyses of cellular including collagen 1, fibrinogen, fibrin, fragment E and fibrinogen-like-protein 1. Cells were
metabolism. harvested after 48hrs and RNA was isolated for subsequent qPCR analysis on progenitor
cell markers.
Results: HCC development was significantly accelerated in metabolically challenged
animals. We identified thyroid hormone interacting protein (TRIP) to be consistently induced Results: Exposure of the LX2 cells with FnE and TGF-beta lead to a 2-fold increase
in liver tumors, with the same induction observed in human HCC. Additionally, we found of smooth muscle actin and collagen, compared to TGF-beta alone. Stimulating HepG2
hepatic TRIP expression to be upregulated in genetic and diet-induced obesity mouse cells with medium collected from activated hepatic stellate cells, caused a significantly
models as well as in NASH. Notably, TRIP knockdown markedly reduced proliferation of increased expression of prominin-1 and CD44 in the condition where TGF-beta and FnE
hepatoma cells. Supporting the pro-proliferative function of TRIP, reduced cellular glucose was used together to stimulate the stellate cells. Possibly, this was caused by an increased
consumption was evident post-knockdown, suggesting a more oxidative metabolic state. production of collagen after stimulation with TGF-beta and FnE, since growing human HCC
cells on collagen coated plates, also caused an increased expression of progenitor cell
Conclusions: Overall, our results strongly indicate TRIP is a novel oncogenic factor, markers prominin-1 and CK19. Interestingly, fibrin and fibrinogen significantly increased
which may integrate metabolic control and HCC development. Further functional CD44 expression.
characterization will provide valuable clues for the exploitation of the TRIP pathway in
future metabolocentric approaches of liver cancer prevention and treatment. Conclusions: ECM proteins cause a de-differentiation of HCC cells towards a more stem
cell like phenotype, which is associated with more aggressive tumors.