Page 147 - ebook HCC

PROGRAMME AND ABSTRACTSAND ABSTRACTS
EASL HCC SUMMITHCC SUMMIT
GENEV
145
144 PROGRAMME GENEVA, SWITZERLANDA, SWITZERLAND EASL 145
144
FEBRUAR
FEBRUARY 13 - 16, 2014Y 13 - 16, 2014
Poster Board Number B34 Poster Board Number B35
SOLUBLE MIC PROTEINS IN HEPATITIS B VIRUS GLUTAMINE PROTECTS AGAINST
INDUCED HEPATOCELLULAR CARCINOMA BETA-CATENIN-DEPENDENT TUMOR
DEVELOPMENT IN LIVER
Van Tong Hoang , Nguyen L. Toan , Le H. Song , Nghiem X. Hoan ,
1
3
3
2
Bui K. Cuong , Ho A. Son , Thomas Bock , Velavan TP 1 Cécile Godard , Chiara Sartor , Moinard Christophe , Wouter H Lamers ,
4
2
2
1
1
2
3
1 Institute of Tropical Medicine, University of Tuebingen, Tuebingen, Germany, Christine Perret , Sabine Colnot 1
1
2 Department of Pathophysiology, Vietnam Military Medical University, Tran Hung Dao 1 Inserm, Faculté de Pharmacie, Paris, France,
3
2
Hospital, Hanoi, Vietnam, Department of Infectious Diseases, 3 University of Amsterdam, Amsterdam, Netherlands
4
Robert Koch Institute, Berlin, Germany
Corresponding author’s e-mail: cecile.godard@inserm.fr
Corresponding author’s e-mail: tong.van-hoang@uni-tuebingen.de
Introduction: Oncogenic events are known to alter cell metabolism, supporting the
aberrant growth of cancer cells. Tumors usually fuel their energetic needs through
aerobic glycolysis and/or through an enhanced glutamine metabolism. Twenty to 40%
Introduction: HBV infection is a main risk factor for HCC, which is the third leading of hepatocarcinomas present β-catenin-activating mutations: they strongly express
cause of cancer related deaths, and is associated with high incidence of HCC in high Glutamine Synthetase (GS), the major glutamine producer, which is also a transcriptional
prevalence areas of HBV infection. The human major histocompatibility complex class I β-catenin target in the liver.
chain-related gene A and B (MICA, MICB) induced in response to viral infection including
HBV, modulates the NK and T cell mediated immune responses through NKG2D receptor Aims: We asked what is the role played by glutamine in β-catenin-driven tumor
and is associated with several diseases including HCC. development. For that purpose, we suppressed Glutamine Synthetase expression in mice
with an over-activated hepatic β-catenin.
BASIC POSTER ABSTRACTS sMICB) protein in the progression of HBV-related liver disease and treatment response to Methodology: We previously studied the consequences of a conditional and hepato- BASIC POSTER ABSTRACTS
Aims: The aim of this study is to investigate the role of soluble MICA and MICB (sMICA,
specific Adenomatous Polyposis Coli (Apc) gene invalidation (Cre-loxP strategy), leading
HBV-related HCC.
to β-catenin over-activation (Colnot, PNAS 2004). When Apc is lost in all hepatocytes by
injecting a high dose of Cre-expressing adenovirus (AdCre), the quiescent hepatocytes
Methodology: The sMICA and sMICB serum levels were measured in chronically HBV-
engage in cell division and accumulate a high amount of glutamine. Then the mice rapidly
infected Vietnamese patients including HCC and healthy controls by ELISA and correlated
with clinical and laboratory parameters as well as with therapeutic interventions of HBV-
Apc in single hepatocytes (by injecting a low dose of AdCre) is compatible with survival
and leads to the development of β-catenin-activated liver tumors 9 months thereafter.
related HCC. become hepatomegalic and die from metabolic alterations. On the other hand, the loss of
We took advantage of these mouse models and interbred them with mice carrying floxed
nd
th
Results: The soluble MICA and MICB serum levels were elevated significantly in on the 2 to 6 exons of Glul gene encoding GS (He, Glia 2010). In this compound
HBV patients compared to healthy controls. Among patient subgroups, asymptomatic invalidation model, we investigated hepatomegaly, proliferation, survival and followed
individuals have highest sMICB serum levels while liver cirrhosis patients revealed lowest tumor development by echography.
sMICB serum levels. The sMICB serum levels were decreased in treated HCC patients Results: The combined loss of GS and Apc in the whole liver strongly decreased glutamine
compared to non-treated HCC patients and were significantly correlated with platelet liver accumulation. In this context, these lower glutamine levels seem to have no influence
counts. In addition, the liver enzymes such as alanine amino transferase (ALT), aspartate on hepatocyte proliferation and hepatomegaly. Unexpectedly, the survival of compound
transaminase (AST), total bilirubin and direct bilirubin were positively correlated with invalidated mice is shortened. In the tumoral model, the combined loss of GS and Apc
sMICA levels. led to an earlier tumoral development, compared to Apc-null mice: GS-null/β-catenin-
activated tumors appeared as soon as 4 months after AdCre injection.
Conclusions: The study demonstrated an important role of sMICA and sMICB serum
levels during immune response to the HBV infection, liver disease progression and Conclusions: Despite an enhanced glutamine anabolism in β-catenin over-activated
response to the HCC treatment. livers/tumors, glutamine seems to have no implication on hepatocyte proliferation, but
surprisingly protects against tumor development. This protection could occur through
the role played by glutamine in autophagy and in oxidative stress (as a precursor of
glutathione).