Page 76 - ebook HCC

74 PROGRAMME AND ABSTRACTS GENEVA, SWITZERLAND EASL HCC SUMMIT 75
FEBRUARY 13 - 16, 2014

CENTROSOMES AND F BOX PROTEINS METHYLOME IN HCC

Nisar P. Malek , Uta Kossatz , Benita Wolf 1 Thomas Longerich 1
2
1
2
1 University Hospital Tübingen, University Hospital Tuebingen, Tübingen, Germany 1 Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
Corresponding author’s e-mail: Nisar.Malek@med.uni-tuebingen.de Corresponding author’s e-mail: thomas.longerich@med.uni-heidelberg.de

Introduction: HCC is a genetically highly unstable tumor. In the past we have shown that Introduction: Human hepatocarcinogenesis is considered a step-wise process in which
the dysregulation of ubiquitin ligases can result in the formation of liver cancer stem cells genetic and epigenetic alterations result in the activation of oncogenes and the inactivation
and in the induction of genetic instability. of tumor suppressor genes. Epigenetic alterations include aberrant methylation and histone
modifications, which do not alter the genetic information per se, but affect its transcription.
Aims: We have used mouse strains in which components of the Cul3 system were deleted
to study the effects of dysregulated ubiquitylation in vitro and in vivo. We were particularly Aims: While overall tumor DNA is hypomethylated, which may promote genomic instability,
BASIC SPEAKERS ABSTRACTS Methodology: For our studies we used inducible cul3 knockout mice and transposon Methodology: In the past DNA methylation analyses have been carried out mainly by BASIC SPEAKERS ABSTRACTS
interested in the mechanisms which promoted the formation of liver cancer stem cells and
aberrant hypermethylation of promoter-associated CpG islands has been observed in
in processes which dysregulated centrosome duplication.
human HCC and may result in the inactivation of tumor suppressor genes.
locus specific techniques following bisulfite conversion of unmethylated cytosines, while
driven gene transfer technologies.
nowadays array- and next generation sequencing-based techniques are used for high-
resolution genome-wide analysis.
Results: Our current research shows that loss of cul3 in the liver leads to the formation
of cancer stem cells which produce high levels of Il8/KC. This factor results in a block to
stem cell differentiation and which again results in treatment resistance. As Il8 leads to an
inactivated by the polycomb repressive complex 2, while hypomethylation is associated
activation of the mTOR signalling pathway we showed that treating cul3 deficient cancer Results: In human HCC, hypermethylation is frequently observed in genes known to be
stem cells with mTOR inhibitors induces stem cell differentiation and overcomes treatment with loss of imprinting. Vertical integration of genome-wide methylation analysis with other
resistance in vitro and in vivo. Interestingly the number of circulating tumor stem cells in levels of genetic and expression profiling has allowed for the identification of new tumor
HCC patients correlated significantly with the levels of Il8 in vivo. suppressor gene candidates in human HCC.

Conclusions: We present evidence that liver cancer stem cells produce IL8 to maintain Conclusions: In addition, significantly higher methylation has been demonstrated in the
their stem cell state and at the same time protect themselves against cytotoxic drugs. group of CTNNB1-mutated HCCs suggesting that methylation profiling may significantly
mTOR inhibition presents a way to overcome this block and sensitize these cells to contribute to a comprehensive molecular classification of human hepatocarcinogenesis.
treament.