Page 47 - ebook HCC

44 PROGRAMME AND ABSTRACTS GENEVA, SWITZERLAND EASL HCC SUMMIT 45
FEBRUARY 13 - 16, 2014

OXIDATIVE STRESS PROMOTES PATHOLOGICAL TRANSCRIPTIONAL PATHWAYS IN METABOLISM
LIVER POLYPLOIDIZATION IN NAFLD AND HEPATOCELLULAR CARCINOMA

Géraldine Gentric , Dominique Couton , Valérie Paradis , Bernard Fromenty , Stephan Herzig 1
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Séverine Celton-Morizur , Chantal Desdouets 1 1 Joint Department Molecular Metabolic Control, German Cancer Research Center and
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1 Development Reproduction and Cancer, Institut Cochin Inserm U1016, Paris 75014, Center for Molecular Biology Heidelberg, Heidelberg, Germany
2 Pathology Department, Beaujon Hospital, Clichy, Université de Rennes, Inserm U991,
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Rennes, France Corresponding author’s e-mail: s.herzig@dkfz.de
Corresponding author’s e-mail: chantal.desdouets@inserm.fr Cancer development and progression are influenced by genetic, epigenetic, and
environmental factors. Large-scale epidemiological studies have demonstrated that
Introduction: Polyploidization is one of the most dramatic changes that occur in the the Metabolic Syndrome and its components obesity, insulin resistance, and type 2
genome. Physiological polyploidization events have been observed both during liver diabetes are associated with a substantial increase in cancer risk, particularly including
development and throughout adult life. We now show that pathological polyploidization hepatocellular carcinoma (HCC). Consequently, the American Cancer Society has named
takes place in nonalcoholic fatty liver disease (NAFLD), a widespread hepatic metabolic
obesity as one of the most important risk factors for a broad range of cancer entities, being
BASIC SPEAKERS ABSTRACTS carcinoma (HCC) development. While a plethora of data confirms increased cancer risk in obese and diabetic patients, BASIC SPEAKERS ABSTRACTS
disorder that is nowadays suspected as being an emerging menace for hepatocellular
responsible for up to 20% of all cancer deaths in the United States.
common pathways in metabolism and cancer development and the mechanistic links
between the Metabolic Syndrome and HCC remain elusive.
Results: Using NAFLD murine models, we demonstrate that fatty liver parenchyma
In this respect, major components of the Metabolic Syndrome, including insulin resistance,
shows altered polyploidization process, with a specific increase in the highly mononuclear
polyploid population, rarely observed in normal hepatic parenchyma. Significantly, this
hepatocyte ploidy alteration is also observed in patients with nonalcoholic steatohepatitis
molecular checkpoints in energy homeostasis. A metabolic checkpoint function can in
(NASH). We also found that NAFLD polyploidization occurs in response to a G2/M DNA dyslipidemia, and chronic inflammation are triggered by the de-regulation of specific
many cases be attributed to the activity of transcription factors, integrating and translating
damage signal, preventing activation of the Cyclin B1/Cdk1 complex and thus inducing dietary, hormonal, and inflammatory signals into alterations of genetic and metabolic
endoreplication cycles. Oxidative stress during NAFLD induces this DNA damage programs in corresponding target tissues.
response. Upon antioxidant treatment, NAFLD hepatocytes resume normal cell division
cycles leading to the restoration of physiological polyploidy. This presentation will discuss if and how aberrations in normal transcription factor functions
are causally linked not only to the pathogenesis of obesity-related type 2 diabetes but also
Conclusions: Collectively, these findings indicate that oxidative stress promotes to metabolic aberrations in the tumor-bearing state as well as the risk for HCC.
pathological polyploidization, which represents an early event in NAFLD and might have
a pathogenic role in HCC.