Page 62 - ebook HCC

60 PROGRAMME AND ABSTRACTS GENEVA, SWITZERLAND EASL HCC SUMMIT 61
FEBRUARY 13 - 16, 2014

NEUTROPHILS PROMOTE ROS-MEDIATED
TELOMERE DAMAGE AND HEPATOCELLULAR
CARCINOMA THAT IS NEGATIVELY REGULATED
BY HOMODIMERS OF THE NF-KB P50 SUBUNIT

Caroline L. Wilson , Saimir Luli , Diana Jurk , Paul Banks , Nicola Fullard , Neutrophil depleting antibody LY6G dramatically decreased tumor number and telomere
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Jelena Mann , Fiona Oakley , Derek A. Mann 1 damage even when used late in disease with both wt and nfkb1-/- DEN mice. Absence
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1 Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, of hepatic p50 was associated with over-expression of CXCL1 and CXCL2 and failure to
2 Institute for Ageing & Health, Newcastle University, Newcastle upon Tyne, recruit transcriptional repressor HDAC1 to their genes. In vivo imaging of transfused labeled
United Kingdom wt neutrophils confirmed that DEN-injured p50-deficient liver attracts neutrophils more
efficiently than wt liver. Antibody-mediated depletion of CXCL1 and CXCL-2 suppressed
Corresponding author’s e-mail: c.wilson@ncl.ac.uk DEN-induced neutrophil recruitment. HDAC1-mediated transcriptional repression of NF-
κB target genes is thought to be regulated by p50:p50:HDAC1 complexes. A specific
amino acid residue (Ser340) was identified as absolutely required for p50 homodimers
BASIC SPEAKERS ABSTRACTS The functional contribution of neutrophils to HCC is poorly defined. The role of neutrophils following DEN injury was phenotypically almost identical to nfkb1-/-. BASIC SPEAKERS ABSTRACTS
Introduction: High neutrophil/lymphocyte ratio is a poor prognostic indicator for HCC.
), which
S340A+/+
(but not for RelA:p50). This mutation was engineered into a mouse (nfκb1
in HCC was established in that their depletion was a successful therapeutic strategy in a
Conclusions: Hence, p50:p50:HDAC1 suppression of hepatic neutrophil chemokine
mouse model. Mechanistic work to be presented supports (i) NF-κB p50:p50 homodimer
as a tumor suppressor that limits neutrophil-mediated hepatocellular genotoxic damage
expression is an important homeostatic mechanism preventing neutrophil-mediated
by suppressing hepatic neutrophil chemokine expression and (ii) the neutrophil as a
genotoxic damage and HCC.
stimulator of ROS-induced telomere damage.
Aims: To discover the regulation of neutrophil-driven tumorogenesis in HCC.
Methodology: nfκb1 , nfκb1 S340A+/+ and wt mice challenged with diethylnitrosamine
-/-
(DEN) to induce HCC. Hepatic neutrophils and telomere DNA damage determined by
IHC and FISH. in vivo imaging (IVIS) used to track neutrophil recruitment. To determine
the contribution of neutrophil recruitment on DEN induced liver damage and tumour
development, animals were treated with anti-CXCL1 and 2 or LY6G neutrophil depleting
antibodies.
Results: DEN-induced liver cancer and human HCC is associated with striking neutrophil
accumulation and telomere damage. The nfkb1-/- mouse which lacks p50 spontaneously
develops HCC at 20 months and displays accelerated DEN-induced HCC; both models are
associated with elevated hepatic neutrophils and ROS-associated cellular and telomere
DNA damage.