NFκB1 is a suppressor of neutrophil-driven hepatocellular carcinoma

C. L. Wilson, D. Jurk, N. Fullard, P. Banks, A. Page, S. Luli, A. M. Elsharkawy, R. G. Gieling, J. Bagchi Chakraborty, C. Fox, C. Richardson, K. Callaghan, G. E. Blair, N. Fox, A. Lagnado, J. F. Passos, A. J. Moore, G. R. Smith, D. G. Tiniakos, J. Mann, F. Oakley () and D. A. Mann ()
Additional contact information
C. L. Wilson: Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University
D. Jurk: Newcastle University Institute for Ageing and Institute for Cell and Molecular Biosciences, Newcastle University
N. Fullard: Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University
P. Banks: Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University
A. Page: Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University
S. Luli: Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University
A. M. Elsharkawy: Liver Unit, University Hospitals Birmingham
R. G. Gieling: Hypoxia and Therapeutics Group, Manchester Pharmacy School, University of Manchester
J. Bagchi Chakraborty: Immunology and Inflammation, Imperial College of Science, Technology and Medicine, Hammersmith Hospital
C. Fox: Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University
C. Richardson: Centre for Behaviour and Evolution/Institute of Neuroscience, Medical School, Newcastle University
K. Callaghan: Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University
G. E. Blair: Faculty of Biological Sciences, School of Molecular and Cellular Biology, University of Leeds
N. Fox: Faculty of Biological Sciences, School of Molecular and Cellular Biology, University of Leeds
A. Lagnado: Newcastle University Institute for Ageing and Institute for Cell and Molecular Biosciences, Newcastle University
J. F. Passos: Newcastle University Institute for Ageing and Institute for Cell and Molecular Biosciences, Newcastle University
A. J. Moore: Institute for Cell and Molecular Biosciences, Newcastle University
G. R. Smith: Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University
D. G. Tiniakos: Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University
J. Mann: Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University
F. Oakley: Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University
D. A. Mann: Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University

Nature Communications, 2015, vol. 6, issue 1, 1-15

Abstract: Abstract Hepatocellular carcinoma (HCC) develops on the background of chronic hepatitis. Leukocytes found within the HCC microenvironment are implicated as regulators of tumour growth. We show that diethylnitrosamine (DEN)-induced murine HCC is attenuated by antibody-mediated depletion of hepatic neutrophils, the latter stimulating hepatocellular ROS and telomere DNA damage. We additionally report a previously unappreciated tumour suppressor function for hepatocellular nfkb1 operating via p50:p50 dimers and the co-repressor HDAC1. These anti-inflammatory proteins combine to transcriptionally repress hepatic expression of a S100A8/9, CXCL1 and CXCL2 neutrophil chemokine network. Loss of nfkb1 promotes ageing-associated chronic liver disease (CLD), characterized by steatosis, neutrophillia, fibrosis, hepatocyte telomere damage and HCC. Nfkb1S340A/S340Amice carrying a mutation designed to selectively disrupt p50:p50:HDAC1 complexes are more susceptible to HCC; by contrast, mice lacking S100A9 express reduced neutrophil chemokines and are protected from HCC. Inhibiting neutrophil accumulation in CLD or targeting their tumour-promoting activities may offer therapeutic opportunities in HCC.

Date: 2015
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DOI: 10.1038/ncomms7818

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