@article{1e6458cbc70440a09ea44fe9e45b3af9,
title = "NFκB1 is a suppressor of neutrophil-driven hepatocellular carcinoma",
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.",
author = "Wilson, {C. L.} and D. Jurk and N. Fullard and P. Banks and A. Page and S. Luli and Elsharkawy, {A. M.} and Gieling, {R. G.} and Chakraborty, {J. Bagchi} and C. Fox and C. Richardson and K. Callaghan and Blair, {G. E.} and N. Fox and A. Lagnado and Passos, {J. F.} and Moore, {A. J.} and Smith, {G. R.} and Tiniakos, {D. G.} and J. Mann and F. Oakley and Mann, {D. A.}",
year = "2015",
month = apr,
day = "16",
doi = "10.1038/ncomms7818",
language = "English",
volume = "6",
pages = "1--13",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Research",
number = "1",
}