NFκB1 is a suppressor of neutrophil-driven hepatocellular carcinoma

Wilson, C. L., Jurk, D., Fullard, N., Banks, P., Page, A., Luli, S., Elsharkawy, A. M., Gieling, Roben, Chakraborty, J. Bagchi, Fox, C., Richardson, C., Callaghan, K., Blair, G. E., Fox, N., Lagnado, A., Passos, J. F., Moore, A. J., Smith, G. R., Tiniakos, D. G., Mann, J., Oakley, F. and Mann, D. A. (2015) NFκB1 is a suppressor of neutrophil-driven hepatocellular carcinoma. Nature Communications, 6 (1). p. 6818. ISSN 2041-1723

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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.

Item Type: Article
Additional Information: Funding information: We thank Professor Nancy Hogg (CRUK London Research Institute) for kindly providing s100a9−/− mice, Professor Alistair Burt (The University of Adelaide) for access to human patient tissue and the Newcastle University Bioinformatics Unit for assistance with in silico analysis of p50 protein structure. This work was funded by a European Commission FP7 grant ‘INFLA-CARE’ (EC Contract No. 223151; and supported by grants from the UK Medical Research Council (Grant G0700890, MR/K0019494/1 and M501700 to D.A.M. and G0900535 to F.O.) and the Wellcome Trust (WT086755MA to D.A.M.). The IVIS system was purchased under a Wellcome Trust Equipment Grant (087961) awarded to D.A.M and others.
Subjects: A300 Clinical Medicine
Department: Faculties > Health and Life Sciences > Applied Sciences
Depositing User: Paul Burns
Date Deposited: 06 Jul 2018 16:39
Last Modified: 30 May 2023 08:00

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