NFκ B1 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; D. A. Mann

doi:10.1038/ncomms7818

NFκ B1 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. MannF. Oakley, D. A. Mann

Physiology & Biomedical Engineering

Research output: Contribution to journal › Article › peer-review

74 Scopus citations

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. Nfkb1 S340A/S340A mice 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.

Original language	English (US)
Article number	6818
Journal	Nature communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms7818
State	Published - Apr 16 2015

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/ncomms7818

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Wilson, C. L., Jurk, D., Fullard, N., Banks, P., Page, A., Luli, S., Elsharkawy, A. M., Gieling, R. G., Chakraborty, J. B., 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, D. A. (2015). NFκ B1 is a suppressor of neutrophil-driven hepatocellular carcinoma. Nature communications, 6, Article 6818. https://doi.org/10.1038/ncomms7818

Wilson, CL, Jurk, D, Fullard, N, Banks, P, Page, A, Luli, S, Elsharkawy, AM, Gieling, RG, Chakraborty, JB, Fox, C, Richardson, C, Callaghan, K, Blair, GE, Fox, N, Lagnado, A, Passos, JF, Moore, AJ, Smith, GR, Tiniakos, DG, Mann, J, Oakley, F & Mann, DA 2015, 'NFκ B1 is a suppressor of neutrophil-driven hepatocellular carcinoma', Nature communications, vol. 6, 6818. https://doi.org/10.1038/ncomms7818

@article{a9d6a7516b2949eaa34bb240a7be543e,

title = "NFκ B1 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. Nfkb1 S340A/S340A mice 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.}",

note = "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 {\textquoteleft}INFLA-CARE{\textquoteright} (EC Contract No. 223151; http:// inflacare.imbb.forth.gr/) 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.",

year = "2015",

month = apr,

day = "16",

doi = "10.1038/ncomms7818",

language = "English (US)",

volume = "6",

journal = "Nature communications",

issn = "2041-1723",

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T1 - NFκ B1 is a suppressor of neutrophil-driven hepatocellular carcinoma

AU - Wilson, C. L.

AU - Jurk, D.

AU - Fullard, N.

AU - Banks, P.

AU - Page, A.

AU - Luli, S.

AU - Elsharkawy, A. M.

AU - Gieling, R. G.

AU - Chakraborty, J. Bagchi

AU - Fox, C.

AU - Richardson, C.

AU - Callaghan, K.

AU - Blair, G. E.

AU - Fox, N.

AU - Lagnado, A.

AU - Passos, J. F.

AU - Moore, A. J.

AU - Smith, G. R.

AU - Tiniakos, D. G.

AU - Mann, J.

AU - Oakley, F.

AU - Mann, D. A.

N1 - 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; http:// inflacare.imbb.forth.gr/) 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.

PY - 2015/4/16

Y1 - 2015/4/16

N2 - 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. Nfkb1 S340A/S340A mice 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.

AB - 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. Nfkb1 S340A/S340A mice 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.

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SN - 2041-1723

VL - 6

JO - Nature communications

JF - Nature communications

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ER -

NFκ B1 is a suppressor of neutrophil-driven hepatocellular carcinoma

Abstract

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