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; D. A. Mann

doi:10.1038/ncomms7818

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. MannF. Oakley, D. A. Mann

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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.

Original language	English
Article number	6818
Pages (from-to)	1-13
Number of pages	13
Journal	Nature Communications
Volume	6
Issue number	1
DOIs	https://doi.org/10.1038/ncomms7818
Publication status	Published - 16 Apr 2015
Externally published	Yes

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Wilson et al - NFκB1 is a suppressor of neutrophil-driven hepatocellular carcinoma OAFinal published version, 3.85 MBLicence: CC BY

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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). NFκB1 is a suppressor of neutrophil-driven hepatocellular carcinoma. Nature Communications, 6(1), 1-13. [6818]. https://doi.org/10.1038/ncomms7818

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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",

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doi = "10.1038/ncomms7818",

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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, 'NFκB1 is a suppressor of neutrophil-driven hepatocellular carcinoma', Nature Communications, vol. 6, no. 1, 6818, pp. 1-13. https://doi.org/10.1038/ncomms7818

TY - JOUR

T1 - NFκB1 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.

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. 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.

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. 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.

U2 - 10.1038/ncomms7818

DO - 10.1038/ncomms7818

M3 - Article

VL - 6

SP - 1

EP - 13

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 6818

ER -

NFκB1 is a suppressor of neutrophil-driven hepatocellular carcinoma

Abstract

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