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. 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.
authors: Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors: C L
authors: CL
authors: Wilson
authors: Newcastle University Institute for Ageing and Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle Upon Tyne NE4 5PL, UK.
authors: D
authors: D
authors: Jurk
authors: Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors: N
authors: N
authors: Fullard
authors: Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors: P
authors: P
authors: Banks
authors: Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors: A
authors: A
authors: Page
authors: Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors: S
authors: S
authors: Luli
authors: Liver Unit, University Hospitals Birmingham, Birmingham B15 2TH, UK.
authors: A M
authors: AM
authors: Elsharkawy
authors: Hypoxia and Therapeutics Group, Manchester Pharmacy School, University of Manchester, Manchester M13 9PT, UK.
authors: R G
authors: RG
authors: Gieling
authors: Department of Medicine, Immunology and Inflammation, Imperial College of Science, Technology and Medicine, Hammersmith Hospital, London W12 0NN, UK.
authors: J Bagchi
authors: JB
authors: Chakraborty
authors: Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors: C
authors: C
authors: Fox
authors: Centre for Behaviour and Evolution/Institute of Neuroscience, Medical School, Newcastle University, Newcastle Upon Tyne NE2 4HH, UK.
authors: C
authors: C
authors: Richardson
authors: Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors: K
authors: K
authors: Callaghan
authors: Faculty of Biological Sciences, School of Molecular and Cellular Biology, University of Leeds, Garstang Building, Leeds LS2 9JT, UK.
authors: G E
authors: GE
authors: Blair
authors: Faculty of Biological Sciences, School of Molecular and Cellular Biology, University of Leeds, Garstang Building, Leeds LS2 9JT, UK.
authors: N
authors: N
authors: Fox
authors: Newcastle University Institute for Ageing and Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle Upon Tyne NE4 5PL, UK.
authors: A
authors: A
authors: Lagnado
authors: Newcastle University Institute for Ageing and Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle Upon Tyne NE4 5PL, UK.
authors: J F
authors: JF
authors: Passos
authors: Institute for Cell and Molecular Biosciences, Newcastle University, Catherine Cookson Building, Framlington Place, Newcastle Upon Tyne NE2 4HH, UK.
authors: A J
authors: AJ
authors: Moore
authors: Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors: G R
authors: GR
authors: Smith
authors: Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors: D G
authors: DG
authors: Tiniakos
authors: Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors: J
authors: J
authors: Mann
authors: Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors: F
authors: F
authors: Oakley
authors: Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors: D A
authors: DA
authors: Mann
mesh_terms: D000477:Alkylating Agents / Q000633:toxicity; D000818:Animals; D040501:Calgranulin A / Q000235:genetics; D040502:Calgranulin B / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology; D054360:Chemokine CXCL1 / Q000235:genetics; D054426:Chemokine CXCL2 / Q000235:genetics; D004052:Diethylnitrosamine / Q000633:toxicity; D008107:Liver Diseases / Q000235:genetics / Q000276:immunology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D052002:NF-kappa B p50 Subunit / Q000235:genetics*; D009504:Neutrophils / Q000276:immunology*
chemical_list: D000477:Alkylating Agents; D040501:Calgranulin A; D040502:Calgranulin B; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; C475895:Cxcl1 protein, mouse; C404915:Cxcl2 protein, mouse; D052002:NF-kappa B p50 Subunit; C576329:S100A9 protein, mouse; C086145:S100a8 protein, mouse; C073701:Nfkb1 protein, mouse; D004052:Diethylnitrosamine