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). ISSN 2041-1723
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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.
Item Type: | Article |
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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: | 12 Oct 2019 10:45 |
URI: | http://nrl.northumbria.ac.uk/id/eprint/34864 |
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