NFkB1 is a suppressor of neutrophil-driven hepatocellular carcinoma

C.L. Wilson1, D. Jurk, N. Fullard1, P. Banks1, A. Page1, S. Luli1, A.M. Elsharkawy, R.G. Gieling, Bagchi Chakraborty, C. Fox1 , C. Richardson, K. Callaghan1, G.E. Blair, N. Fox, A. Lagnado,

Nature Communications 6, Article number: 6818

Speaker: Yi-Zhen Wu (吳宜臻)                            Time: 14:00~15:00, Apr, 13 2016

Commentator: Dr. Chia-Jui Yen (顏家瑞醫師)    Place: Room 601

Abstract:

Hepatocellular carcinoma (HCC), also called malignant hepatoma, is the most common type of liver cancer. Leukocytes are considered to be a regulator of tumour growth which found in the HCC microenvironment and persistence of neutrophils is a pathological feature in the chronic liver disease. Hence the authors want to explore how neutrophils contribute to disease progression and tumour development. In this study, authors used a diethylnitrosamine (DEN)-induced murine HCC model, where they found that neutrophils are the important functional contributors to inflammation-driven HCC and also a pro-tumor mechanism of stimulating hepatocellular ROS and telomere DNA damage in bystander hepatocytes. In the authors previous study has shown that neutrophil recruitment is enhanced in nfkb1^-/- mice. Here, authors further found that the p50:p50 dimers of NFkBcooperated with HDAC1 are able to repress the neutrophil chemokine network, including S100A8/9, CXCL1 and CXCL2. Therefore, the function of tumour suppression in nfkb1 for HCC is operated via p50:p50 dimers. Authors also generated a genetically modified mouse bring a single alanine (Ala) mutation at Ser340, Nfkb1^S340A/S340A which can not interact with HDAC1 is able to enhance DEN injury-induced expression of neutrophil chemokines and increase the susceptibility to HCC. The pro-tumour functions for neutrophils and that inhibition of neutrophil recruitment or activities may be potential treatment options to chronic inflammatory disease

References:

1.         Moles, A. et al. A TLR2/S100A9/CXCL-2 signaling network is necessary for neutrophil recruitment in acute and chronic liver injury in the mouse. J. Hepatol. 60, 782–791 (2014).

2.         Rajendrasozhan, S., Chung, S., Sundar, I. K., Yao, H. & Rahman, I. Targeted disruption of NF-{kappa}B1 (p50) augments cigarette smoke-induced lung inflammation and emphysema in mice: a critical role of p50 in chromatin remodeling. Am. J. Physiol. Lung Cell. Mol. Physiol. 298, L197–L209 (2010).