Wilson C L, Jurk D, Fullard N, Banks P, Page A, Luli S, Elsharkawy A M, Gieling R G, 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, Mann D A
Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
Newcastle University Institute for Ageing and Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle Upon Tyne NE4 5PL, UK.
Nat Commun. 2015 Apr 16;6:6818. doi: 10.1038/ncomms7818.
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.
肝细胞癌（HCC）在慢性肝炎的背景下发生。在HCC微环境中发现的白细胞被认为是肿瘤生长的调节因子。我们发现，抗体介导的肝中性粒细胞耗竭可减轻二乙基亚硝胺（DEN）诱导的小鼠HCC，后者会刺激肝细胞ROS和端粒DNA损伤。我们还报告了肝细胞nfkb1通过p50:p50二聚体和共抑制因子HDAC1发挥的一种以前未被认识的肿瘤抑制功能。这些抗炎蛋白共同转录抑制S100A8/9、CXCL1和CXCL2中性粒细胞趋化因子网络的肝脏表达。nfkb1的缺失会促进与衰老相关的慢性肝病（CLD），其特征为脂肪变性、中性粒细胞增多、纤维化、肝细胞端粒损伤和HCC。携带旨在选择性破坏p50:p50:HDAC1复合物的突变的Nfkb1(S340A/S340A)小鼠对HCC更易感；相比之下，缺乏S100A9的小鼠表达的中性粒细胞趋化因子减少，可免受HCC侵害。抑制CLD中中性粒细胞的积聚或靶向其促肿瘤活性可能为HCC提供治疗机会。
