Discovering the tumour suppressor function of hepatocyte NF-κB1

Abstract

Aberrant activation of the NF-κB signalling pathway is associated with the development of many cancers. We have previously demonstrated that global NFKB1 knock-out mice (Nfkb1-/-) develop spontaneous low-level chronic inflammation, liver disease and cancer as they age. In addition, when they are given the carcinogen diethylnitrosamine (DEN) to induce liver cancer they develop significantly more tumours and at an earlier stage. Nfkb1-/- mice present with defects in both the immune and the epithelial compartment, therefore it is not possible to dissect the cell-specific role of NFKB1 as a tumour suppressor. To determine the hepatocyte-specific tumour suppressor role of NFKB1, we have generated a novel hepatocyte-specific NFKB1 knock-out mouse (Nfkb1hep-/-). WT or Nfkb1hep-/- mice were subjected to different treatment regimens with either the hepatotoxin CCl4 or the carcinogen DEN to induce acute inflammation, fibrosis or hepatocellular carcinoma, to assess the role of hepatocyte NFKB1 in the progression from liver inflammation to cancer. In addition, acute CCl4 injury and chronic DEN injury experiments were conducted in AAV-TBG-CRE mice, whereby adenoviral deletion of hepatocyte NFKB1 was induced. Here we demonstrate that, while hepatocyte Nfkb1 showed a limited protective role in acute inflammation and fibrosis, mice lacking hepatocyte Nfkb1 displayed a significant increase in tumour number and grade when compared with WT mice in the chronic DEN model. Importantly, they also displayed a higher percentage of PCNA+ proliferative tumours, indicative of a more aggressive tumour phenotype. Immune cell infiltration including monocytes, macrophages and neutrophils was significantly increased in Nfkb1hep-/- mice. These data provide strong evidence that NFKB1 acts as a hepatocyte-specific tumour suppressor, playing an essential role in the control of inflammation, tumour initiation, progression and proliferation.