Loss of NF-κB1 Promotes Gastric Cancer through Cytokine Driven Chronic Inflammation (#312)
Gastric cancer (GC) is the second most common cause of cancer-associated mortality. It has a poor prognosis, with new treatment and prevention strategies focused on impeding the role of chronic inflammation in disease progression. We present a new mouse model of invasive GC based on the loss of the NF-κB family member, NF-κB1. We show that loss of NF-κB1 results in the induction of inflammation (gastritis), gastric atrophy and a series of malignant changes that culminate in invasive gastric adeno-carcinoma. Importantly, disease manifestation occurs independently of H. pylori infection and even in the complete absence of commensal microbiota. This is the first GC model that recapitulates all stages of invasive human disease and pertinently, reduced nfκb1 promoter activity due to polymorphisms/mutations are associated with a significant fraction of human GC in North East Asia
We have generated bone marrow chimeric mice to demonstrate that loss of NF-κB1 in both inflammatory and gastric epithelial cells (GECs) is required for the development of GC. We also demonstrate that nuclear extracts from gastric epithelial cells of wt mice predominantly contained NF-κB1 homodimer complexes, which were of course absent from the cells of nfkb1-/-mice. NF-κB1 homo-dimers are known to associate with Histone deacetylase-1 (HDAC-1) to function as a repressor of NF-κB driven activation of several inflammatory genes within T cells and macrophages. Pertinently we found elevated levels of several pro-inflammatory cytokines (e.g. IL-1β, IL-6, IL-8, IL-17 and TNF-α, all known NF-κB targets) in the sera and GC lesions of nfkb1-/- mice. RNAseq analysis of the lymphoid, myeloid and epithelial cells isolated from the stomachs of young nfkb1-/-mice identified myeloid cells as the dominant source of these cytokines. Collectively, our findings demonstrate that NF-κB1 functions as a tumour suppressor in GC and provides anovel model to test emerging therapeutic strategies for gastric cancer treatment.