Activity of NFkB transcription factors and signaling via STAT are frequently altered in gastric cancer cells. Mice lacking NFKB1 (Nfkb1 mice) develop invasive gastric cancer and their gastric tissues have increased levels of cytokines, such as interleukin (IL)6, IL22, IL11, and tumor necrosis factor (TNF), as well as increased activation of signal transducer and activator of transcription 1 (STAT1). We investigated whether these cytokines were required for STAT1 activation in gastric tissues of mice and critical for gastric tumorigenesis. We crossed Nfkb1 mice with Il6, Il22, Il11Rα and Tnf mice. Stomach tissues from compound mutant mice were analyzed by histology, immunoblotting and RNA sequencing. Lymphoid, myeloid and epithelial cells were isolated from stomachs and the levels of cytokines were determined by flow cytometric analysis. Nfkb1 mice developed gastritis, oxyntic atrophy, gastric dysplasia and invasive tumors, whereas Nfkb1Stat1 mice did not, even when followed for as long as 2 years. The levels of Il6, Il11, and Il22 and Tnf mRNA were increased in the body and antrum of the stomachs from Nfkb1 mice, from 6 months of age. However, Nfkb1Il6, Nfkb1Il22 and Nfkb1Il11Rα mice still developed gastric tumors, although the absence of IL11 receptor (IL11R) significantly reduced development of invasive gastric tumors. Stomachs from Nfkb1Tnf mice exhibited significantly less gastritis and oxyntic atrophy and fewer tumors than Nfkb1 mice. This correlated with reduced activation of STAT1 and STAT3 and fewer numbers of T cells and B cells infiltrating the gastric body. Loss of STAT1 significantly reduced expression of PD-L1 on epithelial and myeloid (CD11b) cells in the gastric mucosa of Nfkb1 mice, indeed to the levels observed on the corresponding cells from wild-type mice. In studies of gastric tumor development in knockout mice, we found that loss of NFKB1 causes increased expression of TNF in the stomach and thereby drives activation of STAT1, resulting in an inflammatory immune response and the development of gastric cancer. IL11R appears to be required for the progression of gastric tumors to the invasive stage. These findings suggest that inhibitors of TNF, and possibly also inhibitors of IL11/IL11Rα, might be useful in the treatment of gastric cancer.
Low, Jun T ; Christie, Michael ; Ernst, Matthias ; Dumoutier, Laure ; Preaudet, Adele ; et. al. Loss of NFKB1 Results in Expression of Tumor Necrosis Factor and Activation of STAT1 to Promote Gastric Tumorigenesis in Mice.. In: Gastroenterology, (2020)