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Title: Loss of NFKB1 Results in Expression of Tumor Necrosis Factor and Activation of STAT1 to Promote Gastric Tumorigenesis in Mice.
Austin Authors: Low, Jun T;Christie, Michael;Ernst, Matthias ;Dumoutier, Laure;Preaudet, Adele;Ni, Yanhong;Griffin, Michael D W;Mielke, Lisa A;Strasser, Andreas;Putoczki, Tracy L;O'Reilly, Lorraine A
Affiliation: Institut de Duve, Avenue Hippocrate 75 - B1.74.05, B-1200 Bruxelles, Belgium
Department of Surgery, The University of Melbourne, Parkville, Victoria 3050, Australia
La Trobe University School of Cancer Medicine, Heidelberg, Victoria 3084, Australia
Department of Pathology, University of Melbourne, Parkville, Victoria 3010, Australia
Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, 3010, Australia
Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, 3010, Australia
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia
Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3050, Australia
Visiting scientist from Central Laboratory, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China to The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia
Issue Date: 19-Jun-2020 2020-06-19
Publication information: Gastroenterology 2020; online first: 19 June
Abstract: 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 Nfkb1-/-Stat1-/- 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, Nfkb1-/-Il6-/-, Nfkb1-/-Il22-/- and Nfkb1-/-Il11Rα-/- mice still developed gastric tumors, although the absence of IL11 receptor (IL11R) significantly reduced development of invasive gastric tumors. Stomachs from Nfkb1-/-Tnf-/- 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.
DOI: 10.1053/j.gastro.2020.06.039
ORCID: 0000-0002-6399-1177
PubMed URL: 32569771
Type: Journal Article
Subjects: inflammation
inhibitory signal
programmed cell death 1 ligand 1
Appears in Collections:Journal articles

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