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Immunity. 2018 Mar 20;48(3):570-583.e8. doi: 10.1016/j.immuni.2018.03.003.

Loss of NF-κB1 Causes Gastric Cancer with Aberrant Inflammation and Expression of Immune Checkpoint Regulators in a STAT-1-Dependent Manner.

Author information

1
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia. Electronic address: oreilly@wehi.edu.au.
2
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia.
3
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
4
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia; Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK.
5
Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia.
6
Healthy Ageing, Life Sciences Discipline, The Burnet Institute, Melbourne, Victoria 3004, Australia; Central Clinical School, Monash University, Melbourne, Victoria 3004, Australia.
7
Centre for Translational Pathology, University of Melbourne, Parkville, Victoria 3010, Australia.
8
Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia; Cancer Program, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Victoria, Australia.
9
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.
10
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Mathematics and Statistics, The University of Melbourne, Parkville, Victoria 3010, Australia.
11
Olivia Newton-John Cancer Research Institute and La Trobe University School of Cancer Medicine, Heidelberg, Victoria 3084, Australia.
12
Department of Pathology, The University of Melbourne, Parkville 3052, Victoria, Australia.
13
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia. Electronic address: strasser@wehi.edu.au.

Abstract

Polymorphisms in NFKB1 that diminish its expression have been linked to human inflammatory diseases and increased risk for epithelial cancers. The underlying mechanisms are unknown, and the link is perplexing given that NF-κB signaling reportedly typically exerts pro-tumorigenic activity. Here we have shown that NF-κB1 deficiency, even loss of a single allele, resulted in spontaneous invasive gastric cancer (GC) in mice that mirrored the histopathological progression of human intestinal-type gastric adenocarcinoma. Bone marrow chimeras revealed that NF-κB1 exerted tumor suppressive functions in both epithelial and hematopoietic cells. RNA-seq analysis showed that NF-κB1 deficiency resulted in aberrant JAK-STAT signaling, which dysregulated expression of effectors of inflammation, antigen presentation, and immune checkpoints. Concomitant loss of STAT1 prevented these immune abnormalities and GC development. These findings provide mechanistic insight into how polymorphisms that attenuate NFKB1 expression predispose humans to epithelial cancers, highlighting the pro-tumorigenic activity of STAT1 and identifying targetable vulnerabilities in GC.

PMID:
29562203
DOI:
10.1016/j.immuni.2018.03.003
[Indexed for MEDLINE]

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