Loss of NF-kappaB1 causes gastric cancer with aberrant inflammation and expression of immune checkpoint regulators in a STAT-1-dependent manner
- O'Reilly, LA; Putoczki, TL; Mielke, LA; Low, JT; Lin, A; Preaudet, A; Herold, MJ; Yaprianto, K; Tai, L; Kueh, A; Pacini, G; Ferrero, RL; Gugasyan, R; Hu, Y; Christie, M; Wilcox, S; Grumont, R; Griffin, MDW; O'Connor, L; Smyth, GK; Ernst, M; Waring, P; Gerondakis, S; Strasser, A;
Publication Year 2018-03-20, Volume 48, Issue #3, Page 570-583 e8
- Journal Title
- Publication Type
- Journal Article
- 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-kappaB signaling reportedly typically exerts pro-tumorigenic activity. Here we have shown that NF-kappaB1 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-kappaB1 exerted tumor suppressive functions in both epithelial and hematopoietic cells. RNA-seq analysis showed that NF-kappaB1 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.
- PubMed ID
- Publisher's Version
- Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2018-04-11 08:53:37Last Modified: 2018-04-11 09:52:08