TY - JOUR
T1 - Loss of NF-κB1 Causes Gastric Cancer with Aberrant Inflammation and Expression of Immune Checkpoint Regulators in a STAT-1-Dependent Manner
AU - O'Reilly, Lorraine A.
AU - Putoczki, Tracy L.
AU - Mielke, Lisa A.
AU - Low, Jun T.
AU - Lin, Ann
AU - Preaudet, Adele
AU - Herold, Marco J.
AU - Yaprianto, Kelvin
AU - Tai, Lin
AU - Kueh, Andrew
AU - Pacini, Guido
AU - Ferrero, Richard L.
AU - Gugasyan, Raffi
AU - Hu, Yifang
AU - Christie, Michael
AU - Wilcox, Stephen
AU - Grumont, Raelene
AU - Griffin, Michael D.W.
AU - O'Connor, Liam
AU - Smyth, Gordon K.
AU - Ernst, Mathias
AU - Waring, Paul
AU - Gerondakis, Steve
AU - Strasser, Andreas
PY - 2018/3/20
Y1 - 2018/3/20
N2 - 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. The links between NF-κB signaling, inflammation, and tumorigenesis are poorly understood. O'Reilly et al. reveal that NF-κB1 deficiency causes gastric cancer by dysregulating inflammation and immune checkpoints through a STAT1-dependent process. This may explain how polymorphisms in NFKB1 that impair its expression predispose to the development of epithelial cancers.
AB - 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. The links between NF-κB signaling, inflammation, and tumorigenesis are poorly understood. O'Reilly et al. reveal that NF-κB1 deficiency causes gastric cancer by dysregulating inflammation and immune checkpoints through a STAT1-dependent process. This may explain how polymorphisms in NFKB1 that impair its expression predispose to the development of epithelial cancers.
UR - http://www.scopus.com/inward/record.url?scp=85043771139&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2018.03.003
DO - 10.1016/j.immuni.2018.03.003
M3 - Article
AN - SCOPUS:85043771139
SN - 1074-7613
VL - 48
SP - 570
EP - 583
JO - Immunity
JF - Immunity
IS - 3
ER -