Publications & Reports

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
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.

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-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.

Link to publisher’s web site

Publication

  • Journal: Immunity
  • Published: 20/03/2018
  • Volume: 48
  • Issue: 3
  • Pagination: 570-583

Author