The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia.
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia.
Immunity. 2018 Mar 20;48(3):570-583.e8. doi: 10.1016/j.immuni.2018.03.003.
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.
NFKB1 基因的多态性使其表达减少与人类炎症性疾病和上皮性癌症的风险增加有关。其潜在机制尚不清楚，鉴于 NF-κB 信号通路通常具有促进肿瘤发生的活性，这种关联令人费解。在这里，我们已经表明，NF-κB1 缺失，即使缺失一个等位基因，也会导致小鼠自发性侵袭性胃癌 (GC)，这与人类肠型胃腺癌的组织病理学进展相吻合。骨髓嵌合体显示，NF-κB1 在上皮细胞和造血细胞中都发挥肿瘤抑制功能。RNA-seq 分析表明，NF-κB1 缺失导致 JAK-STAT 信号异常，从而导致炎症、抗原呈递和免疫检查点效应物的表达失调。STAT1 的同时缺失阻止了这些免疫异常和 GC 的发生。这些发现为阐明降低 NFKB1 表达的多态性如何使人类易患上皮性癌症提供了机制上的见解，突出了 STAT1 的促肿瘤发生活性，并确定了 GC 的可靶向弱点。
