Loss of NFKB1 Results in Expression of Tumor Necrosis Factor and Activation of Signal Transducer and Activator of Transcription 1 to Promote Gastric Tumorigenesis in Mice
Loss of NFKB1 Results in Expression of Tumor Necrosis Factor and Activation of Signal Transducer and Activator of Transcription 1 to Promote Gastric Tumorigenesis in Mice
复制标题
DOI：
10.1053/j.gastro.2020.06.039
复制
发表时间：
2020-10-01
期刊：
影响因子：
29.4
通讯作者：
O'Reilly, Lorraine A.
中科院分区：
文献类型：
--
作者：
Low, Jun T.;Christie, Michael;O'Reilly, Lorraine A.
背景与目的：胃癌细胞核因子κ B转录因子的活性及信号转导和转录激活因子（STAT）的信号转导经常发生改变。缺乏NFKB 1的小鼠（Nfkb 1（-/-）小鼠）发生浸润性胃癌，其胃组织中细胞因子水平升高，如白细胞介素（IL）6、IL 22、IL 11和肿瘤坏死因子（TNF），以及STAT 1活化增加。我们研究了这些细胞因子是否是小鼠胃组织中STAT 1激活所必需的，并且对胃肿瘤发生至关重要。方法：我们将Nfkb 1（-/-）小鼠与Il 6（-/-）、Il 22（-/-）、Il 11 R α（-/-）和Tnf（-/-）小鼠杂交。通过组织学、免疫印迹和RNA测序分析来自复合突变小鼠的胃组织。从胃中分离出类淋巴细胞、髓样细胞和上皮细胞，并通过流式细胞术分析确定细胞因子的水平。研究结果：Nfkb 1（-/-）小鼠出现胃炎、泌酸性萎缩、胃发育不良和侵袭性肿瘤，而Nfkb 1（-/-）Stat 1（-/-）小鼠没有，即使随访长达2年。IL 6、IL 11、IL 22和TNF信使RNA水平在3-6月龄Nfkb 1（-/-）小鼠的体部和胃窦中增加。然而，Nfkb 1（-/-）Il 6（-/-）、Nfkb 1（-/-）Il 22（-/-）和Nfkb 1（-/-）Il 11 R α（-/-）小鼠仍然发生胃肿瘤，尽管IL 11受体（IL 11 R）的缺失显著降低了侵袭性胃肿瘤的发生。Nfkb 1（-/-）Tnf（-/-）小鼠的胃表现出比Nfkb 1（-/-）小鼠显著更少的胃炎和泌酸性萎缩以及更少的肿瘤。这与STAT 1和STAT 3的活化减少以及浸润胃体的T细胞和B细胞数量减少相关。Nfkb 1（-/-）小鼠胃粘膜上皮细胞和髓样（CD 11b（+））细胞上STAT 1或TNF的缺失显著降低了PD-L1的表达--事实上，降低到野生型小鼠相应细胞上观察到的水平。结论：在基因敲除小鼠胃肿瘤发展的研究中，我们发现NFKB 1的缺失导致胃中TNF表达增加，从而驱动STAT 1的激活，导致炎症免疫反应和胃癌的发展。IL 11 R似乎是胃肿瘤进展到侵袭性阶段所必需的。这些发现表明，TNF抑制剂，也可能是IL 11/IL 11 R α抑制剂，可能在胃癌的治疗中是有用的。
BACKGROUND & AIMS: Activity of nuclear factor kappa B transcription factors and signaling via signal transducer and activator of transcription (STAT) are frequently altered in gastric cancer cells. Mice lacking NFKB1 (Nfkb1(-/-) mice) develop invasive gastric cancer, and their gastric tissues have increased levels of cytokines, such as interleukin (IL) 6, IL22, IL11, and tumor necrosis factor (TNF), as well as increased activation of STAT1. We investigated whether these cytokines were required for STAT1 activation in gastric tissues of mice and critical for gastric tumorigenesis. METHODS: We crossed Nfkb1(-/-) mice with Il6(-/-), Il22(-/-), Il11R alpha(-/-), and Tnf(-/-) mice. Stomach tissues from compound mutant mice were analyzed by histology, immunoblotting, and RNA sequencing. Lymphoid, myeloid, and epithelial cells were isolated from stomachs, and the levels of cytokines were determined by flow cytometric analysis. RESULTS: Nfkb1(-/-) mice developed gastritis, oxyntic atrophy, gastric dysplasia, and invasive tumors, whereas Nfkb1(-/-)Stat1(-/-) mice did not, even when followed for as long as 2 years. The levels of Il6, Il11, Il22, and Tnf messenger RNA were increased in the body and antrum of the stomachs from Nfkb1(-/-) mice, from 3-6 months of age. However, Nfkb1(-/-)Il6(-/-), Nfkb1(-/-)Il22(-/-), and Nfkb1(-/-)Il11R alpha(-/-) mice still developed gastric tumors, although the absence of IL11 receptor (IL11R) significantly reduced development of invasive gastric tumors. Stomachs from Nfkb1(-/-)Tnf(-/-) mice exhibited significantly less gastritis and oxyntic atrophy and fewer tumors than Nfkb1(-/-) mice. This correlated with reduced activation of STAT1 and STAT3 and fewer numbers of T cells and B cells infiltrating the gastric body. Loss of STAT1 or TNF significantly reduced expression of PD-L1 on epithelial and myeloid (CD11b(+)) cells in the gastric mucosa of Nfkb1(-/-) mice-indeed, to the levels observed on the corresponding cells from wild-type mice. CONCLUSIONS: In studies of gastric tumor development in knockout mice, we found that loss of NFKB1 causes increased expression of TNF in the stomach and thereby drives activation of STAT1, resulting in an inflammatory immune response and the development of gastric cancer. IL11R appears to be required for the progression of gastric tumors to the invasive stage. These findings suggest that inhibitors of TNF, and possibly also inhibitors of IL11/IL11R alpha, might be useful in the treatment of gastric cancer.y