Inflammasome Adaptor ASC Suppresses Apoptosis of Gastric Cancer Cells by an IL18-Mediated Inflammation-Independent Mechanism
Inflammasome Adaptor ASC Suppresses Apoptosis of Gastric Cancer Cells by an IL18-Mediated Inflammation-Independent Mechanism
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DOI：
10.1158/0008-5472.can-17-1887
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发表时间：
2018-03-01
期刊：
影响因子：
11.2
通讯作者：
Jenkins, Brendan J.
中科院分区：
文献类型：
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作者：
Deswaerte, Virginie;Nguyen, Paul;Jenkins, Brendan J.
炎性小体是慢性炎症性疾病和自身免疫性疾病中先天免疫的关键调节因子，但其在炎症相关肿瘤发生中的作用仍不明确。在这里，我们揭示了一个protumorigenic作用，在胃癌的关键炎性小体适配器凋亡相关的斑点样蛋白含有一个CARD（ASC）及其效应细胞因子IL 18。在gp 130（F/F）自发性胃癌小鼠模型中，ASC的基因消融通过增加胃上皮中的caspase-8样细胞凋亡来抑制肿瘤发生，与对骨髓细胞和粘膜炎症的影响无关。这种表型的特征在于胃肿瘤中caspase-1和NF-κ B活化的减少以及成熟IL 18表达的减少，而不是IL 1 β。在相同的模型中，IL 18的基因消融也抑制了胃肿瘤的发生，而在IL 1受体的基因消融后，IL 1 β和IL 1 α活性的阻断没有效果。与IL 1 β相比，IL 18的特异性促肿瘤作用与IL 18基因在胃肿瘤上皮中的高表达相关，IL 1 β优先在免疫细胞中表达。支持上皮特异性作用的IL 18，我们发现它是高度分泌的人胃癌细胞系。此外，通过中和抗IL 18抗体或通过CRISPR/Cas9驱动的ASC缺失的IL 18阻断增强了人胃癌细胞中的细胞凋亡。在人胃癌肿瘤的临床标本中，我们观察到升高的成熟IL 18蛋白和ASC mRNA水平之间的显著正相关。总的来说，我们的研究结果揭示了ASC/IL 18信号轴作为胃癌的候选治疗靶点。意义：炎症体激活，提高IL 18有助于驱动胃癌保护癌细胞凋亡，在这种情况下的新的治疗策略的潜在影响。(C)2017年AACR。
Inflammasomes are key regulators of innate immunity in chronic inflammatory disorders and autoimmune diseases, but their role in inflammation-associated tumorigenesis remains ill-defined. Here we reveal a protumorigenic role in gastric cancer for the key inflammasome adaptor apoptosis-related speck-like protein containing a CARD (ASC) and its effector cytokine IL18. Genetic ablation of ASC in the gp130(F/F) spontaneous mouse model of intestinal-type gastric cancer suppressed tumorigenesis by augmenting caspase-8-like apoptosis in the gastric epithelium, independently from effects on myeloid cells and mucosal inflammation. This phenotype was characterized by reduced activation of caspase-1 and NF-kappa B activation and reduced expression of mature IL18, but not IL1 beta, in gastric tumors. Genetic ablation of IL18 in the same model also suppressed gastric tumorigenesis, whereas blockade of IL1 beta and IL1 alpha activity upon genetic ablation of the IL1 receptor had no effect. The specific protumorigenic role for IL18 was associated with high IL18 gene expression in the gastric tumor epithelium compared with IL1 beta, which was preferentially expressed in immune cells. Supporting an epithelial-specific role for IL18, we found it to be highly secreted from human gastric cancer cell lines. Moreover, IL18 blockade either by a neutralizing anti-IL18 antibody or by CRISPR/Cas9-driven deletion of ASC augmented apoptosis in human gastric cancer cells. In clinical specimens of human gastric cancer tumors, we observed a significant positive correlation between elevated mature IL18 protein and ASC mRNA levels. Collectively, our findings reveal the ASC/IL18 signaling axis as a candidate therapeutic target in gastric cancer.Significance: Inflammasome activation that elevates IL18 helps drive gastric cancer by protecting cancer cells against apoptosis, with potential implications for new therapeutic strategies in this setting. (C) 2017 AACR.