STAT3-mediated upregulation of the AIM2 DNA sensor links innate immunity with cell migration to promote epithelial tumourigenesis
STAT3-mediated upregulation of the AIM2 DNA sensor links innate immunity with cell migration to promote epithelial tumourigenesis
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DOI：
10.1136/gutjnl-2020-323916
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发表时间：
2021-09-06
期刊：
影响因子：
24.5
通讯作者：
Jenkins, Brendan J.
中科院分区：
文献类型：
--
作者：
Dawson, Ruby E.;Deswaerte, Virginie;Jenkins, Brendan J.
目的 黑色素瘤 2 (AIM2) 胞质模式识别受体和 DNA 传感器的缺失通过含有 caspase-1 的炎症小体复合物促进自身免疫和慢性炎症性疾病的发病。然而，AIM2 在癌症中的作用尚不明确。设计 在人类胃癌 (GC) 患者队列中评估 AIM2 的表达及其临床意义。在基因工程 gp130 (F/F) 自发 GC 小鼠模型以及人 GC 细胞系异种移植物中对 AIM2 表达和活性进行遗传或治疗操作。 AIM2 在胃肿瘤发生中的生物学作用和作用机制，包括其参与炎症小体活性以及与微管相关末端结合蛋白 1 (EB1) 的功能相互作用，均在体外和体内进行了测定。结果 在 GC 小鼠模型和 GC 患者的肿瘤上皮中，白细胞介素 11 细胞因子介导的致癌潜伏转录因子 STAT3 的激活上调了 AIM2 的表达。 gp130 (F/F) 小鼠中 AIM2 的遗传和治疗靶向可抑制肿瘤发生。相反，AIM2 过表达增加了人 GC 细胞系异种移植物的肿瘤负荷。 AIM2 的促肿瘤功能不依赖于炎性体活性和炎症。相反，在体内和体外，AIM2 与 EB1 发生物理相互作用，促进上皮细胞迁移和肿瘤发生。此外，GC 患者肿瘤上皮中 AIM2 和 EB1 表达上调与患者生存率低独立相关。结论 AIM2 可以通过连接细胞因子-STAT3 信号、先天免疫和上皮细胞迁移，在上皮癌发生中发挥驱动作用，不依赖于炎症小体的激活。
Objective The absent in melanoma 2 (AIM2) cytosolic pattern recognition receptor and DNA sensor promotes the pathogenesis of autoimmune and chronic inflammatory diseases via caspase-1-containing inflammasome complexes. However, the role of AIM2 in cancer is ill-defined. Design The expression of AIM2 and its clinical significance was assessed in human gastric cancer (GC) patient cohorts. Genetic or therapeutic manipulation of AIM2 expression and activity was performed in the genetically engineered gp130 (F/F) spontaneous GC mouse model, as well as human GC cell line xenografts. The biological role and mechanism of action of AIM2 in gastric tumourigenesis, including its involvement in inflammasome activity and functional interaction with microtubule-associated end-binding protein 1 (EB1), was determined in vitro and in vivo. Results AIM2 expression is upregulated by interleukin-11 cytokine-mediated activation of the oncogenic latent transcription factor STAT3 in the tumour epithelium of GC mouse models and patients with GC. Genetic and therapeutic targeting of AIM2 in gp130 (F/F) mice suppressed tumourigenesis. Conversely, AIM2 overexpression augmented the tumour load of human GC cell line xenografts. The protumourigenic function of AIM2 was independent of inflammasome activity and inflammation. Rather, in vivo and in vitro AIM2 physically interacted with EB1 to promote epithelial cell migration and tumourigenesis. Furthermore, upregulated expression of AIM2 and EB1 in the tumour epithelium of patients with GC was independently associated with poor patient survival. Conclusion AIM2 can play a driver role in epithelial carcinogenesis by linking cytokine-STAT3 signalling, innate immunity and epithelial cell migration, independent of inflammasome activation.