STAT3-mediated upregulation of the AIM2 DNA sensor links innate immunity with cell migration to promote epithelial tumourigenesis

ObjectiveThe 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.DesignThe expression of AIM2 an...

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Veröffentlicht in:Gut Jg. 71; H. 8; S. 1515 - 1531
Hauptverfasser: Dawson, Ruby E, Deswaerte, Virginie, West, Alison C, Tang, Ke, West, Alice J, Balic, Jesse J, Gearing, Linden J, Saad, Mohamed I, Yu, Liang, Wu, Yonghui, Bhathal, Prithi S, Kumar, Beena, Chakrabarti, Jayati T, Zavros, Yana, Oshima, Hiroko, Klinman, Dennis M, Oshima, Masanobu, Tan, Patrick, Jenkins, Brendan J
Format: Journal Article
Sprache:Englisch
Veröffentlicht: London BMJ Publishing Group Ltd and British Society of Gastroenterology 01.08.2022
BMJ Publishing Group LTD
Schlagworte:
Animal models
Apoptosis
Biopsy
Carcinogenesis
Caspase-1
Cell adhesion & migration
Cell migration
Cytokines
Deoxyribonucleic acid
DNA
Epithelial cells
Epithelium
Gastric cancer
Gene expression
Genetic engineering
immunology
Inflammasomes
Inflammation
Inflammatory diseases
Innate immunity
Interleukin 11
Medical research
Melanoma
molecular biology
Pathogenesis
Patients
Pattern recognition
Pattern recognition receptors
Protein expression
Proteins
Sensors
Stat3 protein
Stomach
Survival analysis
Therapeutic targets
Tumorigenesis
Tumors
Xenografts
Singapore
ISSN:0017-5749, 1468-3288, 1468-3288
Online-Zugang:Volltext
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Zusammenfassung:ObjectiveThe 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.DesignThe 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.ResultsAIM2 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.ConclusionAIM2 can play a driver role in epithelial carcinogenesis by linking cytokine-STAT3 signalling, innate immunity and epithelial cell migration, independent of inflammasome activation.
Bibliographie:Original research
ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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ISSN:0017-5749
1468-3288
1468-3288
DOI:10.1136/gutjnl-2020-323916