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 gp130F/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 gp130F/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.
- gastric cancer
- cell migration
- molecular biology
Data availability statement
Data are available on reasonable request.
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Twitter @Mohamed_I_Saad, @babs
Contributors RD and VD contributed equally to this manuscript. BJJ designed and supervised the study, and wrote the manuscript. RD, VD, ACW, KT, AJW, JJB, MS, LY, YW, JC, YZ and HO performed experimentation, including animal studies, and acquired the data. RD, VD, YZ, MO, PT and BJJ analysed and interpreted the data. DK, YZ, MO and PT provided technical and material support. PSB and BK performed histopathological scoring. All contributing authors have agreed to submission of this manuscript for publication.
Funding This work was funded by the National Health and Medical Research Council (NHMRC) of Australia (BJ), and the Operational Infrastructure Support Program by the Victorian Government of Australia. JB and AJW were supported by Australian Postgraduate Awards from the Australian Government, and ACW was supported by an NHMRC Early Career Fellowship. BJ was supported by an NHMRC Senior Medical Research Fellowship.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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