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

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Original research
STAT3-mediated upregulation of the AIM2 DNA sensor links innate immunity with cell migration to promote epithelial tumourigenesis
  1. Ruby E Dawson1,2,
  2. Virginie Deswaerte1,2,
  3. Alison C West1,2,
  4. Ke Tang1,2,
  5. Alice J West1,2,
  6. Jesse J Balic1,2,
  7. Linden J Gearing1,2,
  8. Mohamed I Saad1,2,
  9. Liang Yu1,2,
  10. Yonghui Wu3,
  11. Prithi S Bhathal2,
  12. Beena Kumar4,
  13. Jayati T Chakrabarti5,
  14. Yana Zavros5,
  15. Hiroko Oshima6,
  16. Dennis M Klinman7,
  17. Masanobu Oshima6,
  18. Patrick Tan8,9,10,
  19. Brendan J Jenkins1,2
  1. 1Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia
  2. 2Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
  3. 3Cellular and Molecular Research, National Cancer Centre of Singapore, Singapore
  4. 4Department of Anatomical Pathology, Monash Health, Clayton, Victoria, Australia
  5. 5Department of Cellular and Molecular Medicine, College of Medicine, University of Arizona, Tucson, Arizona, USA
  6. 6Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan
  7. 7Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
  8. 8Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore
  9. 9Genome Institute of Singapore, Singapore
  10. 10Cancer Science Institute of Singapore, National University of Singapore, Singapore
  1. Correspondence to Professor Brendan J Jenkins, Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia; brendan.jenkins{at}hudson.org.au

Abstract

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.

  • cytokines
  • gastric cancer
  • cell migration
  • immunology
  • molecular biology

Data availability statement

Data are available on reasonable request. Data are available from the corresponding author upon reasonable request.

https://doi.org/10.1136/gutjnl-2020-323916

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    Data availability statement

    Data are available on reasonable request. Data are available from the corresponding author upon reasonable request.

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    Footnotes

    • 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.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.