Journal
CELL REPORTS
Volume 8, Issue 1, Pages 50-58Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2014.06.003
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Funding
- Translational and Clinical Research Flagship Programme
- National Research Foundation Singapore
- Singapore Ministry of Education under Research Centres of Excellence Initiative
- National University of Singapore Graduate School for Integrative Sciences and Engineering scholarship
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RUNX3 functions as a tumor suppressor in the gastric epithelium, where its inactivation is frequently observed during carcinogenesis. We identified IL23A as a RUNX3 target gene in gastric epithelial cells. This was confirmed in a series of in vitro analyses in gastric epithelial cell lines. In elucidating the underlying regulatory network, we uncovered a prominent role for the TNF-alpha/NF-kappa B pathway in activating IL23A transcription. Moreover, the activating effect of TNF-alpha was markedly augmented by the infection of Helicobacter pylori, the primary cause of human gastritis. Of note, H. pylori utilized the CagA/SHP2 pathway to activate IL23A, as well as the induction of the NOD1 pathway by iE-DAP. Importantly, RUNX3 synergized strongly with these physiologically relevant stimuli to induce IL23A. Lastly, we present evidence for the secretion of IL23A by gastric epithelial cells in a form that is distinct from canonical IL-23 (IL23A/IL12B).
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