Journal
STEM CELLS
Volume 30, Issue 10, Pages 2088-2099Publisher
WILEY
DOI: 10.1002/stem.1183
Keywords
RUNX3; Epithelial-mesenchymal transition; Lgr5; Gastric cancer stem cell; Wnt; TGF-ss
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Funding
- National Research Foundation (NRF)
- Translational and Clinical Research (TCR) Flagship Programme
- Singapore Stem Cell Consortium (SSCC)
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The transcription factor RUNX3 functions as a tumor suppressor in the gastrointestinal epithelium, where its loss is an early event in carcinogenesis. While RUNX3 acts concurrently as a mediator of TGF-beta signaling and an antagonist of Wnt, the cellular changes that follow its loss and their contribution to tumorigenicity are not fully understood. Here, we report that the loss of Runx3 in gastric epithelial cells results in spontaneous epithelial-mesenchymal transition (EMT). This produces a tumorigenic stem cell-like subpopulation, which remarkably expresses the gastric stem cell marker Lgr5. This phenomenon is due to the compounding effects of the dysregulation of the TGF-beta and Wnt pathways. Specifically, Runx3-/-p53-/- gastric epithelial cells were unexpectedly sensitized for TGF-beta-induced EMT, during which the resultant induction of Lgr5 was enhanced by an aberrantly activated Wnt pathway. These data demonstrate a protective role for RUNX3 in safeguarding gastric epithelial cells against aberrant growth factor signaling and the resultant cellular plasticity and stemness. STEM Cells2012;30:20882099
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