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Cancer Stem Cells
Article first published online: 20 SEP 2012
Copyright © 2012 AlphaMed Press
Volume 30, Issue 10, pages 2088–2099, October 2012
How to Cite
Voon, D. C.-C., Wang, H., Koo, J. K. W., Nguyen, T. A. P., Hor, Y. T., Chu, Y.-S., Ito, K., Fukamachi, H., Chan, S. L., Thiery, J. P. and Ito, Y. (2012), Runx3 Protects Gastric Epithelial Cells Against Epithelial-Mesenchymal Transition-Induced Cellular Plasticity and Tumorigenicity. STEM CELLS, 30: 2088–2099. doi: 10.1002/stem.1183
Author contributions: D.C.V.: conception and design, collection of data, data analysis/interpretation, and manuscript writing; H.J.W., J.K.W.K., T.A.P.N., and Y.T.H.: collection of data and data analysis/interpretation; Y.S.C. and J.P.T.: concept and design, collection, and analysis/interpretation of data (imaging and microscopy); S.L.C.: conception and design and data interpretation (sphere culture); K.I. and H.F.: provision of study materials (GIF cell lines); Y.I.: conception and design, financial support, and final approval of manuscript. D.C.V. and H.J.W. contributed equally to this article.
Disclosure of potential conflicts of interest is found at the end of this article.
First published online in STEM CELLSEXPRESS August 16, 2012.
- Issue published online: 20 SEP 2012
- Article first published online: 20 SEP 2012
- Accepted manuscript online: 16 AUG 2012 12:49PM EST
- Manuscript Accepted: 3 JUL 2012
- Manuscript Revised: 15 JUN 2012
- Manuscript Received: 18 JAN 2012
- National Research Foundation (NRF)
- Translational and Clinical Research (TCR) Flagship Programme
- Singapore Stem Cell Consortium (SSCC)
- Epithelial-mesenchymal transition;
- Gastric cancer stem cell;
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-β 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-β and Wnt pathways. Specifically, Runx3−/−p53−/− gastric epithelial cells were unexpectedly sensitized for TGF-β-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;30:2088–2099