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Title: Runx3 protects gastric epithelial cells against epithelial-mesenchymal transition-induced cellular plasticity and tumorigenicity
Keywords: Runx3, Epithelial-mesenchymal transition, TGF-b, Wnt, cellular plasticity, Lgr5
Issue Date: 19-Jan-2012
Source: WANG HUAJING (2012-01-19). Runx3 protects gastric epithelial cells against epithelial-mesenchymal transition-induced cellular plasticity and tumorigenicity. ScholarBank@NUS Repository.
Abstract: The Runt domain transcription factor RUNX3 is a prominent tumour suppressor in the gastrointestinal tract where it is required for proper proliferation and differentiation of gastric epithelial cells. These functions are partly elicited by mediating the tumour suppressive TGF-b/SMAD signaling and antagonising the oncogenic Wnt pathway. Consistent with these, immoralised Runx3-/- gastric epithelial cells (GIF lines) are refractory to TGF-b-induced apoptosis and are tumorigenic in nude mice, but not their Runx3+/+ equivalents. In this study, we observed the spontaneous emergence of a tumorigenic and stem-cell like subpopulation, P2 through Epithelial-Mesenchymal Transition (EMT) in Runx3-/- GIF-14 cells. Paradoxically, EMT was driven by aberrantly activated TGF-b signaling, suggesting that the loss of Runx3 render cells sensitised to the EMT-promoting functions of TGF-b. Interestingly, the P2 subpopulation expressed markedly higher levels of Lgr5, a canonical Wnt target gene that is exclusively expressed in the pyloric gastric stem cells. Moreover, TGF-b1-induced EMT reactivates Lgr5 which acts synergistically with Wnt3a to cause amplified activation of Lgr5. This observation was largely absent in Runx3+/+ GIF-13 cells. Finally, the re-introduction of RUNX3 in GIF-14 cells strongly abrogated Wnt3a-induced Lgr5, reduced the P2 subpopulation and TGF-b1-activated EMT- and stemness-related genes, confirming the negative roles of RUNX3 on EMT and stemness. Taken together, our data revealed that Runx3 maintains gastric epithelial cell integrity and its absence causes sensitisation to Wnt and EMT-activating properties of TGF-b, resulting in increased cellular plasticity and the emergence of a tumorigenic, stem cell-like subpopulation.
Appears in Collections:Ph.D Theses (Open)

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