Abstract
Recent studies have revealed that differentiated epithelial cells would acquire stem cell-like and tumorigenic properties following an Epithelial-Mesenchymal Transition (EMT). However, the signaling pathways that participate in this novel mechanism of tumorigenesis have not been fully characterized. In Runx3 −/− p53 −/− murine gastric epithelial (GIF-14) cells, EMT-induced plasticity is reflected in the expression of the embryonal proto-oncogene Hmga2 and Lgr5, an exclusive gastrointestinal stem cell marker. Here, we report the concurrent activation of an EGFR/Ras gene expression signature during TGF-β1-induced EMT in GIF-14 cells. Amongst the altered genes was the induction of Egfr, which corresponded with a delayed sensitization to EGF treatment in GIF-14. Co-treatment with TGF-β1 and EGF or the expression of exogenous KRas led to increased Hmga2 or Lgr5 expression, sphere initiation and colony formation in soft agar assay. Interestingly, the gain in cellular plasticity/tumorigenicity was not accompanied by increased EMT. This uncoupling of EMT and the induction of plasticity reveals an involvement of distinct signaling cues, whereby the EGFR/Ras pathway specifically promotes stemness and tumorigenicity in EMT-altered GIF-14 cells. These data show that the EGFR/Ras pathway requisite for the sustenance of gastric stem cells in vivo and in vitro is involved in the genesis and promotion of EMT-induced tumor-initiating cells.
Highlights
Epithelial-Mesenchymal Transition (EMT) is a developmental program that plays an instrumental role in early embryo patterning during gastrulation [1]
An Epidermal Growth Factor Receptor (EGFR)/RAS gene expression signature corresponds with transforming growth factor-beta 1 (TGF-b1)-induced EMT in GIF-14 cells
In addition to changes in genes associated with Transforming Growth Factor beta (TGF-b) and EMT, Gene Set Enrichment Analysis (GSEA) revealed a significant enrichment of gene sets belonging to the Epidermal Growth Factor Receptor (EGFR) and RAS pathways (Figure 1A)
Summary
Epithelial-Mesenchymal Transition (EMT) is a developmental program that plays an instrumental role in early embryo patterning during gastrulation [1]. We observed the activation of an EGFR/Ras gene expression signature during TGF-b1-induced EMT in GIF-14 cells, which included increased Egfr expression.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
