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EMT-Induced Stemness and Tumorigenicity Are Fueled by the EGFR/Ras Pathway

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....

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Autores principales: Voon, Dominic Chih-Cheng, Wang, Huajing, Koo, Jason Kin Wai, Chai, Juin Hsien, Hor, Yit Teng, Tan, Tuan Zea, Chu, Yeh-Shiu, Mori, Seiichi, Ito, Yoshiaki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3741305/
https://www.ncbi.nlm.nih.gov/pubmed/23950932
http://dx.doi.org/10.1371/journal.pone.0070427
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author Voon, Dominic Chih-Cheng
Wang, Huajing
Koo, Jason Kin Wai
Chai, Juin Hsien
Hor, Yit Teng
Tan, Tuan Zea
Chu, Yeh-Shiu
Mori, Seiichi
Ito, Yoshiaki
author_facet Voon, Dominic Chih-Cheng
Wang, Huajing
Koo, Jason Kin Wai
Chai, Juin Hsien
Hor, Yit Teng
Tan, Tuan Zea
Chu, Yeh-Shiu
Mori, Seiichi
Ito, Yoshiaki
author_sort Voon, Dominic Chih-Cheng
collection PubMed
description 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.
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spelling pubmed-37413052013-08-15 EMT-Induced Stemness and Tumorigenicity Are Fueled by the EGFR/Ras Pathway Voon, Dominic Chih-Cheng Wang, Huajing Koo, Jason Kin Wai Chai, Juin Hsien Hor, Yit Teng Tan, Tuan Zea Chu, Yeh-Shiu Mori, Seiichi Ito, Yoshiaki PLoS One Research Article 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. Public Library of Science 2013-08-12 /pmc/articles/PMC3741305/ /pubmed/23950932 http://dx.doi.org/10.1371/journal.pone.0070427 Text en © 2013 Voon et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Voon, Dominic Chih-Cheng
Wang, Huajing
Koo, Jason Kin Wai
Chai, Juin Hsien
Hor, Yit Teng
Tan, Tuan Zea
Chu, Yeh-Shiu
Mori, Seiichi
Ito, Yoshiaki
EMT-Induced Stemness and Tumorigenicity Are Fueled by the EGFR/Ras Pathway
title EMT-Induced Stemness and Tumorigenicity Are Fueled by the EGFR/Ras Pathway
title_full EMT-Induced Stemness and Tumorigenicity Are Fueled by the EGFR/Ras Pathway
title_fullStr EMT-Induced Stemness and Tumorigenicity Are Fueled by the EGFR/Ras Pathway
title_full_unstemmed EMT-Induced Stemness and Tumorigenicity Are Fueled by the EGFR/Ras Pathway
title_short EMT-Induced Stemness and Tumorigenicity Are Fueled by the EGFR/Ras Pathway
title_sort emt-induced stemness and tumorigenicity are fueled by the egfr/ras pathway
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3741305/
https://www.ncbi.nlm.nih.gov/pubmed/23950932
http://dx.doi.org/10.1371/journal.pone.0070427
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