EGFR and mutant p53 expand esophageal cellular subpopulation capable of epithelial-to-mesenchymal transition through ZEB transcription factors

Transforming growth factor (TGF)-β is a potent inducer of epithelial to mesenchymal transition (EMT). However, it remains elusive as to which molecular mechanisms determine the cellular capacity to undergo EMT in response to TGF-β. We have found that both epidermal growth factor receptor (EGFR) over...

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Published in:Cancer research (Chicago, Ill.) Ill.), 2010-04, Vol.70 (10), p.4174-4184
Main Authors: Ohashi, Shinya, Natsuizaka, Mitsuteru, Wong, Gabrielle S., Michaylira, Carmen Z., Grugan, Katharine D., Stairs, Douglas B., Kalabis, Jiri, Vega, Maria E., Kalman, Ross A., Nakagawa, Momo, Klein-Szanto, Andres J, Herlyn, Meenhard, Diehl, J. Alan, Rustgi, Anil K., Nakagawa, Hiroshi
Format: Article
Language:English
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Summary:Transforming growth factor (TGF)-β is a potent inducer of epithelial to mesenchymal transition (EMT). However, it remains elusive as to which molecular mechanisms determine the cellular capacity to undergo EMT in response to TGF-β. We have found that both epidermal growth factor receptor (EGFR) overexpression and mutant p53 tumor suppressor genes contribute to enrichment of an EMT-competent cellular subpopulation amongst telomerase-immortalized human esophageal epithelial cells during malignant transformation. EGFR overexpression triggers oncogene-induced senescence, accompanied by induction of cyclin dependent kinase inhibitors p15 INK4B , p16 INK4A and p21. Interestingly, a subpopulation of cells emerges by negating senescence without loss of EGFR overexpression. Such cell populations express increased levels of zinc finger E-box binding (ZEB) transcription factors ZEB1 and ZEB2, and undergo EMT upon TGF-β stimulation. Enrichment of EMT-competent cells was more evident in the presence of p53 mutation, which diminished EGFR-induced senescence. RNA interference directed against ZEB resulted in induction of p15 INK4B and p16 INK4A , reactivating the EGFR-dependent senescence program. Importantly, TGF-β-mediated EMT did not take place when cellular senescence programs were activated by either ZEB knockdown or activation of wild-type p53 function. Thus, senescence checkpoint functions activated by EGFR and p53 may be evaded through the induction of ZEB, thereby allowing expansion of an EMT-competent unique cellular subpopulation, providing novel mechanistic insights into the role of ZEB in esophageal carcinogenesis.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-09-4614