EGFR and mutant p53 expand esophageal cellular subpopulation capable of epithelial-to-mesenchymal transition through ZEB transcription factors
| Autor: | 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 |
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| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Esophageal Neoplasms
Blotting Western Fluorescent Antibody Technique Article Mesoderm Esophagus Transforming Growth Factor beta Humans RNA Messenger Luciferases Telomerase Cells Cultured Cellular Senescence Cyclin-Dependent Kinase Inhibitor p16 Cell Proliferation Cyclin-Dependent Kinase Inhibitor p15 Zinc Finger E-box Binding Homeobox 2 Homeodomain Proteins Reverse Transcriptase Polymerase Chain Reaction Zinc Finger E-box-Binding Homeobox 1 Epithelial Cells ErbB Receptors Repressor Proteins Cell Transformation Neoplastic Carcinoma Squamous Cell Tumor Suppressor Protein p53 Signal Transduction Transcription Factors |
| Popis: | Transforming growth factor-beta (TGF-beta) is a potent inducer of epithelial to mesenchymal transition (EMT). However, it remains elusive about which molecular mechanisms determine the cellular capacity to undergo EMT in response to TGF-beta. We have found that both epidermal growth factor receptor (EGFR) overexpression and mutant p53 tumor suppressor genes contribute to the enrichment of an EMT-competent cellular subpopulation among telomerase-immortalized human esophageal epithelial cells during malignant transformation. EGFR overexpression triggers oncogene-induced senescence, accompanied by the 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 on TGF-beta 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 the induction of p15(INK4B) and p16(INK4A), reactivating the EGFR-dependent senescence program. Importantly, TGF-beta-mediated EMT did not take place when cellular senescence programs were activated by either ZEB knockdown or the 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 the expansion of an EMT-competent unique cellular subpopulation, providing novel mechanistic insights into the role of ZEB in esophageal carcinogenesis. |
| Databáze: | OpenAIRE |
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