| Autor: |
Hiroshi Nakagawa, Anil K. Rustgi, J. Alan Diehl, Meenhard Herlyn, Andres J. Klein-Szanto, Momo Nakagawa, Ross A. Kalman, Maria E. Vega, Jiri Kalabis, Douglas B. Stairs, Katharine D. Grugan, Carmen Z. Michaylira, Gabrielle S. Wong, Mitsuteru Natsuizaka, Shinya Ohashi |
| Rok vydání: |
2023 |
| DOI: |
10.1158/0008-5472.c.6500397 |
| Popis: |
Transforming growth factor-β (TGF-β) 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-β. 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 p15INK4B, p16INK4A, 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-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 the induction of p15INK4B and p16INK4A, 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 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. Cancer Res; 70(10); 4174–84. ©2010 AACR. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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