Epidermal growth factor receptor and mutant p53 expand an esophageal cellular subpopulation capable of epithelial-to-mesenchymal transition through ZEB transcription factors

Shinya Ohashi, Mitsuteru Natsuizaka, Gabrielle S. Wong, Carmen Z. Michaylira, Katharine D. Grugan, Douglas B. Stairs, Jiri Kalabis, Maria E. Vega, Ross A. Kalman, Momo Nakagawa, Andres J. Klein-Szanto, Meenhard Herlyn, J. Alan Diehl, Anil K. Rustgi, Hiroshi Nakagawa

Research output: Contribution to journalArticlepeer-review

101 Scopus citations

Abstract

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, 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-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.

Original languageEnglish (US)
Pages (from-to)4174-4184
Number of pages11
JournalCancer Research
Volume70
Issue number10
DOIs
StatePublished - May 15 2010

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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