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Ohashi S , Natsuizaka M , Wong GS , Michaylira CZ , Grugan KD , Stairs DB , Kalabis J , Vega ME , Kalman RA , Nakagawa M , Klein-Szanto AJ , Herlyn M , Diehl JA , Rustgi AK , Nakagawa H
Epidermal Growth Factor Receptor and Mutant p53 Expand an Esophageal Cellular Subpopulation Capable of Epithelial-to-Mesenchymal Transition through ZEB Transcription Factors
Cancer Research. 2010 May;70(10) :4174-4184
PMID: ISI:000278486300035    PMCID: PMC3007622   
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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. Cancer Res; 70(10); 4174-84. (C) 2010 AACR.
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 NIH [R01DK077005, P01-CA-098101, K01-DK066205]; Uehara Memorial Foundation ; NIH/National Cancer Institute [T32-CA115299, P30-DK050306]; American Gastroenterological Association Foundation ; NIH/National Institutes of Diabetes, Digestive and Kidney Diseases Center for Molecular Studies in Digestive and Liver Diseases [P30-DK050306]; NIH/NRSA [F32-CA103085, F32-DK075230, F32-DK082149]; [NIH/K99-CA138498] NIH grants R01DK077005 (M. Natsuizaka, S. Ohashi, and H. Nakagawa), P01-CA-098101 Mechanisms of Esophageal Carcinogenesis (H. Nakagawa, S. Ohashi, M. Natsuizaka, G.S. Wong, K.D. Grugan, D.B. Stairs, J. Kalabis, C.Z. Michaylira, A.J. Klein-Szanto, M. Herlyn, J.A. Diehl, and A.K. Rustgi), K01-DK066205 (H. Nakagawa), Uehara Memorial Foundation Research fellowship (S. Ohashi), NIH/K99-CA138498 and NIH/NRSA F32-CA103085 (D.B. Stairs), NIH/NRSA F32-DK075230 (C.Z. Michaylira), NIH/NRSA F32-DK082149 (K.D. Grugan), NIH/National Cancer Institute T32-CA115299 (J. Kalabis and G. S. Wong), P30-DK050306 (R.A. Kalman), American Gastroenterological Association Foundation Student Research Fellowship Award (M. Nakagawa), and the NIH/National Institutes of Diabetes, Digestive and Kidney Diseases Center for Molecular Studies in Digestive and Liver Diseases (P30-DK050306) and its core facilities. 46 Amer assoc cancer research; 615 chestnut st, 17th floor, philadelphia, pa 19106-4404 usa 607ge