Epidermal growth factor receptor and mutant p53 expand an esophageal cellular subpopulation capable of epithelial-to-mesenchymal transition through ZEB transcription factors.
Epidermal growth factor receptor and mutant p53 expand an esophageal cellular subpopulation capable of epithelial-to-mesenchymal transition through ZEB transcription factors.
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DOI：
10.1158/0008-5472.can-09-4614
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发表时间：
2010-05-15
期刊：
影响因子：
11.2
通讯作者：
Nakagawa H
中科院分区：
文献类型：
--
作者：
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
转化生长因子（TGF）-β是上皮细胞向间质细胞转化（EMT）的有效诱导剂。然而，关于哪些分子机制决定细胞响应TGF-β而经历EMT的能力仍然难以捉摸。我们已经发现，表皮生长因子受体（EGFR）的过度表达和突变型p53肿瘤抑制基因的端粒酶永生化的人食管上皮细胞在恶性转化过程中的EMT主管细胞亚群的富集。EGFR过表达触发癌基因诱导的衰老，伴随着细胞周期蛋白依赖性激酶抑制剂p15 INK 4 B、p16 INK 4A和p21的诱导。有趣的是，通过否定衰老而不丧失EGFR过表达，出现了细胞亚群。这样的细胞群表达增加水平的锌指E盒结合（ZEB）转录因子ZEB 1和ZEB 2，并且在TGF-β刺激后经历EMT。EMT感受态细胞的富集在p53突变的存在下更明显，这减少了EGFR诱导的衰老。针对ZEB的RNA干扰导致p15 INK 4 B和p16 INK 4A的诱导，重新激活EGFR依赖性衰老程序。重要的是，当细胞衰老程序被ZEB敲低或野生型p53功能激活时，TGF-β介导的EMT不会发生。因此，由EGFR和p53激活的衰老检查点功能可以通过ZEB的诱导来规避，从而允许EMT能力的独特细胞亚群的扩增，为ZEB在食管癌发生中的作用提供了新的机制见解。
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 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 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 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 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.