ZEB1 在肺癌中具有遗传细胞上下文依赖性作用。

A genetic cell context-dependent role for ZEB1 in lung cancer.

机构信息

Thoracic Disease Research Unit, Division of Pulmonary and Critical Care Medicine, Cancer Center and College of Medicine, Mayo Clinic, 200 First Street SW, Stabile Building Room st8-08 Rochester, Minnesota 55905, USA.

Department of Biochemistry and Molecular Biology, Cancer Center and College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.

出版信息

Nat Commun. 2016 Jul 26;7:12231. doi: 10.1038/ncomms12231.

The Zinc-finger E-box-binding Homeobox-1 (ZEB1) is a transcription factor that promotes epithelial-mesenchymal transition (EMT) and acts as an oncogene in KRAS-mutated lung cancer models. Here we report that ZEB1 exerts the opposite effect in EGFR-mutated lung cancer cells, where it suppresses growth by increasing microRNA-200 targets to antagonize ERBB3, a driver of mutant EGFR-dependent cell growth. Among these targets, NOTCH1 represses ERBB3 promoter activity and the expression of ERBB3. Furthermore, we find that EGFR inhibitor treatment, which inhibits the growth of EGFR-mutated cells, induces ZEB1. Despite its growth-inhibiting effect, EGFR inhibitor-induced ZEB1 strongly promotes EMT-dependent resistance to EGFR inhibitors partially through NOTCH1, suggesting a multifunctional role for NOTCH1 in EGFR-mutated cells. These results support a previously unrecognized genetic cell context-dependent role for ZEB1 and suggest that NOTCH1 may be a useful target for treating resistance to EGFR inhibitors, especially EMT-driven resistance.

锌指 E 盒结合同源盒 1（ZEB1）是一种转录因子，可促进上皮-间充质转化（EMT），并在 KRAS 突变型肺癌模型中作为癌基因发挥作用。在这里，我们报告 ZEB1 在 EGFR 突变型肺癌细胞中发挥相反的作用，通过增加 microRNA-200 的靶标来拮抗 ERBB3，从而抑制生长，ERBB3 是驱动突变型 EGFR 依赖性细胞生长的驱动基因。在这些靶标中，NOTCH1 抑制 ERBB3 启动子活性和 ERBB3 的表达。此外，我们发现 EGFR 抑制剂治疗（抑制 EGFR 突变型细胞的生长）可诱导 ZEB1。尽管 ZEB1 具有抑制生长的作用，但 EGFR 抑制剂诱导的 ZEB1 强烈促进 EMT 依赖性对 EGFR 抑制剂的耐药性，部分通过 NOTCH1 促进，这表明 NOTCH1 在 EGFR 突变型细胞中具有多功能作用。这些结果支持 ZEB1 以前未被认识的遗传细胞上下文依赖性作用，并表明 NOTCH1 可能是治疗 EGFR 抑制剂耐药性的有用靶点，特别是 EMT 驱动的耐药性。