The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs
The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs
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DOI：
10.1038/ncb1998
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发表时间：
2009-12-01
影响因子：
21.3
通讯作者：
Brabletz, Thomas
中科院分区：
文献类型：
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作者：
Wellner, Ulrich;Schubert, Joerg;Brabletz, Thomas
癌的侵袭和转移是通过胚胎“上皮向间质转化”（EMT）程序的激活来促进的，该程序触发细胞移动性和随后的肿瘤细胞的传播。我们最近发现EMT激活剂ZEB 1（锌指E-box binding homeobox 1）是转移的关键启动子，并证明ZEB 1抑制microRNA-200（miR-200）家族的表达，其成员是上皮分化的强诱导剂。在这里，我们报告说，ZEB 1不仅促进肿瘤细胞的传播，但也是必要的胰腺癌和结直肠癌细胞的肿瘤启动能力。我们发现ZEB 1抑制抑制干细胞抑制miR-203的表达，并且miR-200家族成员的候选靶点也是干细胞因子，如Sox 2和Klf 4。此外，miR-200 c、miR-203和miR-183协同抑制癌细胞和小鼠胚胎干（ES）细胞中干细胞因子的表达，如多梳阻遏物Bmi 1所示。我们提出ZEB 1通过抑制抑制干细胞性的微小RNA（miRNAs）来连接EMT激活和干细胞性维持，从而是移动的迁移性癌症干细胞的启动子。因此，靶向ZEB 1-miR-200反馈环可能成为治疗致命肿瘤（如胰腺癌）的基础。
Invasion and metastasis of carcinomas is promoted by the activation of the embryonic 'epithelial to mesenchymal transition' (EMT) program, which triggers cellular mobility and subsequent dissemination of tumour cells. We recently showed that the EMT-activator ZEB1 (zinc finger E-box binding homeobox 1) is a crucial promoter of metastasis and demonstrated that ZEB1 inhibits expression of the microRNA-200 (miR-200) family, whose members are strong inducers of epithelial differentiation. Here, we report that ZEB1 not only promotes tumour cell dissemination, but is also necessary for the tumour-initiating capacity of pancreatic and colorectal cancer cells. We show that ZEB1 represses expression of stemness-inhibiting miR-203 and that candidate targets of miR-200 family members are also stem cell factors, such as Sox2 and Klf4. Moreover, miR-200c, miR-203 and miR-183 cooperate to suppress expression of stem cell factors in cancer cells and mouse embryonic stem (ES) cells, as demonstrated for the polycomb repressor Bmi1. We propose that ZEB1 links EMT-activation and stemness-maintenance by suppressing stemness-inhibiting microRNAs (miRNAs) and thereby is a promoter of mobile, migrating cancer stem cells. Thus, targeting the ZEB1-miR-200 feedback loop might form the basis of a promising treatment for fatal tumours, such as pancreatic cancer.