Suppression of the Epithelial-Mesenchymal Transition by Grainyhead-like-2

被引：171

作者：

Cieply, Benjamin ^{[1
]}

Riley, Philip ^{[1
]}

Pifer, Phillip M. ^{[1
]}

Widmeyer, Joseph ^{[1
]}

Addison, Joseph B. ^{[1
]}

Ivanov, Alexey V. ^{[1
,2
]}

Denvir, James ^{[3
]}

Frisch, Steven M. ^{[1
,2
]}

机构：

[1] W Virginia Univ, Mary Babb Randolph Canc Ctr, Morgantown, WV 26506 USA

[2] W Virginia Univ, Dept Biochem, Morgantown, WV 26506 USA

[3] Marshall Univ, Dept Biochem & Microbiol, Huntington, WV USA

来源：

CANCER RESEARCH | 2012年 / 72卷 / 09期

关键词：

GENE-EXPRESSION; GRAINY-HEAD; TGF-BETA; TRANSCRIPTION FACTORS; CANCER SUBTYPES; E-CADHERIN; BREAST; ZEB1; CELLS; ANOIKIS;

D O I：

10.1158/0008-5472.CAN-11-4038

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Grainyhead genes are involved in wound healing and developmental neural tube closure. In light of the high degree of similarity between the epithelial-mesenchymal transitions (EMT) occurring in wound-healing processes and the cancer stem cell-like compartment of tumors, including TGF-beta dependence, we investigated the role of the Grainyhead gene, Grainyhead-like-2 (GRHL2) in oncogenic EMT. GRHL2 was downregulated specifically in the claudin-low subclass breast tumors and in basal-B subclass breast cancer cell lines. GRHL2 suppressed TGF-beta-induced, Twist-induced or spontaneous EMT, enhanced anoikis sensitivity, and suppressed mammosphere generation in mammary epithelial cells. These effects were mediated in part by suppression of ZEB1 expression via direct repression of the ZEB1 promoter. GRHL2 also inhibited Smad-mediated transcription and it upregulated mir-200b/c as well as the TGF-beta receptor antagonist, BMP2. Finally, ectopic expression of GRHL2 in MDA-MB-231 breast cancer cells triggered an MET and restored sensitivity to anoikis. Taken together, our findings define a major role for GRHL2 in the suppression of oncogenic EMT in breast cancer cells. Cancer Res; 72(9); 2440-53. (C) 2012 AACR.

引用

页码：2440 / 2453

页数：14

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