Suppression of the epithelial-mesenchymal transition by Grainyhead-like-2.
Suppression of the epithelial-mesenchymal transition by Grainyhead-like-2.
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DOI：
10.1158/0008-5472.can-11-4038
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发表时间：
2012-05-01
期刊：
影响因子：
11.2
通讯作者：
Frisch SM
中科院分区：
文献类型：
--
作者：
Cieply B;Riley P 4th;Pifer PM;Widmeyer J;Addison JB;Ivanov AV;Denvir J;Frisch SM
颗粒头基因与伤口愈合和发育中的神经管闭合有关。鉴于创伤愈合过程中发生的上皮-间充质转化与肿瘤干细胞样区的高度相似性，包括对转化生长因子-β的依赖，我们研究了Grainyhead基因，Grainyhead-like-2(GRHL2)在肿瘤发生的EMT中的作用。Grhl2在claudin-low亚类乳腺肿瘤和Basal-B亚类乳腺癌细胞系中表达下调。Grhl2抑制转化生长因子-β诱导的乳腺上皮细胞、扭转诱导的或自发的乳腺上皮细胞转化，增强失巢细胞敏感性，并抑制乳房上皮细胞的乳房小球生成。这些作用部分是通过直接抑制ZEB1启动子而抑制ZEB1的表达而实现的。Grhl2还抑制Smad介导的转录，上调mir200b/c和转化生长因子-β受体拮抗剂BMP2。最后，GRHL2在MDA-MB-231乳腺癌细胞中的异位表达触发了间充质向上皮的转变，并恢复了对失巢凋亡的敏感性。综上所述，我们的发现确定了GRHL2在抑制乳腺癌细胞中致癌EMT方面的主要作用。
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-β-dependence, we investigated the role of the Grainyhead gene, Grainyhead-Like-2 (GRHL2) in oncogenic EMT. GRHL2 was down-regulated specifically in the claudin-low subclass breast tumors and in basal-B subclass breast cancer cell lines. GRHL2 suppressed TGF-β-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 mir200b/c as well as the TGF-β receptor antagonist, BMP2. Lastly, ectopic expression of GRHL2 in MDA-MB-231 breast cancer cells triggered a mesenchymal-to-epithelial transition 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.