Grainyhead-like 2 regulates epithelial plasticity and stemness in oral cancer cells
Grainyhead-like 2 regulates epithelial plasticity and stemness in oral cancer cells
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DOI：
10.1093/carcin/bgw027
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发表时间：
2016-05-01
期刊：
影响因子：
4.7
通讯作者：
Kang, Mo K.
中科院分区：
文献类型：
--
作者：
Chen, Wei;Yi, Jin Kyu;Kang, Mo K.
GRHL 2是果蝇Grainyhead的3个同源基因之一，与口腔鳞状细胞癌的发生、发展密切相关，其中miR-200家族基因部分介导了GRHL 2对口腔鳞状细胞癌形成的影响。我们最近发现，GRHL 2也控制正常上皮细胞的增殖和分化。在这项研究中，我们研究了GRHL 2在口腔癌发生中的作用及其机制。GRHL 2在口腔鳞状细胞癌（OSCC）的细胞和组织中的表达高于正常对照组。GRHL 2的敲低导致口腔癌细胞的体内致瘤性、癌干细胞性和上皮表型的丧失。GRHL 2的缺失也抑制口腔癌细胞增殖和集落形成。GRHL 2通过直接与启动子DNA结合来调控miR-200家族和Octamer-binding transcription factor 4（Oct-4）基因的表达。miR-200基因在缺失GRHL 2的口腔癌细胞中的过表达部分恢复了上皮表型、增殖率和癌症干性，表明miR-200基因部分介导GRHL 2的功能效应。综上所述，本研究证明了GRHL 2和miR-200之间的新联系，并支持GRHL 2对OSCC的促肿瘤作用。
We demonstrate that GRHL2 plays pivotal roles in the maintenance of tumorigenicity, cancer stemness and epithelial phenotype of oral cancer cells, in which miR-200 family genes partially mediate the effect of GRHL2 on oral squamous cell carcinomas formation.Grainyhead-like 2 (GRHL2) is one of the three mammalian homologues of Drosophila Grainyhead involved in epithelial morphogenesis. We recently showed that GRHL2 also controls normal epithelial cell proliferation and differentiation. In this study, we investigated the role of GRHL2 in oral carcinogenesis and the underlying mechanism. GRHL2 expression was elevated in cells and tissues of oral squamous cell carcinomas (OSCCs) compared with normal counterparts. Knockdown of GRHL2 resulted in the loss of in vivo tumorigenicity, cancer stemness and epithelial phenotype of oral cancer cells. GRHL2 loss also inhibited oral cancer cell proliferation and colony formation. GRHL2 regulated the expression of miR-200 family and Octamer-binding transcription factor 4 (Oct-4) genes through direct promoter DNA binding. Overexpression of miR-200 genes in the oral cancer cells depleted of GRHL2 partially restored the epithelial phenotype, proliferative rate and cancer stemness, indicating that miR-200 genes in part mediate the functional effects of GRHL2. Taken together, this study demonstrates a novel connection between GRHL2 and miR-200, and supports protumorigenic effect of GRHL2 on OSCCs.