Forkhead box P3 regulates ARHGAP15 expression and affects migration of glioma cells through the Rac1 signaling pathway.
Forkhead box P3 regulates ARHGAP15 expression and affects migration of glioma cells through the Rac1 signaling pathway.
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Forkhead Box P3调节ARHGAP15表达，并影响神经胶质瘤细胞通过RAC1信号通路的迁移。
DOI：
10.1111/cas.13118
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发表时间：
2017-01
期刊：
影响因子：
5.7
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Sun Z;Zhang B;Wang C;Fu T;Li L;Wu Q;Cai Y;Wang J
叉头盒P3（FOXP 3）在调节性T细胞的发育和功能中发挥着至关重要的作用，最近被确定为不同癌症类型的肿瘤抑制因子。叉头盒P3在正常脑组织中表达，但在胶质母细胞瘤中强烈下调或缺失。为了了解FOXP 3在胶质瘤细胞中的调节机制，我们在过表达FOXP 3的U87细胞中进行了DNA微阵列，并使用定量真实的时间PCR，Western印迹分析和免疫组织化学在体外和体内验证了差异。我们发现FOXP 3可以调节ARHGAP 15的表达。FOXP 3的表达也与ARHGAP 15在胶质瘤样品中相关。FOXP 3过表达通过ARHGAP 15上调和Rac 1失活抑制胶质瘤细胞迁移。FOXP 3的沉默通过ARHGAP 15下调和Rac 1激活促进迁移。ARHGAP 15是Rac 1的一种GTP酶激活蛋白，以双阴性方式抑制小GTP酶信号传导。我们发现ARHGAP 15的表达与胶质瘤的级别相关。小GTPase Rac 1在细胞迁移中发挥重要作用。此外，我们发现FOXP 3调节上皮-间充质转化标志物E-钙粘蛋白和N-钙粘蛋白的表达，这一点很重要，因为上皮-间充质转化与肿瘤扩散和播散密切相关。因此，FOXP 3或ARHGAP 15可作为胶质瘤抗转移治疗的新分子靶点。
Forkhead box P3 (FOXP3) plays a crucial role in the development and function of regulatory T cells and was recently identified as a tumor suppressor in different cancer types. Forkhead box P3 is expressed in normal brain tissues, but is strongly downregulated or absent in glioblastomas. In order to understand the FOXP3 adjustment mechanisms in glioma cells, we performed a DNA microarray in U87 cells overexpressing FOXP3 and validated the differences using quantitative real‐time PCR, Western blot analysis, and immunohistochemistry in vitro and in vivo. We found that FOXP3 can regulate the expression of ARHGAP15. Expression of FOXP3 was also correlated with ARHGAP15 in glioma samples. Overexpression of FOXP3 inhibited glioma cell migration through ARHGAP15 upregulation and Rac1 inactivation. Silencing of FOXP3 promoted migration through ARHGAP15 downregulation and Rac1 activation. ARHGAP15, a GTPase‐activating protein for Rac1, inhibits small GTPase signaling in a dual negative manner. We found that there is a correlation between expression of ARHGAP15 and glioma level. The small GTPase Rac1 plays an important role in cell migration. In addition, we found that FOXP3 regulates expression of epithelial–mesenchymal transition markers E‐cadherin and N‐cadherin, which is important given that epithelial–mesenchymal transition is critically involved in tumor spreading and dissemination. Thus, FOXP3 or ARHGAP15 may serve as a new molecular target for antimetastatic therapies in treating glioma.