TLR9 is critical for glioma stem cell maintenance and targeting.
TLR9 is critical for glioma stem cell maintenance and targeting.
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DOI：
10.1158/0008-5472.can-14-1151
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发表时间：
2014-09-15
期刊：
影响因子：
11.2
通讯作者：
Yu H
中科院分区：
文献类型：
--
作者：
Herrmann A;Cherryholmes G;Schroeder A;Phallen J;Alizadeh D;Xin H;Wang T;Lee H;Lahtz C;Swiderski P;Armstrong B;Kowolik C;Gallia GL;Lim M;Brown C;Badie B;Forman S;Kortylewski M;Jove R;Yu H
了解肿瘤干细胞在恶性胶质瘤中的作用，可能为消除它们提供治疗策略。本研究表明toll样受体TLR9在胶质瘤干细胞（GSC）中升高，并促进胶质瘤的生长。TLR9过表达受STAT3调控，而STAT3是维持GSC所必需的。CpG配体（CpG ODN）刺激TLR9促进了GSC的生长，而沉默TLR9表达则破坏了GSC的发育。CpG-ODN处理诱导frizzled4依赖性JAK2激活，从而激活STAT3。使用CpG-siRNA偶联物通过TLR9将siRNA靶向递送到GSC中。通过局部或全身治疗，在体内给药CpG-Stat3 siRNA来沉默STAT3，可以减少GSC和胶质瘤的生长。我们的研究结果确定TLR9是GSC的功能标记物和胶质瘤治疗有效疗法的靶标。
Understanding supports for cancer stem-like cells in malignant glioma may suggest therapeutic strategies for their elimination. Here we show that the Toll-like receptor TLR9 is elevated in glioma stem-like cells (GSC) where it contributes to glioma growth. TLR9 overexpression is regulated by STAT3 which was required for GSC maintenance. Stimulation of TLR9 with a CpG ligand (CpG ODN) promoted GSC growth, whereas silencing TLR9 expression abrogated GSC development. CpG-ODN treatment induced Frizzled4-dependent activation of JAK2, thereby activating STAT3. Targeted delivery of siRNA into GSC was achieved via TLR9 using CpG-siRNA conjugates. Through local or systemic treatment, administration of CpG-Stat3 siRNA to silence STAT3 in vivo reduced GSC along with glioma growth. Our findings identify TLR9 as a functional marker for GSC and a target for the delivery of efficacious therapeutics for glioma treatment.