RTVP-1 promotes mesenchymal transformation of glioma via a STAT-3/IL-6-dependent positive feedback loop.
RTVP-1 promotes mesenchymal transformation of glioma via a STAT-3/IL-6-dependent positive feedback loop.
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DOI：
10.18632/oncotarget.4205
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发表时间：
2015-09-08
期刊：
影响因子：
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通讯作者：
Brodie C
中科院分区：
文献类型：
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作者：
Giladi ND;Ziv-Av A;Lee HK;Finniss S;Cazacu S;Xiang C;Waldman Ben-Asher H;deCarvalho A;Mikkelsen T;Poisson L;Brodie C
胶质母细胞瘤（GBM）是最具侵袭性的原发性脑肿瘤，表现出增加的侵袭性和对抗肿瘤治疗的抗性。我们探讨了RTVP-1（一种促进胶质瘤细胞迁移的胶质瘤相关蛋白）在GBM间充质转化中的作用。癌症基因组图谱（TCGA）的分析表明，RTVP-1在间充质GBM中的表达较高，并预测肿瘤复发和不良临床结局。芯片分析显示，RTVP-1启动子结合STAT 3和C/EBPβ，这两个主转录因子调节GBM的间充质转化。此外，IL-6以STAT 3依赖性方式诱导RTVP-1表达。RTVP-1促进胶质瘤细胞的迁移和间质转化。类似地，RTVP-1在人神经干细胞中的过表达诱导间充质分化，而RTVP-1在胶质瘤干细胞（GSC）中的沉默降低了这些细胞的间充质转化和干细胞性。RTVP-1的沉默也增加了携带GSC衍生的异种移植物的小鼠的存活率。使用RTVP-1沉默的胶质瘤细胞的基因阵列分析，我们鉴定了IL-6作为RTVP-1对GSC的间充质转化和迁移作用的介导物，因此通过STAT 3途径上调RTVP-1表达而在正反馈回路中起作用。总的来说，这些结果暗示RTVP-1作为GBM的新的预后标志物和治疗靶点。
Glioblastomas (GBMs), the most aggressive primary brain tumors, exhibit increased invasiveness and resistance to anti-tumor treatments. We explored the role of RTVP-1, a glioma-associated protein that promotes glioma cell migration, in the mesenchymal transformation of GBM. Analysis of The Cancer Genome Atlas (TCGA) demonstrated that RTVP-1 expression was higher in mesenchymal GBM and predicted tumor recurrence and poor clinical outcome. ChiP analysis revealed that the RTVP-1 promoter binds STAT3 and C/EBPβ, two master transcription factors that regulate mesenchymal transformation of GBM. In addition, IL-6 induced RTVP-1 expression in a STAT3-dependent manner. RTVP-1 increased the migration and mesenchymal transformation of glioma cells. Similarly, overexpression of RTVP-1 in human neural stem cells induced mesenchymal differentiation, whereas silencing of RTVP-1 in glioma stem cells (GSCs) decreased the mesenchymal transformation and stemness of these cells. Silencing of RTVP-1 also increased the survival of mice bearing GSC-derived xenografts. Using gene array analysis of RTVP-1 silenced glioma cells we identified IL-6 as a mediator of RTVP-1 effects on the mesenchymal transformation and migration of GSCs, therefore acting in a positive feedback loop by upregulating RTVP-1 expression via the STAT3 pathway. Collectively, these results implicate RTVP-1 as a novel prognostic marker and therapeutic target in GBM.