ERK-Mediated Loss of miR-199a-3p and Induction of EGR1 Act as a "Toggle Switch" of GBM Cell Dedifferentiation into NANOG- and OCT4-Positive Cells
ERK-Mediated Loss of miR-199a-3p and Induction of EGR1 Act as a "Toggle Switch" of GBM Cell Dedifferentiation into NANOG- and OCT4-Positive Cells
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DOI：
10.1158/0008-5472.can-19-0855
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发表时间：
2020-08-15
期刊：
影响因子：
11.2
通讯作者：
Virolle, Thierry
中科院分区：
文献类型：
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作者：
Almairac, Fabien;Turchi, Laurent;Virolle, Thierry
人们对了解癌症干细胞群如何在实体瘤中维持有很大的兴趣。在这里，我们表明，肿瘤细胞表现出干细胞样的特性和多能性标志物NANOG和OCT 4的表达，可以从原始分化的肿瘤细胞新鲜分离的人胶质母细胞瘤（GBM），从来没有知道任何血清培养条件。EGFR/ERK信号对EGR 1的诱导促进细胞从侵袭性较低、分化程度较高的细胞状态转化为自我更新和强烈致瘤状态，表达NANOG和OCT 4。这些多能性标志物的表达发生在细胞重新进入细胞周期之前，证明了它们在没有任何细胞分裂的情况下改变和去分化的能力。在分化的GBM细胞中，ERK介导的miR-199 a-3 p抑制诱导EGR 1蛋白表达并触发去分化。总的来说，这一信号通路构成了一个ERK介导的“开关”，促进多能性标志物的表达和干细胞样功能GBM cells.Significance：这项研究定义了ERK介导的GBM细胞去分化成干细胞样状态的分子机制，表达多能性标志物。
There is great interest in understanding how the cancer stem cell population may be maintained in solid tumors. Here, we show that tumor cells exhibiting stem-like properties and expression of pluripotency markers NANOG and OCT4 can arise from original differentiated tumor cells freshly isolated from human glioblastomas (GBM) and that have never known any serum culture conditions. Induction of EGR1 by EGFR/ERK signaling promoted cell conversion from a less aggressive, more differentiated cellular state to a self-renewing and strongly tumorigenic state, expressing NANOG and OCT4. Expression of these pluripotency markers occurred before the cells re-entered the cell cycle, demonstrating their capacity to change and dedifferentiate without any cell divisions. In differentiated GBM cells, ERK-mediated repression of miR-199a-3p induced EGR1 protein expression and triggered dedifferentiation. Overall, this signaling pathway constitutes an ERK-mediated "toggle switch" that promotes pluripotency marker expression and stem-like features in GBM cells.Significance: This study defines an ERK-mediated molecular mechanism of dedifferentiation of GBM cells into a stem-like state, expressing markers of pluripotency.