Petersburg Nuclear Physics Institute named by B.P. Konstantinov of National Research Centre "Kurchatov Institute", Gatchina, Russia.
N.N. Petrov National Medical Research Center of Oncology, St. Petersburg, Pesochnyj, Leningradskaya, Russia.
PLoS One. 2019 Feb 7;14(2):e0211980. doi: 10.1371/journal.pone.0211980. eCollection 2019.
Malignant transformation is associated with loss of cell differentiation, anaplasia. Transcription factors gli, required for embryonic development, may be involved in this process. We studied the activity of transcription factors gli in high-grade gliomas and their role in maintenance of stem cell state and glioma cell survival. 20 glioma cell lines and a sample of a normal adult brain tissue were used in the present study. We found the expression of gli target genes, including GLI1 and FOXM1, in all tested glioma cell lines, but not in the normal tissue. Interestingly, the expression of gli target genes in some glioma cell lines was observed together with a high level of their transcriptional repressor, Gli3R. Knockdown of GLI3 in one of these lines resulted in decrease of gli target gene expression. These data suggest that Gli3R does not prevent the gli target genes transcription, and gli3 acts in glioma cells more as an activator, than a repressor of transcription. We observed that gli regulated the expression of such genes, as SOX2 or OCT4 that maintain stem cell state, and TET1, involving in DNA demethylation. Treatment with GANT61 or siRNA against GLI1, GLI2, or GLI3 could result in complete glioma cell death, while cyclopamine had a weaker and line-specific effect on glioma cell survival. Thus, the gli transcription factors are abnormally active in high-grade gliomas, regulate expression of genes, maintaining the stem cell state, and contribute to glioma cell survival.
恶性转化与细胞分化丧失、去分化有关。胚胎发育所必需的转录因子Gli 可能参与这一过程。我们研究了高级别神经胶质瘤中Gli 转录因子的活性及其在维持干细胞状态和神经胶质瘤细胞存活中的作用。本研究使用了 20 种神经胶质瘤细胞系和一份正常成人脑组织样本。我们发现所有测试的神经胶质瘤细胞系中都表达了Gli 靶基因，包括 GLI1 和 FOXM1，但在正常组织中没有表达。有趣的是，一些神经胶质瘤细胞系中Gli 靶基因的表达与它们的转录抑制剂 Gli3R 的高水平同时存在。在其中一种细胞系中敲低 Gli3 导致Gli 靶基因表达下降。这些数据表明，Gli3R 并不能阻止Gli 靶基因的转录，Gli3 在神经胶质瘤细胞中更像是转录激活剂，而不是转录抑制剂。我们观察到Gli 调节了一些基因的表达，如维持干细胞状态的 SOX2 或 OCT4 基因，以及参与 DNA 去甲基化的 TET1 基因。用 GANT61 或针对 GLI1、GLI2 或 GLI3 的 siRNA 处理可导致神经胶质瘤细胞完全死亡，而 cyclopamine 对神经胶质瘤细胞存活的影响较弱且具有细胞系特异性。因此，Gli 转录因子在高级别神经胶质瘤中异常活跃，调节维持干细胞状态的基因表达，并有助于神经胶质瘤细胞存活。
