Department of Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, 211166, China.
Jiangsu Province Key Laboratory of Modern Pathogen Biology, Nanjing, Jiangsu, 211166, China.
Int J Biol Sci. 2019 Jan 1;15(3):533-543. doi: 10.7150/ijbs.30114. eCollection 2019.
Glioma is one of the most common brain tumors, suggesting the importance of investigating the molecular mechanism of gliomas. We studied the roles of Ribonucleotide Reductase Regulatory Subunit M2 (RRM2) in glioma. Expressions of RRM2 are higher in glioma tissues evidenced by TCGA data, western blot and immunohistochemistry. RRM2 is negatively correlated with glioma patient's survival. RNA-seq showed that genes involved in apoptosis, proliferation, cell adhesion and negative regulation of signaling were up-regulated upon RNAi-mediated knock-down of RRM2. Cell phenotypes specific for stably knocking down RRM2 were determined using stable transfection . In an model, knock-down of RRM2 inhibited tumor growth and caused suppression of AKT and ERK1/2 signalings. Interfering RRM2 also down-regulated the expression of cyclin A, cyclin B1, cyclin D1, Vimentin, and N-cadherin, and elevated E-cadherin expression. Moreover, overexpression of RRM2 failed to increase the expression of cyclin B1, cyclin D1, and N-cadherin when phosphorylation of AKT and ERK1/2 was suppressed by LY294002 or PD98059. These findings indicated that RRM2 is a positive regulator of glioma progression which contributes to the migration and proliferation of glioma cells through ERK1/2 and AKT signalings and might be a novel prognostic indicator for glioma patients.
神经胶质瘤是最常见的脑肿瘤之一，这表明研究神经胶质瘤的分子机制非常重要。我们研究了核苷酸还原酶调节亚基 M2（RRM2）在神经胶质瘤中的作用。TCGA 数据、western blot 和免疫组织化学结果表明，RRM2 在神经胶质瘤组织中的表达更高。RRM2 的表达与神经胶质瘤患者的生存呈负相关。RNA-seq 显示，RNAi 介导的 RRM2 敲低后，涉及细胞凋亡、增殖、细胞黏附和信号转导负调控的基因上调。通过稳定转染确定了稳定敲低 RRM2 的细胞表型。在 模型中，敲低 RRM2 抑制肿瘤生长并抑制 AKT 和 ERK1/2 信号转导。干扰 RRM2 还下调了细胞周期蛋白 A、B1、D1、波形蛋白和 N-钙黏蛋白的表达，并上调了 E-钙黏蛋白的表达。此外，当 AKT 和 ERK1/2 的磷酸化被 LY294002 或 PD98059 抑制时，RRM2 的过表达未能增加 cyclin B1、cyclin D1 和 N-钙黏蛋白的表达。这些发现表明，RRM2 是神经胶质瘤进展的正调节剂，通过 ERK1/2 和 AKT 信号通路促进神经胶质瘤细胞的迁移和增殖，可能是神经胶质瘤患者的一个新的预后指标。
