Key Laboratory of Glycoconjuates Research, Ministry of Public Health & Gene Research Center, Shanghai Medical College of Fudan University, Shanghai 200032, China.
Biochem Biophys Res Commun. 2010 Jul 9;397(4):711-7. doi: 10.1016/j.bbrc.2010.06.015. Epub 2010 Jun 9.
Sox2, a master transcription factor, contributes to the generation of induced pluripotent stem cells and plays significant roles in sustaining the self-renewal of neural stem cells and glioma-initiating cells. Understanding the functional differences of Sox2 between glioma-initiating cells and normal neural stem cells would contribute to therapeutic approach for treatment of brain tumors. Here, we first demonstrated that Sox2 could contribute to the self-renewal and proliferation of glioma-initiating cells. The following experiments showed that Sox2 was activated at translational level in a subset of human glioma-initiating cells compared with the normal neural stem cells. Further investigation revealed there was a positive correlation between Sox2 and eukaryotic initiation factor 4E (eIF4E) in glioma tissues. Down-regulation of eIF4E decreased Sox2 protein level without altering its mRNA level in glioma-initiating cells, indicating that Sox2 was activated by eIF4E at translational level. Furthermore, eIF4E was presumed to regulate the expression of Sox2 by its 5' untranslated region (5' UTR) sequence. Our results suggest that the eIF4E-Sox2 axis is a novel mechanism of unregulated self-renewal of glioma-initiating cells, providing a potential therapeutic target for glioma.
Sox2 是一种主要的转录因子，有助于诱导多能干细胞的生成，并在维持神经干细胞和神经胶质瘤起始细胞的自我更新方面发挥重要作用。了解 Sox2 在神经胶质瘤起始细胞和正常神经干细胞中的功能差异将有助于为脑肿瘤的治疗方法做出贡献。在这里，我们首先证明 Sox2 有助于神经胶质瘤起始细胞的自我更新和增殖。后续实验表明，与正常神经干细胞相比，在人类神经胶质瘤起始细胞的一部分中 Sox2 在翻译水平上被激活。进一步的研究表明，在神经胶质瘤组织中 Sox2 与真核起始因子 4E（eIF4E）之间存在正相关。下调 eIF4E 会降低神经胶质瘤起始细胞中 Sox2 蛋白水平，而不会改变其 mRNA 水平，表明 Sox2 在翻译水平上被 eIF4E 激活。此外，eIF4E 被推测通过其 5'非翻译区（5'UTR）序列来调节 Sox2 的表达。我们的结果表明，eIF4E-Sox2 轴是神经胶质瘤起始细胞不受控制的自我更新的新机制，为神经胶质瘤提供了一个潜在的治疗靶点。
