Cell Growth Regulation Laboratory, School of Life Sciences and Biotechnology, Korea University, Seoul, 136-713, Korea.
Mol Cells. 2010 Nov;30(5):403-8. doi: 10.1007/s10059-010-0122-z. Epub 2010 Aug 31.
A growing body of evidence indicates that deregulation of stem cell fate determinants is a hallmark of many types of malignancies. The neural stem cell fate determinant TLX plays a pivotal role in neurogenesis in the adult brain by maintaining neural stem cells. Here, we report a tumorigenic role of TLX in brain tumor initiation and progression. Increased TLX expression was observed in a number of glioma cells and glioma stem cells, and correlated with poor survival of patients with gliomas. Ectopic expression of TLX in the U87MG glioma cell line and Ink4a/Arf-deficient mouse astrocytes (Ink4a/Arf(-/-) astrocytes) induced cell proliferation with a concomitant increase in cyclin D expression, and accelerated foci formation in soft agar and tumor formation in in vivo transplantation assays. Furthermore, overexpression of TLX in Ink4a/Arf(-/-) astrocytes inhibited cell migration and invasion and promoted neurosphere formation and Nestin expression, which are hallmark characteristics of glioma stem cells, under stem cell culture conditions. Our results indicate that TLX is involved in glioma stem cell genesis and represents a potential therapeutic target for this type of malignancy.
越来越多的证据表明，干细胞命运决定因子的失调是许多类型恶性肿瘤的标志。神经干细胞命运决定因子 TLX 通过维持神经干细胞在成人脑中的神经发生中发挥关键作用。在这里，我们报告了 TLX 在脑肿瘤起始和进展中的致癌作用。在许多神经胶质瘤细胞和神经胶质瘤干细胞中观察到 TLX 表达增加，并且与神经胶质瘤患者的不良生存相关。TLX 在 U87MG 神经胶质瘤细胞系和 Ink4a/Arf 缺失型小鼠星形胶质细胞（Ink4a/Arf(-/-) 星形胶质细胞）中的异位表达诱导细胞增殖，同时 cyclin D 表达增加，并加速软琼脂中的焦点形成和体内移植实验中的肿瘤形成。此外，在 Ink4a/Arf(-/-) 星形胶质细胞中过表达 TLX 可抑制细胞迁移和侵袭，并促进神经球形成和巢蛋白表达，这是神经胶质瘤干细胞的标志性特征，在干细胞培养条件下。我们的研究结果表明，TLX 参与了神经胶质瘤干细胞的发生，是这种类型恶性肿瘤的潜在治疗靶点。
