Chavali P L, Saini R K R, Zhai Q, Vizlin-Hodzic D, Venkatabalasubramanian S, Hayashi A, Johansson E, Zeng Z-j, Mohlin S, Påhlman S, Hansford L, Kaplan D R, Funa K
1] Sahlgrenska Cancer Center at the Sahlgrenska Academy, University of Gothenburg, Box 425, Gothenburg SE 40530, Sweden [2] Department of Oncology, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
Sahlgrenska Cancer Center at the Sahlgrenska Academy, University of Gothenburg, Box 425, Gothenburg SE 40530, Sweden.
Cell Death Dis. 2014 Oct 30;5(10):e1502. doi: 10.1038/cddis.2014.449.
Nuclear orphan receptor TLX (Drosophila tailless homolog) is essential for the maintenance of neural stem/progenitor cell self-renewal, but its role in neuroblastoma (NB) is not well understood. Here, we show that TLX is essential for the formation of tumor spheres in three different NB cell lines, when grown in neural stem cell media. We demonstrate that the knock down of TLX in IMR-32 cells diminishes its tumor sphere-forming capacity. In tumor spheres, TLX is coexpressed with the neural progenitor markers Nestin, CD133 and Oct-4. In addition, TLX is coexpressed with the migratory neural progenitor markers CD15 and matrix metalloproteinase-2 (MMP-2) in xenografts of primary NB cells from patients. Subsequently, we show the effect of TLX on the proliferative, invasive and migratory properties of IMR-32 cells. We attribute this to the recruitment of TLX to both MMP-2 and Oct-4 gene promoters, which resulted in the respective gene activation. In support of our findings, we found that TLX expression was high in NB patient tissues when compared with normal peripheral nervous system tissues. Further, the Kaplan-Meier estimator indicated a negative correlation between TLX expression and survival in 88 NB patients. Therefore, our results point at TLX being a crucial player in progression of NB, by promoting self-renewal of NB tumor-initiating cells and altering their migratory and invasive properties.
核孤儿受体TLX（果蝇无尾同源物）对于神经干/祖细胞自我更新的维持至关重要，但其在神经母细胞瘤（NB）中的作用尚不清楚。在此，我们表明，当在神经干细胞培养基中培养时，TLX对于三种不同NB细胞系中肿瘤球的形成至关重要。我们证明，在IMR-32细胞中敲低TLX会降低其形成肿瘤球的能力。在肿瘤球中，TLX与神经祖细胞标志物巢蛋白、CD133和Oct-4共表达。此外，在来自患者的原发性NB细胞异种移植中，TLX与迁移性神经祖细胞标志物CD15和基质金属蛋白酶-2（MMP-2）共表达。随后，我们展示了TLX对IMR-32细胞增殖、侵袭和迁移特性的影响。我们将此归因于TLX被募集到MMP-2和Oct-4基因启动子上，从而导致各自基因的激活。为支持我们的发现，我们发现与正常外周神经系统组织相比，NB患者组织中TLX表达较高。此外，Kaplan-Meier估计表明，88例NB患者中TLX表达与生存呈负相关。因此，我们的结果表明，TLX通过促进NB肿瘤起始细胞的自我更新并改变其迁移和侵袭特性，在NB进展中起着关键作用。
