Regulation of neuroblastoma differentiation by forkhead transcription factors FOXO1/3/4 through the receptor tyrosine kinase PDGFRA
Regulation of neuroblastoma differentiation by forkhead transcription factors FOXO1/3/4 through the receptor tyrosine kinase PDGFRA
复制标题
叉头转录因子FOXO1/3/4通过受体酪氨酸激酶PDGFRA调节神经母细胞瘤分化
DOI：
10.1073/pnas.1119535109
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发表时间：
2012-03-27
影响因子：
11.1
通讯作者：
You, Han
中科院分区：
文献类型：
--
作者：
Mei, Yang;Wang, Zhanxiang;You, Han
神经母细胞瘤是一种常见的儿童恶性肿瘤，起源于神经脊来源的交感神经系统。神经母细胞瘤发病机制中的一个关键早期事件是不同阶段的神经母细胞分化受阻。TPA和PDGF-BB联合治疗神经母细胞瘤可诱导神经母细胞瘤细胞终末分化。然而，参与这一过程的信号通路在很大程度上仍然不清楚。在这里，我们报告内源性FOXO蛋白的抑制减弱了TPA/PDGF-BB介导的神经母细胞瘤细胞的分化。激活的FOXO转录因子作用于PDGFRA启动子，指导其基础mRNA的表达，并在血清剥夺条件下诱导其表达。在TPA/PDGF-BB治疗下，神经母细胞瘤细胞内源性PDGFRA的缺失显著减少了轴突的形成和延伸。此外，PDGFRA的异位表达可通过抑制FOXOS来阻断神经母细胞瘤的分化。这些发现将FOXO-PDGFRA轴定义为控制TPA诱导的神经母细胞瘤分化的关键机制组件。
Neuroblastoma is a common childhood malignant tumor originated from the neural crest-derived sympathetic nervous system. A crucial early event in neuroblastoma pathogenesis is arrested differentiation of neuroblasts at various stages. Treatment of neuroblastoma with TPA and PDGF-BB leads to terminal differentiation of neuroblastoma cells. However, the signaling pathways that are involved in this process remain largely unknown. Here, we report that inhibition of endogenous FOXO proteins attenuated TPA/PDGF-BB mediated differentiation of neuroblastoma cells. Activated FOXO transcription factors acted on PDGFRA promoter to direct its basal mRNA expression as well as its induction upon serum deprivation. Depletion of endogenous PDGFRA in neuroblastoma cells significantly diminished neurite formation and extension under TPA/PDGF-BB treatment. Furthermore, ectopic expression of PDGFRA abolished the blockage of neuroblastoma differentiation by FOXOs inhibition. These findings define the FOXO–PDGFRA axis as crucial mechanistic components that govern TPA-induced neuroblastoma differentiation.