Department of Pediatrics, The Affiliated Hospital of Jining Medical University, Jining City, Shandong Province, China.
Lab of Hematology Department, The Affiliated Hospital of Jining Medical University, Jining City, Shandong Province, China.
Biofactors. 2019 May;45(3):355-363. doi: 10.1002/biof.1505. Epub 2019 Apr 15.
Neuroblastoma (NB) is one of the most common malignant tumors derived from pluripotent cells of the neural crest. Nodal is an important embryonic morphogen which can re-express in cancer cells. The roles of Nodal in the progression of NB are not illustrated. Our present study reveals that Nodal is upregulated in NB cells and tissues. Targeted inhibition of Nodal can suppress the in vitro migration and invasion of NB cells while increase its chemo-sensitivity to doxorubicin (Dox) treatment. Nodal positively regulates the expression of Zeb1, one well-known transcription factors of epithelial to mesenchymal transition (EMT) of cancer cells. Knockdown of Zeb1 can attenuate Nodal-induced malignancy of NB cells. Mechanistically, Nodal increases the protein stability of Zeb1 while has no effect on its mRNA expression. It is due to that Nodal can increase the expression of Ataxia telangiectasia mutated kinase (ATM), which can phosphorylate and stabilize Zeb1 in cancer cells. Collectively, our data revealed that Nodal can increase the malignancy of NB cells via increasing the expression of Zeb1. It suggests that targeted inhibition of Nodal might be a potential therapy approach for NB treatment. © 2019 BioFactors, 45(3):355-363, 2019.
神经母细胞瘤（NB）是一种源自神经嵴多能细胞的最常见的恶性肿瘤之一。Nodal 是一种重要的胚胎形态发生素，可在癌细胞中重新表达。Nodal 在 NB 进展中的作用尚未阐明。我们的研究表明，Nodal 在 NB 细胞和组织中上调。Nodal 的靶向抑制可以抑制 NB 细胞的体外迁移和侵袭，同时增加其对阿霉素（Dox）治疗的化学敏感性。Nodal 正向调节 Zeb1 的表达，Zeb1 是癌细胞上皮间质转化（EMT）的一个众所周知的转录因子。Zeb1 的敲低可以减弱 Nodal 诱导的 NB 细胞恶性。机制上，Nodal 增加了 Zeb1 的蛋白稳定性，而对其 mRNA 表达没有影响。这是因为 Nodal 可以增加共济失调毛细血管扩张突变激酶（ATM）的表达，ATM 可以在癌细胞中磷酸化并稳定 Zeb1。总之，我们的数据表明，Nodal 通过增加 Zeb1 的表达来增加 NB 细胞的恶性程度。这表明靶向抑制 Nodal 可能是 NB 治疗的一种潜在治疗方法。
