Nodal increases the malignancy of childhood neuroblastoma cells via regulation of Zeb1.

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.