Endogenous Nodal promotes melanoma undergoing epithelial-mesenchymal transition via Snail and Slug in vitro and in vivo.

Nodal, an important embryonic morphogen, has been reported to modulate tumorigenesis. Epithelial-mesenchymal transition (EMT) plays an important role in cancer metastasis. We have previously reported that recombinant Nodal treatment can promote melanoma undergoing EMT, but the effects of endogenous Nodal on EMT are still unknown. Here we generated both Nodal-overexpression and -knockdown stable cell lines to investigate the in vitro and in vivo characteristics of Nodal-induced EMT in murine melanoma cells. Nodal-overexpression cells displayed increased migration ability, accompanied by typical phenotype changes of EMT. In contrast, Nodal-knockdown stable cells repressed the EMT phenotype as well as reduced cell motility. Results of animal experiments confirmed that overexpression of Nodal can promote the metastasis of melanoma tumor in vivo. Mechanistically, we found that Nodal-induced expression of Snail and Slug involves its activation of ALK/Smads and PI3k/AKT pathways, which is an important process in the Nodal-induced EMT. However, we also found that the EMT phenotype was not completely inhibited by blocking the paracrine activity of Nodal in Nodal overexpression cell line suggesting the presence of additional mechanism(s) in the Nodal-induced EMT. This study provides a better understanding of Nodal function in melanoma, and suggests targeting Nodal as a potential strategy for melanoma therapey.