Lefty inhibits glioma growth by suppressing Nodal-activated Smad and ERK1/2 pathways.

As a common malignant tumor, glioma has long been a refractory disease in the field of neurosurgery. Exploration of its etiology, pathogenesis, biological characteristics, and new treatment measures is a hot topic as well as a problem most difficult to solve in the neurosurgical division. In recent years, the role of Nodal and its feedback inhibitor Lefty in tumors has drawn more and more attention and may form a new target for cancer therapy. Western blot detection indicated that there was almost no expression of Lefty protein in glioma cells. Transfection of Lefty-overexpressing vector into GBM8401 and GBM glioma cells significantly decreased the expression of Nodal. Nodal can significantly increase the phosphorylation levels of Smad2 and Smad3 and activate the ERK1/2 pathway; meanwhile, Nodal promotes the proliferation and invasion of glioma cells and inhibits their apoptosis. However, when cells were co-transfected with both Lefty- and Nodal-overexpressing vectors, Lefty inhibited the above effects of Nodal in glioma cells, hence significantly reduced the levels of phosphorylated Smad2, Smad3, and ERK1/2, inhibited the proliferation and invasion of glioma cells, and increased their apoptosis. These results indicate that in glioma cells, Lefty inhibits Nodal-mediated activation of Smad and ERK1/2 signaling pathways, thereby suppressing the promoting effect of Nodal on tumor growth.