While there were certain studies focusing on the mechanism of TGF-beta promoting the growth of glioma cells, the present work revealed another novel mechanism that TGF-beta may promote glioma cell growth via enhancing Nodal expression. Our results showed that Nodal expression was significantly upregulated in glioma cells when TGF-beta was added, whereas the TGF-beta-induced Nodal expression was evidently inhibited by transfection Smad2 or Smad3 siRNAs, and the suppression was especially significant when the Smad3 was downregulated. Another, the attenuation of TGF-beta-induced Nodal expression was observed with blockade of the ERK1/2 pathway also. Further detection of the proliferation, apoptosis, and invasion of glioma cells indicated that Nodal overexpression promoted the proliferation and invasion of tumor cells and inhibited their apoptosis, resembling the effect of TGF-beta addition. Downregulation of Nodal expression via transfection Nodal-specific siRNA in the presence of TGF-beta weakened the promoting effect of the latter on glioma cells growth, and transfecting Nodal siRNA alone in the absence of exogenous TGF-beta more profoundly inhibited the growth of glioma cells. These results demonstrated that while both TGF-beta and Nodal promoted glioma cells growth, the former might exert such effect by enhancing Nodal expression, which may form a new target for glioma therapy. Crown Copyright (C) 2013 Published by Elsevier Inc. All rights reserved.