In the present study, the activation of the Smad2/3 and Src/MAPK pathways follows the same trend with the up-regulation of GRP78; moreover, knockdown of GRP78 inhibited the activation of Smad2/3 and Src, suggesting a causal link between GRP78 and activation of the two pathways in lung cancer. This evidence concerns the gene SMAD2 and lung cancer.