Taken together, our findings demonstrated that the downregulation of TGF-β via shRNAs induced tumor cell death, an effect that was driven by ASK1–SAPK axis signaling cascade regulated by a positive feedback circuit triggered by Akt inactivation/NOX4 increase-derived ROS-mediated ER stress (A375 cells) or tumor cell death driven by direct ASK1–SAPK axis signaling cascade (HPAC cells). This evidence concerns the gene MAP3K5 and neoplasm.