TGFβ can stimulate the p38/β-catenin/PPARγ signaling pathway to promote the EMT, invasion and migration of non-small cell lung cancer (H460 cells)

Signaling pathway(s) responsible for transforming growth factor beta (TGF beta)-induced epithelial mesenchymal transition (EMT), invasion and migration of H460 cells (non-small cell lung cancer/NSCLC) was identified in the study. The results showed that TGF beta-induced p(38)/beta-catenin/PPAR gamma signaling pathway played a critical role in the promotion of EMT, invasion and migration of H460 cells. All these pathological outcomes attributed to PPAR gamma-increased expression of p-EGFR, p-c-MET and Vimentin and the decrease of E-cadherin. Transforming growth factor beta and p(38)-induced beta-catenin not only stimulated the expression of PPAR gamma but also physically interacted with it. Blocking the ligand binding domain of PPAR gamma (with GW9662) could significantly interfere the binding between PPAR gamma and beta-catenin, and interrupt the nuclear infiltration of both factors. These findings suggested that beta-catenin was an upstream regulator and a ligand of PPAR gamma, and the binding between these two molecules was critical for their nuclear infiltration. Transforming growth factor beta-induced tumor invasion and migration was also seen in U373 cells (brain glioma, with high inducible PPAR gamma) in a PPAR gamma-dependent manner, but not in CH27 cells (squamous NSCLC, with low PPAR gamma). PPAR gamma shRNA, GW9662, JW67 and 2,4-diaminoquinazoline were all revealed to have important values in the control of the intrinsic and TGF beta-induced EMT, tumor invasion and migration of H460 cells. The results further suggested that PPAR gamma and beta-catenin may be the potential markers for the early diagnosis and/or treatment of metastatic tumors.