TGFβ can stimulate the p(38)/β-catenin/PPARγ signaling pathway to promote the EMT, invasion and migration of non-small cell lung cancer (H460 cells).

Abstract

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

• Authors: Li-Chiung Lin, Shih-Lan Hsu, Chieh-Liang Wu, Chi-Mei Hsueh
• Journal: Clinical & experimental metastasis (Clin Exp Metastasis) Vol. 31 Issue 8 Pg. 881-95 (Dec 2014) ISSN: 1573-7276 [Electronic] Netherlands
• PMID: 25168821 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• PPAR gamma
• RNA, Small Interfering
• Transforming Growth Factor beta
• beta Catenin
• p38 Mitogen-Activated Protein Kinases

Topics

• Apoptosis
• Blotting, Western
• Carcinoma, Non-Small-Cell Lung (drug therapy, metabolism, pathology)
• Cell Adhesion
• Cell Cycle
• Cell Movement
• Cell Proliferation
• Epithelial-Mesenchymal Transition
• Fluorescent Antibody Technique
• Humans
• Immunoprecipitation
• Lung Neoplasms (drug therapy, metabolism, pathology)
• PPAR gamma (antagonists & inhibitors, genetics, metabolism)
• RNA, Small Interfering (genetics)
• Signal Transduction
• Transforming Growth Factor beta (pharmacology)
• Tumor Cells, Cultured
• beta Catenin (metabolism)
• p38 Mitogen-Activated Protein Kinases (metabolism)