MIG-7 controls COX-2/PGE2-mediated lung cancer metastasisMore effective treatments for metastatic lung cancer remain a pressing clinical need. In this study we identified MIG-7 protein as critical for COX-2/PGE2- and Akt/GSK-3β-dependent tumor invasion/metastasis. COX-2/PGE2 activated EP4 to enhance Akt and GSK-3β phosphorylation and β-catenin/LEF/TCF signaling leading to MIG-7 upregulation. RNAi-mediated attenuation of MIG-7 blocked COX-2/PGE2- and Akt/GSK-3β-mediated migration/invasion effects. Further, MIG-7 protein inhibited protein phosphatase 2A to sustain Akt/GSK-3β phosphorylation and cancer-cell migration/invasion. Cancer cells overexpressing MIG-7 exhibited increased expression of ZEB-1 and Twist in parallel with epithelial-mesenchymal transition, metastasis and cancer lethality. MIG-7 protein level positively correlated with advanced stages of human lung cancers. MIG-7 thus offers a theranostic target for cancer metastases arising from aberrant activation of the cellular COX-2/PGE2 and Akt/GSK-3β signaling pathways In summary, this report represents the first demonstration of a functional link between COX-2/PGE2, Akt/GSK-3β, β-catenin/LEF/TCF, MIG-7 and PP2A. These findings shed light on the mechanism of action of MIG-7 protein and suggest that MIG-7 may be an important therapeutic target for COX-2/PGE2- and Akt/GSK-3β-driven cancer metastasis (Ho, M. Y. et al., Cancer Res, 2012 ).
Co-researchers:Ho MY, Liang SM, Hung SW, Liang CM.