Transforming growth factor alpha promotes osteosarcoma metastasis by ICAM-1 and PI3K/Akt signaling pathway

Osteosarcoma is the most common primary malignancy of bone and is characterized by a high malignant and metastatic potential. Transforming growth factor alpha (TGF-alpha) is classified as the EGF (epidermal growth factor)-like family, which is involved in cancer cellular activities such as proliferation, motility, migration, adhesion and invasion abilities. However, the effect of TGF-alpha on human osteosarcoma is largely unknown. We found that TGF-alpha increased the cell migration and expression of intercellular adhesion molecule-1 (ICAM-1) in human osteosarcoma cells. Transfection of cells with ICAM-1 siRNA reduced TGF-alpha-mediated cell migration. We also found that the phosphatidylinositol 3'-kinase (PI3K)/Akt/NF-kappa B pathway was activated after TGF-alpha treatment, and TGF-alpha-induced expression of ICAM-1 and cell migration was inhibited by the specific inhibitors and siRNAs of PI3K, Akt, and NF-kappa B cascades. In addition, knockdown of TGF-alpha expression markedly decreased cell metastasis in vitro and in vivo. Our results indicate that TGF-alpha/EGFR interaction elicits PI3K and Akt activation, which in turn activates NF-kappa B, resulting in the expression of ICAM-1 and contributing the migration of human osteosarcoma cells. (C) 2014 Elsevier Inc. All rights reserved.