Abstract
Osteosarcoma, the most common primary bone tumor, occurs most frequently in children and adolescents and has a 5-year survival rate, which is unsatisfactory. As epidermal growth factor receptor (EGFR) positively correlates with TNM (tumor-node-metastasis) stage in osteosarcoma, EGFR may play an important role in its progression. The purpose of this study was to explore potential mechanisms underlying this correlation. We found that EGF promotes MG63 cell migration and invasion as well as stress fiber formation via Rho A activation and that these effects can be reversed by inhibiting Rho A expression. In addition, molecules downstream of Rho A, including ROCK1, LIMK2, and Cofilin, are activated by EGF in MG63 cells, leading to actin stress fiber formation and cell migration. Moreover, inhibition of ROCK1, LIMK2, or Cofilin in MG63 cells using known inhibitors or short hairpin RNA (shRNA) prevents actin stress fiber formation and cell migration. Thus, we conclude that Rho A/ROCK1/LIMK2/Cofilin signaling mediates actin microfilament formation in MG63 cells upon EGFR activation. This novel pathway provides a promising target for preventing osteosarcoma progression and for treating this cancer.
Highlights
Osteosarcoma (OS) is the most common malignant bone-derived tumor and is prevalent among children and adolescents
It is well known that most kinases activate their downstream effectors through phosphorylation; previous reports have shown that small molecule kinase inhibitors, such as Gefitinib and BIBW 2992, have little effect on OS development and no significant inhibitory effect on cell viability in vitro [24]
MG63 cell migration was induced with 10 ng/mL EGF, which is in agreement with a previous study demonstrating that EGF is a cytokine with multifunctional activity, even in the same cell type [25]
Summary
Osteosarcoma (OS) is the most common malignant bone-derived tumor and is prevalent among children and adolescents. Despite recent advances in effective treatments, including surgery and chemotherapy, the 5-year survival rate of OS patients with lung metastasis is less than 30% [4]. A better understanding of the molecular mechanisms involved in cancer progression is needed to reduce the financial burden and suffering of OS patients, to improve the treatment of OS, and to reduce the metastasis rate. Cancer cell migration is a complex process that requires multiple steps and the participation of multiple signaling molecules. These actions are controlled by a signaling cascade that is initiated by adhesion molecules (e.g., integrins) or growth factor receptors, such as the epidermal growth factor receptor (EGFR) [5]. The binding of EGF to its receptor induces EGFR dimerization at the plasma membrane, which results in trans-autophosphorylation and activation of the tyrosine kinase domain [14,15], leading to modulation of a variety of intracellular pathways, including the MAPK and PI3K/AKT pathways [12]
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