Abstract
Osteosarcoma is the most common primary malignancy of bone and is characterized by a high malignant and metastatic potential. Transforming growth factor alpha (TGF-α) 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-α on human osteosarcoma is largely unknown. We found that TGF-α 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-α-mediated cell migration. We also found that the phosphatidylinositol 3'-kinase (PI3K)/Akt/NF-κB pathway was activated after TGF-α treatment, and TGF-α-induced expression of ICAM-1 and cell migration was inhibited by the specific inhibitors and siRNAs of PI3K, Akt, and NF-κB cascades. In addition, knockdown of TGF-α expression markedly decreased cell metastasis in vitro and in vivo. Our results indicate that TGF-α/EGFR interaction elicits PI3K and Akt activation, which in turn activates NF-κB, resulting in the expression of ICAM-1 and contributing the migration of human osteosarcoma cells.
Keywords:
Migration; Osteosarcoma; TGF-α.
Copyright © 2014 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use
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Bone Neoplasms / drug therapy
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Bone Neoplasms / metabolism*
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Bone Neoplasms / pathology
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Cell Line, Tumor
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Cell Movement / drug effects
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ErbB Receptors / agonists*
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ErbB Receptors / antagonists & inhibitors
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ErbB Receptors / metabolism
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Humans
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Intercellular Adhesion Molecule-1 / chemistry
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Intercellular Adhesion Molecule-1 / genetics
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Intercellular Adhesion Molecule-1 / metabolism*
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Lung Neoplasms / metabolism
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Lung Neoplasms / pathology
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Lung Neoplasms / prevention & control
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Lung Neoplasms / secondary
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Male
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Mice
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Mice, SCID
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / genetics
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NF-kappa B / metabolism
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Osteosarcoma / drug therapy
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Osteosarcoma / metabolism
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Osteosarcoma / pathology
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Osteosarcoma / secondary*
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Phosphatidylinositol 3-Kinase / chemistry
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Phosphatidylinositol 3-Kinase / genetics
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Phosphatidylinositol 3-Kinase / metabolism*
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins c-akt / agonists
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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RNA Interference
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Recombinant Proteins / chemistry
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Second Messenger Systems* / drug effects
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Transforming Growth Factor alpha / antagonists & inhibitors
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Transforming Growth Factor alpha / genetics
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Transforming Growth Factor alpha / metabolism*
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Tumor Burden / drug effects
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Up-Regulation / drug effects
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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ICAM1 protein, human
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NF-kappa B
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Phosphoinositide-3 Kinase Inhibitors
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Recombinant Proteins
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TGFA protein, human
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Transforming Growth Factor alpha
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Intercellular Adhesion Molecule-1
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Phosphatidylinositol 3-Kinase
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EGFR protein, human
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ErbB Receptors
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AKT1 protein, human
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Proto-Oncogene Proteins c-akt