Abstract
Recent evidence indicates that cyclooxygenase-2 (COX-2) and epidermal growth factor receptor (EGFR) are involved in hepatocarcinogenesis. This study was designed to evaluate the possible interaction between the COX-2 and EGFR signaling pathways in human hepatocellular carcinoma (HCC) cells. Immunohistochemical analysis using serial sections of human HCC tissues revealed positive correlation between COX-2 and EGFR in HCC cells (P < 0.01). Overexpression of COX-2 in cultured HCC cells (Hep3B) or treatment with PGE(2) or the selective EP(1) receptor agonist, ONO-DI-004, increased EGFR phosphorylation and tumor cell invasion. The PGE(2)-induced EGFR phosphorylation and cell invasiveness were blocked by the EP(1) receptor siRNA or antagonist ONO-8711 and by two EGFR tyrosine kinase inhibitors, AG1478 and PD153035. The EP(1)-induced EGFR transactivation and cell invasion involves c-Src, in light of the presence of native binding complex of EP(1)/Src/EGFR and the inhibition of PGE(2)-induced EGFR phosphorylation and cell invasion by the Src siRNA and the Src inhibitor, PP2. Further, overexpression of COX-2 or treatment with PGE(2) also induced phosphorylation of c-Met, another receptor tyrosine kinase critical for HCC cell invasion. Moreover, activation of EGFR by EGF increased COX-2 promoter activity and protein expression in Hep3B and Huh-7 cells, whereas blocking PGE(2) synthesis or EP(1) attenuated EGFR phosphorylation induced by EGF, suggesting that the COX-2/PGE(2)/EP(1) pathway also modulate the activation of EGFR by its cognate ligand. These findings disclose a cross-talk between the COX-2/PGE(2)/EP(1) and EGFR/c-Met signaling pathways that coordinately regulate human HCC cell invasion.
Publication types
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Research Support, N.I.H., Extramural
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Retracted Publication
MeSH terms
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Alprostadil / analogs & derivatives
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Alprostadil / pharmacology
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Bridged Bicyclo Compounds / pharmacology
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CSK Tyrosine-Protein Kinase
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Caproates / pharmacology
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Carcinoma, Hepatocellular / genetics
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Carcinoma, Hepatocellular / metabolism
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Carcinoma, Hepatocellular / pathology
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Cell Line, Tumor
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Cell Movement / drug effects
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Cell Movement / physiology*
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Cyclooxygenase 2 / analysis
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Cyclooxygenase 2 / genetics
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Cyclooxygenase 2 / metabolism
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Dinoprostone / pharmacology
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Enzyme Activation
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ErbB Receptors / antagonists & inhibitors
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ErbB Receptors / metabolism*
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Gene Expression / genetics
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Humans
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Liver Neoplasms / genetics
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Liver Neoplasms / metabolism
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Liver Neoplasms / pathology
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Membrane Proteins / analysis
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Neoplasm Invasiveness
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Phosphorylation / drug effects
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Protein Binding / drug effects
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Protein Kinase Inhibitors / pharmacology
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Protein-Tyrosine Kinases / metabolism
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-met / metabolism*
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RNA Interference
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RNA, Small Interfering / genetics
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Receptors, Prostaglandin / genetics
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Receptors, Prostaglandin / metabolism
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Receptors, Prostaglandin E / genetics
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Receptors, Prostaglandin E / physiology*
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Receptors, Prostaglandin E, EP1 Subtype
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Transfection
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src-Family Kinases
Substances
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Bridged Bicyclo Compounds
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Caproates
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Membrane Proteins
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ONO 8711
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ONO-DI-004
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PTGER1 protein, human
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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RNA, Small Interfering
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Receptors, Prostaglandin
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Receptors, Prostaglandin E
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Receptors, Prostaglandin E, EP1 Subtype
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Cyclooxygenase 2
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PTGS2 protein, human
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ErbB Receptors
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Protein-Tyrosine Kinases
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Proto-Oncogene Proteins c-met
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CSK Tyrosine-Protein Kinase
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src-Family Kinases
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CSK protein, human
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Alprostadil
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Dinoprostone