Abstract
Heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) has been shown to stimulate the growth of various cell types in an autocrine or paracrine manner. Although HB-EGF is widely expressed in tumors when compared with normal tissue, its contribution to cancer progression remains obscure. The objective of this study was to explore the effects of HB-EGF on proliferation, invasion activity and MMP-9 levels of an oral squamous cell carcinoma cell line, HSC3, in vitro. MTT assays, Matrigel invasion assays and RT-PCR in combination with RNA interference (RNAi) were used in this study. An RNAi-mediated decrease in HB-EGF expression reduced invasion activity and MMP-9 mRNA levels, but not proliferation, in HSC3 cells. The addition of purified HB-EGF to cell culture medium upregulated MMP-9 mRNA levels in HSC3 cells. Furthermore, the TACE inhibitor TAPI-2 or EGFR inhibitor AG1478 decreased MMP-9 mRNA levels in HSC3 cells. These data indicate that HB-EGF released from HSC3 cells by TACE stimulates EGFR in an autocrine manner, which in turn activates invasion activity via MMP-9 upregulation.
MeSH terms
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ADAM Proteins / antagonists & inhibitors
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ADAM Proteins / metabolism
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ADAM17 Protein
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Autocrine Communication
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Carcinoma, Squamous Cell / genetics
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Carcinoma, Squamous Cell / metabolism*
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Carcinoma, Squamous Cell / secondary
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Cell Line, Tumor
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Cell Movement* / drug effects
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Cell Proliferation
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ErbB Receptors / antagonists & inhibitors
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ErbB Receptors / metabolism
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Heparin-binding EGF-like Growth Factor
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Humans
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Hydroxamic Acids / pharmacology
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / metabolism*
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Matrix Metalloproteinase 9 / genetics
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Matrix Metalloproteinase 9 / metabolism
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Neoplasm Invasiveness
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Protease Inhibitors / pharmacology
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Protein Kinase Inhibitors / pharmacology
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Quinazolines / pharmacology
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RNA Interference
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RNA, Messenger / metabolism
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Real-Time Polymerase Chain Reaction
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction
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Time Factors
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Tongue Neoplasms / genetics
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Tongue Neoplasms / metabolism*
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Tongue Neoplasms / pathology
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Tyrphostins / pharmacology
Substances
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HBEGF protein, human
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Heparin-binding EGF-like Growth Factor
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Hydroxamic Acids
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Intercellular Signaling Peptides and Proteins
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Protease Inhibitors
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Protein Kinase Inhibitors
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Quinazolines
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RNA, Messenger
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TAPI-2
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Tyrphostins
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RTKI cpd
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EGFR protein, human
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ErbB Receptors
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ADAM Proteins
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Matrix Metalloproteinase 9
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ADAM17 Protein
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ADAM17 protein, human