Met receptor tyrosine kinase transactivation is involved in proteinase-activated receptor-2-mediated hepatocellular carcinoma cell invasion
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The expression of proteinase-activated receptor (PAR)2 in human hepatocellular carcinoma (HCC) was established by reverse transcription-polymerase chain reaction, confocal immunofluorescence and electron microscopy in permanent cell lines, primary HCC cell cultures and HCC tumor tissue. Stimulation of HCC cells with trypsin and the PAR2-selective activating peptide, 2-furoyl-LIGRLO-NH2, increased cell invasion across Matrigel. Both effects were blocked by a PAR2-selective pepducin antagonist peptide (pal-PAR2) and by PAR2 silencing with specific small interfering RNA (siRNA). PAR2 -initiated HCC cell invasion was also blocked by inhibiting the hepatocyte growth factor receptor (Met receptor tyrosine kinase) with the receptor-targeted kinase inhibitors, SU 11274 and PHA 665752, or by downregulation of Met with specific siRNA. The involvement of Met in PAR2-mediated HCC invasive signaling was further supported by the finding that treatment of HCC cells with trypsin or the PAR2-selective agonist peptide, 2-furoyl-LIGRLO- NH2, stimulated Met activation-phosphorylation. In addition, Met-dependent stimulation of p42/p44 mitogen-activated protein Kinases was found to be critical for the PAR2-Met receptor tyrosine kinase-invasive signaling axis in HCC cells. Our study establishes an important link between the PAR2 and Met receptor tyrosine kinase signaling in promoting HCC cell invasion. © The Author 2009. Published by Oxford University Press. All rights reserved.