Journal Article

Met receptor tyrosine kinase transactivation is involved in proteinase-activated receptor-2-mediated hepatocellular carcinoma cell invasion

Roland Kaufmann, Claudia Oettel, Antje Horn, Karl-Jürgen Halbhuber, Annett Eitner, Reimar Krieg, Kathrin Katenkamp, Peter Henklein, Martin Westermann, Frank D. Böhmer, Rithwik Ramachandran, Mahmoud Saifeddine, Morley D. Hollenberg and Utz Settmacher

in Carcinogenesis

Volume 30, issue 9, pages 1487-1496
Published in print September 2009 | ISSN: 0143-3334
Published online June 2009 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgp153
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.

Journal Article.  6321 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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