Up-regulation of Flotillin-2 is associated with melanoma progression and modulates expression of the thrombin receptor protease activated receptor 1.
Flotillin 2 (flot-2) is a highly conserved protein isolated from caveolae/lipid raft domains that tether growth factor receptors linked to signal transduction pathways. Flot-2 protein and mRNA were increased in tumorigenic and metastatic melanoma cell lines in vitro, and the immunostaining intensity increased substantially across a tissue array of melanocytic ... lesions. Flot-2 transfection transformed SB2 melanoma cells from nontumorigenic, nonmetastatic to highly tumorigenic and metastatic in a nude mouse xenograft model. SB2 cells stably transfected with the flot-2 cDNA (SB2-flot)-2 cells proliferated faster in the absence of serum, and their migration through Matrigel was additionally enhanced by thrombin. When SB2-flot-2 cells were compared with SB2-vector-control cells on a cancer gene pathway array, SB2-flot-2 cells had increased expression of protease activated receptor 1 (PAR-1) mRNA, a transmembrane, G-protein-coupled receptor involved in melanoma progression. PAR-1 and flot-2 were coimmunoprecipitated from SB2-flot-2 cells. Up-regulation of PAR-1 was additionally confirmed in SB2-flot-2 cells and melanoma cell lines. SB2-flot-2 cells transfected with flot-2-specific small-interfering RNAs made substantially less flot-2 and PAR-1 mRNA. In conclusion, flot-2 overexpression is associated with melanoma progression, with increased PAR-1 expression, and with transformation of SB2 melanoma cells to a highly metastatic line. Flot-2 binds to PAR-1, a known upstream mediator of major signal transduction pathways implicated in cell growth and metastasis, and may thereby influence tumor progression.
Mesh Terms:
Animals, Cell Division, Cell Line, Tumor, DNA, Complementary, Disease Progression, Humans, Male, Melanoma, Membrane Proteins, Mice, Mice, Inbred BALB C, Mice, Nude, Neoplasm Metastasis, Neovascularization, Pathologic, RNA, Messenger, Receptor, PAR-1, Transfection, Up-Regulation
Animals, Cell Division, Cell Line, Tumor, DNA, Complementary, Disease Progression, Humans, Male, Melanoma, Membrane Proteins, Mice, Mice, Inbred BALB C, Mice, Nude, Neoplasm Metastasis, Neovascularization, Pathologic, RNA, Messenger, Receptor, PAR-1, Transfection, Up-Regulation
Cancer Res.
Date: Oct. 15, 2004
PubMed ID: 15492257
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