Involvement of ERK1/2/NF-κB signal transduction pathway in TF/FVIIa/PAR2-induced proliferation and migration of colon cancer cell SW620
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Our previous study has demonstrated that TF/FVIIa and protease-activated receptor 2 (PAR2) are closely related to the proliferation and migration of colon cancer cell line SW620. However, the detailed signaling cascades and underlying molecular mechanisms remain unclear. This study has investigated whether extracellular signal-regulated kinase 1 and 2 (ERK1/2) and nuclear factor kappaB (NF-κB) signaling pathways are involved in the events. The results revealed that PAR2-activating peptide (PAR2-AP) or FVIIa elicited time-dependent upregulation of ERK1/2 phosphorylation in SW620 cells, and the effect of FVIIa was significantly attenuated by anti-TF antibody. PAR2-AP or FVIIa also increased NF-κB (p65/RelA) levels among cell nuclear proteins and simultaneously decreased IκB-α levels in the cytoplasmic proteins. Such effects of FVIIa can be inhibited with anti-PAR2 or anti-TF antibodies. While ERK1/2 inhibitor (U0126) intervened with the regulatory effects of PAR2-AP and FVIIa on IκB-α/NF-κB (p65/Rel) expression in the cells, NF-κB inhibitor (PDTC) partially blocked the enhancing effects of PAR2-AP and FVIIa on the proliferating and migratory ability of SW620 cells. Furthermore, the regulatory effects of PAR2-AP and FVIIa on expressions of certain proteins (IL-8, caspase-7, and TF) were also significantly abolished by PDTC. Collectively, the data in this study suggest that the interaction between FVIIa and TF induces PAR2 activation, thereby triggers the ERK1/2 and IκB-α/NF-κB signal transduction pathway to regulate the gene expression of IL-8, TF, and caspase-7, and ultimately promotes SW620 cell proliferation and migration.
KeywordsProtease-activated receptor 2 Factor VIIa Tissue factor Colon cancer cells ERK1/2 NF-κB
This work was supported by grants of Natural Science Foundation of Jiangsu Province, China (no. BK2010336) to Ying Wu and Sci-tech Innovation Team of Jiangsu University (no. 2008-018-02) to Hong Zhou.
Conflicts of interest
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