The Role Of SDF-1/CXCR4 Axis In Ovarian Cancer Metastasis Through Activation Of ERK1/2 Signal Pathway

Objective: To explore the role of SDF-1/CXCR4 in mediating the Metastasis of ovarian cancer cell through activation of ERK1/2 signal pathway.Methods:Intracellular calcium mobilization was detected with a Laser Scanning Confocal Fluorescence Microscopy. Western blotting was used to detect the phospharylation of ERK1/2 in SKOV3 cells after exposure to SDF-1α. Adhesion capability and matrix metalloproteinase(MMP) activity of ovarian cancer cells after exposure to SDF-1αwere mesured by adhesion assay and gelatin zymography.Results:SDF-1αinduced rapid intracellular calcium mobilization in a metastatic ovarian cancer cell line SKOV3. Calcium mobilization assay show that Calcium flux rapidly increased after 20 second of exposure to SDF-1αand the peak time of Calcium flux was 200 second. SDF-1αalso induced rapid phosphorylation of ERK-1/2. Western blotting showed that ERK-1/2 was phosphorylated in SKOV3 cells after 5 minutes of exposure to SDF-1α. There was gradually increase in the ratio of phospho-ERK at 0 minute to at 30 minutes.SDF-1/CXCR4 interaction can activate ERK signal pathway that plays an important role in regulating cell proliferation and migration. Ovarian cancer cell adhesion to fibronectin and collagen IV, increased after SDF-1αtreatment, while the addition of an inhibitor of ERK-1/2 signaling, PD98059, reduced the effects of SDF-1αSDF-1αalso increased the active MMP-2 and MMP-9 secreted.Conclusion:The SDF-1/CXCR4 axis plays a critical role in the migration and metastasis of human ovarian cancer by regulating the adhesion capability and MMP-2 and MMP-9 activity through ERK1/2 signal pathway.Together, these studies reveal important cellular and molecular mechanisms of SDF-1/CXCR4-mediated ovarian cancer migration and invasion and investigate the ways to block this process by inhabiting the MAPK signaling transduction pathway.