[The role and mechanism of CXCR4 and its ligand SDF-1 in the development of cervical cancer metastasis].
OBJECTIVE
The chemokine receptor CXCR4 and its sole ligand stromal cell-derived factor-1 (SDF-1) not only actively participate in inflammation, hematopoiesis, infection of HIV, but also play a pivotal role in migration, invasion and metastasis of some malignant tumors. This study was to investigate the role of CXCR4/SDF-1 axis in mediating metastasis in cervical cancer cells through activating the mitogen-activated protein kinase (MAPK) pathway and its possible mechanism.


METHODS
Intracellular calcium mobilization was observed under laser scanning confocal fluorescence microscopy. The phospharylation of extracellular signal-regulated kinase (ERK) 1/2 in HeLa cells after binding of SDF-1alpha to CXCR4 was measured by Western blot. Adhesion of CXCR4/SDF-1 to cervical cancer cells and secretion of matrix metalloproteinase (MMP) were detected by adhesion assay and gelatin zymography, respectively.


RESULTS
After SDF-1alpha was bound to CXCR4, a rapid and robust mobilization of intracellular calcium in Hela cells was initiated. The difference between the average baseline fluorescence intensity (FI) and the peak FI was significant (P < 0.01). ERK-1/2 was rapidly phosphorylated in Hela cells after its exposure to SDF-1alpha, and the strongest phosphorylation occurred at 30 min. The adhesion ability of Hela cells to fibronectin (FN) and laminin (LN) was increased after SDF-1alpha treatment (P < 0.05 and P < 0.01, respectively), while pretreatment of Hela cells with an ERK-1/2 inhibitor, PD98059, decreased adhesion of Hela cells to extracellular matrix (ECM) with the presence of SDF-1alpha (P < 0.05). Increased amounts of active MMP-2 were secreted in response to increased SDF-1alpha concentrations. When the concentration of SDF-1alpha was 800ng/mL, the secretion of active MMP-2 reached the peak and started to decrease afterwards.


CONCLUSIONS
CXCR4/SDF-1 participates in tumor invasiveness and metastasis in cervical cancer through regulating the adhesion ability by activating the MAPK signaling transduction pathway and promoting secretion of MMP-2.
Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical School, Huazhong University of Science and Technology,Wuhan, Hubei, 430022, P.R. China.
Xiao-Yan
XY
Shen
Shao-Hai
SH
Wang
Ming-Lin
ML
Liang
Hong-Bo
HB
Wang
Lan
L
Xiao
Ze-Hua
ZH
Wang
D002118:Calcium / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D002448:Cell Adhesion; D054377:Chemokine CXCL12 / Q000378:metabolism* / Q000502:physiology; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D007797:Laminin / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D019718:Receptors, CXCR4 / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction
C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D005353:Fibronectins; D005419:Flavonoids; D007797:Laminin; D019718:Receptors, CXCR4; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048052:Mitogen-Activated Protein Kinase 3; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D002118:Calcium