The CXCL12/CXCR4 axis is strongly implicated as key determinant of tumor invasion and metastasis in ovarian cancer. However, little is known about the potential downstream signals of the CXCL12/CXCR4 axis that contribute to ovarian cancer cell invasion and metastasis. ARHGAP10, a member of Rho GTPase activating proteins is a potential tumor suppressor gene in ovarian cancer. In this study, a negative correlation between the protein levels of CXCL12, CXCR4, vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor-2 (VEGFR2) and ARHGAP10 was uncovered in ovarian cancer tissues and paired adjacent noncancerous tissues. CXCL12 stimulation reduced the expression of ARHGAP10. Furthermore, the pretreatment of CXCR4 inhibitor (AMD3100) or the vascular endothelial growth factor receptor-2 (VEGFR2) inhibitor (SU1498) abrogated the CXCL12-deduced expression of ARHGAP10. Finally, an in vitro functional assay revealed that CXCL12 did not stimulate ovarian cancer cell invasion when ARHGAP10 was overexpressed or when ovarian cancer cells were pre-treated with AMD3100 or SU1498. Knockdown of ARHGAP10 significantly suppressed the inhibitory effects of SU1498 on ovarian cancer cell invasion and lung metastasis. In summary, these findings suggest that CXCL12/CXCR4 promotes ovarian cancer cell invasion by suppressing ARHGAP10 expression, which is mediated by VEGF/VEGFR2 signaling.
Keywords: ARHGAP10; CXCL12/CXCR4 axis; Metastasis; Ovarian cancer; VEGF.
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