Ovarian cancer cell proliferation and tumor growth can be suppressed by CXCR4/CXCR7 gene silencing possibly via modulating the CXCL12-CXCR4/CXCR7 chemokine axis and activating the MAPK signaling pathway

Background: Ovarian cancer is the most common malignancy among females. This study aimed to investigate the role of the CXCL12-CXCR4/CXCR7 chemokine axis in ovarian cancer. Methods: SKOV3 cells were transfected with siCXCR4/siCXCR7 plasmids and divided into the SKOV3, LV3, LV3-siCXCR4, and LV3-siCXCR7 groups. The MTT assay and flow cytometry were carried out to examine cell viability and apoptosis. An enzyme-linked-immunosorbent assay (ELISA) was performed to assess the levels of vascular-endothelial growth factor-A (VEGF-A), interleukin-6 (IL-6), and interleukin-8 (IL-8). SKOV3 cells were transplanted into mice to establish a xenograft model. The tumor volume in the xenograft model was recorded. The expressions of CD31, matrix-metalloprotein-9 (MMP-9), vimentin, and E-cadherin in SKOV3 cells and tumor tissues were evaluated using quantitative real-time PCR (qRT-PCR) and western blot. VEGF-A, CD31, MMP-9, vimentin, and E-cadherin were detected in the tumor tissues by immunohistochemistry. Results: The results showed that SKOV3 cells highly expressed CXCR4 and CXCR7. The viability of SKOV3 cells was significantly enhanced by CXCL12, but reduced by CXCR4/CXCR7 inhibitor (P<0.05). CXCR4/CXCR7 gene-silencing significantly decreased the viability of SKOV3 cells compared to the SKOV3 or LV3 group (P<0.05). CXCR4/CXCR7 gene-silencing modulated cell cycle and increased apoptosis rates compared to the SKOV3 or LV3 group (P<0.05). CXCR4/CXCR7 gene-silencing inhibited the secretion of VEGF-1, IL-6, and IL-8, and also modulated the levels of CD31, MMP-9, vimentin, and E-cadherin. CXCR4/CXCR7 gene-silencing suppressed p-ERK1/2 (P<0.05), and strengthened the inhibitive effects of CXCR4/CXCR7 inhibitor on p-ERK1/2. CXCR4/CXCR7 gene-silencing reduced tumor volume and regulated tumorigenesis-associated molecules in the mouse xenograft model. Conclusions: CXCR4/CXCR7 gene-silencing could suppress cell proliferation and tumor growth in ovarian cancer by modulating the CXCL12-CXCR4/CXCR7 chemokine-axis and the mitogen-activated protein kinase signaling pathway.