Abstract:

Objective To investigate the relationship between serum CC-chemokine ligand 18（CCL18） and the prognosis in ovarian cancer patients，and the regulatory effect of serum CCL18 on chemokines and receptors in ovarian cancer microenvironment，and explore the mechanisms of CCL18 in promoting tumor growth and metastasis. Methods Serum CCL18 were examined in 320 cases of ovarian cancer，150 cases of benign pelvic tumor，and 100 cases of healthy women using flow cytometry microspheres. The relation-ship between CCL18 gene expression and prognosis of ovarian cancer patients was analyzed from Gene Expression Omnibus（GEO） and The Cancer Genome Atlas（TCGA）. Mice subcutaneous tumor model with ovarian cancer cell lines SKOV3-GFP-CCL18 which over-expresses CCL18 was established. The expression of chemokines and receptors in transplanted tumors were detected by real-time quantitative PCR （qRT-PCR）. Results The expression level of CCL18  was （238.04±93.59） ng/mL in ovarian cancer patients， which was significantly higher than in benign pelvic tumor patients（94.36±59.17） ng/mL and healthy women（31.68±26.10） ng/mL（P<0.001）. High expression of CCL18 was correlated with poor progression-free survival. Median PFS was 15 months in CCL18 high expression patients，which was significantly lower than 18.2 months in CCL18 low expression patients（HR=1.25,95%CI：1.08~1.44，P=0.003）. CCL18 activated XCL1-XCR1，XCL2-XCR1，CCL2-CCR2，CCL11-CCR3，CCL17-CCR4，CXCL9-CXCR3，CXCL11-CXCR3，CXCL12-CXCR4 chemokine-receptor axes in the ovarian cancer microenvironment，and inhibited CXCL1-CXCR2，CXCL6-CXCR2，CXCL8-CXCR2，CCL5-CCR1，CCL5-CCR5，CCL27-CCR10，and CCL28-CCR10 chemokine-receptor axis. Conclusions CCL18 activates the expression of metastatic chemokine-receptors XCL1-XCR1，XCL2-XCR1，CCL2-CCR2，CCL17-CCR4，and down-regulates the expression of CCL5-CCR5 and CCL27-CCR10，CCL28-CCR10，which can cause poor prognosis.

Key words: Ovarian neoplasms, CCL18, Chemokines, Tumor microenvironment, Gene Expression Omnibus, The Cancer Genome Atlas, Prognosis