CCL18介导肿瘤微环境趋化因子网络导致卵巢癌不良预后的研究

目的 分析血清CC趋化因子配体18（CC-chemokine ligand 18，CCL18）与卵巢癌预后的关系及其对卵巢癌微环境中其他趋化因子及受体的调控作用，探讨CCL18促进肿瘤生长和转移的可能机制。方法 采用流式荧光微球法检测320例卵巢癌患者、150例盆腔良性肿块患者及100名正常对照女性血清样本中CCL18的表达，分析基因表达谱（Gene Expression Omnibus，GEO）以及癌症基因图谱（The Cancer Genome Atlas，TCGA）数据库中CCL18基因表达与卵巢癌患者预后的关系。采用过表达CCL18的卵巢上皮癌细胞SKOV3-GFP-CCL18建立裸鼠皮下移植瘤模型，实时荧光定量PCR（qRT-PCR）检测移植瘤内其他趋化因子及受体的表达。结果 卵巢癌患者血清中CCL18的表达水平显著高于盆腔良性肿块患者和正常对照女性 ［（238.04±93.59） ng/mL vs （94.36±59.17） ng/mL，P<0.001；（238.04±93.59） ng/mL vs（31.68±26.10） ng/mL，P<0.001］，且高表达CCL18的卵巢癌患者中位无疾病进展生存期较低表达者短（15.0 个月 vs 18.2个月，HR=1.25,95%CI：1.08~1.44，P=0.003）。CCL18激活卵巢癌微环境的XCL1-XCR1、XCL2-XCR1、CCL2-CCR2、CCL11-CCR3、CCL17-CCR4、CXCL9-CXCR3、CXCL11-CXCR3、CXCL12-CXCR4趋化因子-受体轴表达，抑制了CXCL1-CXCR2、CXCL6-CXCR2、CXCL8-CXCR2、CCL5-CCR1、CCL5-CCR5、CCL27-CCR10、CCL28-CCR10趋化因子-受体轴的表达。结论 CCL18促进卵巢癌细胞转移可能与激活转移趋化因子-受体XCL1-XCR1、XCL2-XCR1、CCL2-CCR2、CCL17-CCR4表达和下调CCL5-CCR5、CCL27-CCR10和CCL28-CCR10表达有关，其可能造成卵巢癌患者不良预后。

Analysis of poor prognosis leaded by CCL18 mediated chemokine network in tumor microenvironment in ovarian cancer patients

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.