MMP-9和TIMP-1表达在胃癌根治术后患者预后评估中的作用

Effects of MMP-9 and TIMP-1 expressions on prognostic evaluation of gastric cancer patients after radical gastrectomy

目的:分析胃癌患者癌组织中基质金属蛋白酶9(MMP-9)和组织金属蛋白酶抑制剂1(TIMP-1)的表达,探讨其在胃癌根治术后患者预后评估中的价值。方法:选取270例行胃癌根治术的胃癌患者,采用免疫组织化学染色法检测胃癌组织中MMP-9和TIMP-1蛋白阳性表达率。采用χ2检验或Fisher精确概率法分析MMP-9和TIMP-1阳性表达在不同临床病理特征胃癌患者中的分布情况。采用Kaplan-Meier法绘制生存曲线,Log-rank检验比较生存曲线的差异。采用多因素Cox回归模型分析MMP-9和TIMP-1表达与胃癌患者预后的关系。结果:270例胃癌患者中,MMP-9和TIMP-1蛋白的表达部位为肿瘤细胞膜或细胞浆,MMP-9和TIMP-1蛋白阳性表达率分别为30.4%和26.3%。MMP-9和TIMP-1联合表达在不同年龄、性别、肿瘤大小、肿瘤类型、组织学分级、术后化疗和TNM分期胃癌患者中的分布比较差异无统计学意义(P>0.05)。Cox回归模型评估,MMP-9和TIMP-1联合表达、TNM分期和术后化疗是影响胃癌患者预后的独立因素,其中MMP-9^(+)与胃癌患者的良好预后相关,MMP-9-/TIMP-1^(+)胃癌患者的死亡风险提高,预后更差(MMP-9+/TIMP-1^(+)/-vs MMP-9-/TIMP-1^(+):HR=0.537,95%CI:0.338~0.851,P=0.008)。TNM分期为Ⅲ期、未接受术后化疗的胃癌患者较TNM分期为Ⅰ/Ⅱ期、接受化疗的胃癌患者死亡风险更高,预后更差(HR=1.873,95%CI:1.334~2.631,P<0.001;HR=2.301,95%CI:1.656~3.197,P<0.001)。分层分析,在TNM分期为Ⅰ/Ⅱ期、接受术后化疗和非印戒细胞型的胃癌患者中,MMP-9^(+)胃癌患者的死亡风险较MMP-9-/TIMP-1^(+)患者明显降低,预后更好(P<0.05)。结论:MMP-9/TIMP-1联合表达可作为胃癌根治术后患者预后评估的独立预测因子;术后未化疗和TNM分期为Ⅲ期是胃癌根治术后患者预后的独立危险因素。

Objective:To analyze the expressions of matrix metalloproteinase-9(MMP-9)and tissue inhibitor of metalloproteinase-1(TIMP-1)in cancer tissue of the gastric cancer patients,and to investigate their values in prognostic evaluation of the gastric cancer patients underwent radical gastrectomy.Methods:A total of 270 gastric cancer patients who underwent radical gastrectomy were enrolled in this study,and the positive expression rates of MMP-9 and TIMP-1 in cancer tissue of the patients were detected by immunohistochemistry method.Pearsonχ^(2) or Fisher’s exact test was used to assess the distribution of MMP-9 and TIMP-1 positive expressions in the gastric cancer patients with different clinicopathological parameters.Survival curves were plotted using Kaplan-Meier method and the differences were assessed by Log-rank test.Multivariate Cox regression model was conducted to analyze the relationships between the expressions of MMP-9 and TIMP-1 and the prognosis of the gastric cancer patients underwent radical gastrectomy.Results:Among the 270 gastric cancer patients,MMP-9 and TIMP-1 were expressed in cytoplasm or cell membrane of tumor cells,and the positive expression rates of MMP-9 and TIMP-1 were 30.4%and 26.3%,respectively.No correlations between the co-expression of MMP-9,TIMP-1 and the age,gender,tumor size,tumor type,histological type,chemotherapy after operation,and TNM stage of the patients were identified.The results of Cox regression model showed that co-expression of MMP-9 and TIMP-1,postoperative chemotherapy and TNM stage were the significant independent factors for the prognosis of the gastric cancer patients.The gastric cancer patients with MMP-9 positive expression showed the better survival,and among the patients with MMP-9 negative expression,the risk of death in the patients with TIMP-1 positive expression was increased,which indicated the worse prognosis(MMP-9+/TIMP-1^(+/-)vs MMP-9-/TIMP-1^(+):HR=0.537,95%CI:0.338-0.851,P=0.008).Furthermore,compared with the patients with postoperative chemotherapy and TNM stageⅠ/Ⅱ,the patients with no-postoperative chemotherapy and TNM stageⅢhad higher risk of death and worse prognosis(HR=1.873,95%CI:1.334-2.631,P<0.001;HR=2.301,95%CI:1.656-3.197,P<0.001).In the subgroup analysis,among the gastric cancer patients with TNM stageⅠ/Ⅱ,postoperative chemotherapy or no signet-ring cell cancers,the risk of death in MMP-9+group was decreased compared with MMP-9-/TIMP-1^(+)subgroup(P<0.05),which indicated the better prognosis.Conclusion:Co-expression of MMP-9 and TIMP-1 could serve as an independent prognostic predictor in the gastric cancer patients underwent radical gastrectomy;No postoperative chemotherapy and TNM stageⅢare the risk factors for the prognosis of gastric cancer patients underwent radical gastrectomy.