MMP-9和TIMP-1表达在胃癌根治术后患者预后评估中的作用

doi:10.13481/j.1671-587X.20220120

摘要/Abstract

摘要： 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。

关键词: 基质金属蛋白酶9, 组织金属蛋白酶抑制剂1, 胃肿瘤, 预后, 胃癌根治术

Abstract: 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. Pearson χ² 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 withMMP-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 stage Ⅰ/Ⅱ， the patients with no-postoperative chemotherapy and TNM stage Ⅲ had 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 stage Ⅰ/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 stage Ⅲ are the risk factors for the prognosis of gastric cancer patients underwent radical gastrectomy.

Key words: Matrix metalloproteinase-9, Tissue inhibitor of metalloproteinase-1, Stomach neoplasms, Prognosis, Radical gastrectomy

中图分类号:

R735.2

覃丽粒,马小波,赵天业,陶雪蓉,郑敏,王雪莹,易嘉欣,吴燕华,姜晶. MMP-9和TIMP-1表达在胃癌根治术后患者预后评估中的作用[J]. 吉林大学学报(医学版), 2022, 48(1): 163-171.

Lili QIN,Xiaobo MA,Tianye ZHAO,Xuerong TAO,Min ZHENG,Xueying WANG,Jiaxin YI,Yanhua WU,Jing JIANG. Effects of MMP-9 and TIMP-1 expressions on prognostic evaluation of gastric cancer patients after radical gastrectomy[J]. Journal of Jilin University(Medicine Edition), 2022, 48(1): 163-171.

图/表 6

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Tab. 1 Baseline characteristics ofgastric cancer patients
Characteristic	Number (n)	Proportion (η/%)
Age(year)
≤65	162	60.0
>65	108	40.0
Gender
Female	65	24.1
Male	205	75.9
Tumor size
<5 cm	82	30.4
≥5 cm	188	69.6
Type
Signet ring cell	30	11.1
Others	240	88.9
Histological grade
Low grade	57	21.1
High grade	213	78.9
Chemotherapy
Yes	118	43.7
No	152	56.3
TNM stage
Ⅰ/Ⅱ stage	165	61.1
Ⅲ stage	105	38.9
Event
Live	99	36.7
Lose	11	4.1
Death	160	59.2
MMP-9
－	188	69.6
+	82	30.4
TIMP-1
－	199	73.7
+	71	26.3
MMP-9/TIMP-1
－/+	47	17.4
－/－	141	52.2
+/－	58	21.5
+/+	24	8.9

Clinicopathological parameters	MMP-9^－/TIMP-1^－ (n=141)	MMP-9⁺/TIMP-1^－(n=58)	MMP-9^－/TIMP-1⁺ （n=47）	MMP-9⁺/TIMP-1⁺ (n=24)	P
Age(year)
≤65	86(61.0)	29(50.0)	31(66.0)	16(66.7)	0.306
>65	55(39.0)	29(50.0)	16(34.0)	8(33.3)
Gender
Female	28(19.9)	14(24.1)	17(36.2)	6(25.0)	0.161
Male	113(80.1)	44(75.9)	30(63.8)	18(75.0)
Tumor size
<5 cm	45(31.9)	13(22.4)	19(40.4)	5(20.8)	0.159
≥5 cm	96(68.1)	45(77.6)	28(59.6)	19(79.2)
Type
Others	127(90.1)	51(87.9)	42(89.4)	20(83.3)	0.740^*
Signet ring cell	14(9.9)	7(12.1)	5(10.6)	4(16.7)
Grade
Low	30(21.3)	9(15.5)	12(25.5)	6(25.0)	0.602
High	111(78.7)	49(84.5)	35(74.5)	18(75.0)
Chemotherapy
Yes	63(44.7)	18(31.0)	23(48.9)	14(58.3)	0.092
No	78(55.3)	40(69.0)	24(51.1)	10(41.7)
TNM stage
Ⅰ/Ⅱ	85(60.3)	37(63.8)	27(57.4)	16(66.7)	0.851
Ⅲ	56(39.7)	21(36.2)	20(42.6)	8(33.3)

Clinicopathological parameter	n	Number of event [n（η/%）］	MST^*(month)	Ρ
Age(year)
≤65	162	90(55.6)	36.0	0.241
>65	108	70(64.8)	27.0
Gender
Female	65	40(61.5)	26.0	0.549
Male	205	120(58.5)	33.0
Tumor size
<5 cm	82	44(53.7)	42.0	0.114
≥5 cm	188	116(61.7)	26.0
Grade
Low	57	26(45.6)	72.0	0.007
High	213	134(62.9)	26.0
Type
Others	30	20(66.7)	28.0	0.318
Signet ring	240	140(58.3)	31.0
Chemotherapy
Yes	118	57(48.3)	47.0	<0.001
No	152	103(67.8)	21.0
TNM stage
Ⅰ/Ⅱ	165	77(46.7)	72.0	<0.001
Ⅲ	105	83(79.0)	15.0

Clinicopathological parameter	B	SE	Wald	HR	95%CI	Ρ
Age	0.063	0.169	0.137	1.065	0.764－1.483	0.711
Gender	0.013	0.187	0.005	1.013	0.702－1.461	0.944
Tumor size	0.170	0.184	0.847	1.185	0.826－1.701	0.357
Tumor type	－0.071	0.245	0.083	0.932	0.576－1.507	0.773
Histological grade	0.413	0.229	3.247	1.511	0.964－2.366	0.072
Chemotherapy	0.628	0.173	13.118	1.873	1.334－2.631	<0.001
TNM stage	0.833	0.168	24.680	2.301	1.656－3.197	<0.001
MMP-9/TIMP-1
MMP-9^－/TIMP-1⁺	－	－	7.093	－	－	0.029
MMP-9^－/TIMP-1^－	－0.379	0.203	3.489	0.684	0.460－1.019	0.062
MMP-9⁺/TIMP-1^+/－	－0.623	0.235	7.003	0.537	0.338－0.851	0.008
“－”:No data.

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