基质金属蛋白酶-1和膜型1基质金属蛋白酶在胆囊癌血管生成拟态中的表达及临床意义

Expression of matrix metalloproteinase-1 and membrane type-1 matrix metalloproteinase in human primary gallbladder carcinomas with vasculogenic mimicry and its clinical significance

目的 探讨基质金属蛋白酶-1 （MMP-1）和膜型1基质金属蛋白酶（MT1-MMP）在胆囊癌血管生成拟态中的表达及临床意义.方法 收集手术病理确诊的原发性胆囊癌74例和胆囊腺瘤、慢性胆囊炎各10例的石蜡标本及相关临床资料,应用免疫组化测定上述病变组织的MMP-1、MT1-MMP表达.应用Kaplan-Meier生存比较、Cox风险模型分析与胆囊癌血管生成拟态（VM）的相关性和临床意义.结果 ①胆囊癌MMP-1、MT1-MMP表达明显高于胆囊腺瘤、胆囊炎（P＜0.000 1）;VM（＋）胆囊癌MT1-MMP表达明显高于VM（-）胆囊癌（P=0.003 9）,而MMP-1则无差别.②MMP-1表达与VM（-）胆囊癌的Nevin分期（P=0.003 6）、分化程度（P=0.010）、肝转移（P=0.003）和淋巴结转移（P=0.002）正相关;MT1-MMP表达与VM（-）或VM（＋）胆囊癌的Nevin分期（P=0.013或P=0.033）、浸润深度（P=0.045或P=0.035）、淋巴结转移（P=0.046或P=0.025）和肝转移（P=0.030或P=0.027）正相关;MMP-1、MT1-MMP表达与VM（-）胆囊癌正相关.③VM（＋）胆囊癌MT1-MMP表达在Nevin S3-s5期（P =0.000 1）、侵犯浆膜（P=0.001）、淋巴结转移（P =0.000 2）和肝转移（P=0.004）同样分组条件下分别明显高于VM（-）胆囊癌;MMP-1仅在肝转移组,VM（＋）胆囊癌表达显著高于VM（-）（P=0.038）.④无论在MMP-1、MT1-MMP单独表达阳性或二者均阳性,VM（＋）胆囊癌患者术后5年生存期都明显短于VM（-）组（P=0.025 1或P=0.022 5或P=0.025 0）.Cox多因素分析表明,VM、浸润深度、淋巴结转移、肝转移、手术方式是影响胆囊癌患者预后的独立因素.结论 胆囊癌MMP-1、MT1-MMP高表达,MT1-MMP表达与胆囊癌VM相关,MMP-1则与胆囊癌VM无关.MMP-1,MT1-MMP可作为评判胆囊癌Nevin分期、浸润深度、淋巴结或肝转移及判断预后的重要指标;而MT1-MMP还可作为判断胆囊癌否存在VM和VM胆囊癌预后的重要指标.

Objective To evaluate the expression of matrix metaUoproteinase-1 （ MMP-1 ） and membrane type-1matrix metalloproteinase （MT1-MMP） in human primary gallbladder carcinomas with vasculogenic mimicry （VM） and its clinical significance. Methods Seventy-four carcinomas, 10 adenomas and 10 chronic inflammatory lesions of the gallbladder underwent operation and histopathologically and their clinical-pathlogical confirmed data were studied and followedup. Immunohistochemistry （SABC） was used to determine the expression of MMP-1, MT1-MMP proteins in each paraffin section of every patient in vivo. Kaplan-Meier survival curves and Cox multiple factor were used to analyse the relation beteewn VM of gallbladder carcinomas and expression of MMP-1, MT1-MMP. Results （1） Expression of MMP-1 and MT1-MMP was increased significantly in carcinomas with or without VM than adenomas and inflammatory lesions of the gallbladder （P 〈 0.000 1 ） in. Eexpression of MT1-MMP in the gallbladder carcinomas with VM was increased significantly than that without VM〈 P = 0.003 9）, without difference on expression of MMP-1 between VM （ ＋ ） gallbladder carcinomas and VM （ - ） gallbladder carcinomas. （2） There is positive correlation between expression of MMP-1 and VM （ - ） gallbladder carcinomas in the cases of Nevin stage （P = 0.003 6）, differentiation degree （ P = 0. 010） ,liver metastatis （ P = 0. 003 ） and lymph node metastases （ P = 0.002 ）, the same correlation was observed between expression of MT1-MMP and VM （ ＋ ）/（ - ） gallbladder carcinomas in the cases of Nevin stage （P =0. 013 or P =0.003 3） ,invasion depth （P =0.045 or P =0. 035） ,lymph node metastases （P =0.046 or P =0.025 ） and liver metastatis （ P = 0. 030 or P = 0. 027 ） ; MMP-1 expression was positively correlated with MT1 -MMP expression in VM （ - ） gallbladder carcinomas. （3） Expression of MT1-MMP in the same conditions of Nevin stage （ S3 - S5, P = 0. 000 1 ）, serosal invasion （ P = 0.001 ）, lymph node metastases （ P = 0. 000 2）, liver metastatis （ P = 0.004） was higher significantly in VM （ ＋ ） gallbladder carcinomas than VM （ - ） gallbladder carcinomas ; Furthermore, expression of MMP-1 in the cases of liver metastatis （P = 0.0038） was higher significantly in VM （ ＋ ） gallbladder carcinomas than VM （ - ） gallbladder carcinomas. （4） VM （ ＋ ） gallbladder carcinoma group underwent operation with positive expression of MMP-1 and MT1-MMP had shorter 5-year survival than the respectively VM （ - ） group （ P = 0. 025 1 ; P = 0. 022 5 ）, the same correlation was observed in positive coexpression of MMP-1 and MT1 -MMP （ P = 0.025 0 ）. Cox analysis showed that VM, invasion depth, lymph node metastasis, hepatic metastasis, and operation method were independent risk factors of the prognosis of patients with primary gallbladder carcinoma. Conclusions Higher expression of MMP-1, MT1-MMP in gallbladder carcinomas, a positive correlation between expression of MT1 -MMP and VM of gallbladder carcinomas and no correlation between expression of MMP-1 and VM of gallbladder carcinomas were observed. MMP-I and MT1-MMP are important clinical markers for staging of Nevin stage ,judgement of invasion depth, lymph node or liver metastatis, and evaluation of prognosis in patients with gallbladder carcinoma. MT1-MMP may be especially of important for evaluating if there is VM in human gallbladder carcinomas and prognosis of patients with VM （ ＋ ） gallbladder carcinoma.