摘要
[摘要] 目的：探讨纤溶酶原激活因子（PA）及其抑制因子（PAIs）表达与卵巢恶性肿瘤发生、发展、转移和临床病理的关系及其预后价值，探讨中药苦参碱在体外对卵巢癌SKOV3细胞的作用。方法：1、以逆转录多聚酶链反应(reverse transcriptation polymerase chain reaction， RT- PCR)检测43例恶性肿瘤，20例良性肿瘤及20例正常卵巢组织中uPA、tPA、PAI-1、PAI-2mRNA的表达；2、采用SABC免疫组织化学方法检测40例恶性肿瘤，20例良性肿瘤及20例正常卵巢组织中uPA、PAI-1蛋白的表达。并同时分析uPA、PAI-1与恶性卵巢肿瘤组织学类型、分化程度、FIGO分期、腹水、淋巴结转移等临床病理因素的关系。采用Kaplan-Meier/Log Rank分析和COX模型分析uPA、PAI-1表达与卵巢恶性肿瘤预后的关系。3.采用MTT法及细胞计数法，在体外实验条件下，研究中药苦参碱对人类卵巢癌细胞株SKOV3生长的影响；采用SABC免疫组织化学方法检测卵巢癌细胞中uPA、PAI-1蛋白的表达，并观察苦参碱对SKOV3细胞uPA、PAI-1蛋白表达的影响。结果：① 卵巢恶性肿瘤中uPA、PAI-1mRNA阳性率分别为74.42%、65.12%，明显高于良性肿瘤组织(分别为35%和15%)及正常卵巢组织(分别为25%和15%)，相比较差异均有显著性，P<0.05；② 卵巢恶性肿瘤中uPA、PAI-1蛋白阳性表达率分别为52.50%、67.50%，明显高于良性肿瘤组织(分别为20%和30%)及正常组织 (分别为15%和25%)，相比较差异均有显著性，P<0.05；③ 在卵巢恶性肿瘤中，uPA、PAI-1mRNA的表达与肿瘤的病理学类型、腹水的多少及有无肝转移无关，与临床分期、分化程度、术后残余灶密切相关。Ⅲ~Ⅳ期卵巢患者癌组织中uPAmRNA的表达率为90%，明显高于Ⅰ~Ⅱ期的38.46%；Ⅲ~Ⅳ期卵巢患者癌组织中PAI-1mRNA的表达率为76.67%，明显高于Ⅰ~Ⅱ期的38.46%；相比较差异均有显著性，P<0.05。有淋巴结转移者uPA、PAI-1 阳性表达率分别为100%、78.57%，明显高于无淋巴结转移者的26.67%、40%，相比较差异有显著性，P<0.05；大网膜转移者uPAmRNA阳性表达率也明显高于大网膜正常者，P<0.05 ；而PAI-1mRNA在大网膜转移者中的表达与大网膜正常中的表达无显著差异。uPA、PAI-1mRNA在术后残存灶＞2cm中的表达分别为95.24%、90.48%，明显高于残存灶≤2cm中的表达63.64%、4.55%，相比较差异有显著性，P<0.05。④在卵巢恶性肿瘤中，uPA、PAI-1蛋白的表达与肿瘤的病理学类型、腹水的多少、有无淋巴结转移无关，而与临床分期、分化程度、术后残余灶密切相关。Ⅲ~Ⅳ期卵巢患者癌组织中uPA蛋白的表达率为68%，明显高于Ⅰ~Ⅱ期的26.67% ；Ⅲ~Ⅳ期卵巢患者癌组织中PAI-1蛋白的表达率为80% ，明显高于Ⅰ~Ⅱ期的46.67%，相比较差异均
有显著性，P<0.05。有大网膜转移者癌组织中uPA蛋白阳性表达率为92.86%，明显高于大网膜正常者的30.77%，P<0.05 ；而PAI-1蛋白在有大网膜转移者中的阳性表达率与大网膜正常者相比，差异无显著性。在有肝转移患者癌组织中uPA蛋白阳性表达率为78.57%，明显高于无肝转移者的38.46%，P<0.05；而在有肝转移患者癌组织中PAI-1蛋白阳性表达率与无肝转移者相比较，差异无显著性。PAI-1蛋白在术后残存灶＞2cm中的阳性表达率为93.75%，明显高于残存灶≤2cm中的50%，相比较差异有显著性，P<0.05；而uPA蛋白在术后残存灶＞2cm中的阳性表达率与残存灶≤2cm者相比较，差异无显著性。⑤卵巢恶性肿瘤中，uPA、PAI-1表达与恶性卵巢肿瘤的总生存期有关，表达者预后差， COX模型综合分析提示：uPA、PAI-1表达可作为一独立的预后指标。⑥苦参碱对人类卵巢癌细胞SKOV3的体外生长有直接抑制作用。结论：uPA、PAI-1基因表达与卵巢恶性肿瘤的发生、发展相关；与恶性肿瘤的浸润转移有关，因此可作为预测肿瘤转移潜能的指标。苦参碱作用后卵巢癌细胞株SKOV3 uPA、PAI-1蛋白的表达下降，苦参碱的抗肿瘤机制可能通过细胞毒作用、诱导细胞凋亡等多种机制参与，并可能与下调uPA、PAI-1蛋白的表达有关，基于此理论，中药治疗恶性肿瘤将会有广阔的前景。
Objective: To explore the role of PA and PAIs in ovarian tumor growth,invasion and metastasis,and to analyze the relationship between the expression of PA or PAI and clinical-pathologic parameters and overall survive in ovarian cancer, to evaluated the effects of matrine on the growth of SKOV3 in vitro. Methods: Reverse-transcriptase polymerase chain reaction were used to detect the expression of PA and PAIs in 43 ovarian carcinomas ,20 cases of benign tumors and 20 cases of normal controls, meanwhile we detected uPA and PAI-1 protein expression by IHC from another 40 patients with ovarian carcinomas, 20 cases of benign tumor and 20 cases of normal controls. The effect of matrine on the growth of SKOV3 in vivo were also investigate by MTT and cell counting. The expression of uPA and PAI-1 of SKOV3 were also investigate by IHC. Results: Firstly, the expression of uPAmRNA were significantly higher than that in benign tumor and normal control(74.42%,35% and 25%,respectively,P<0.05),the expression of PAI-1mRNA were also significantly higher than that in benign tumor and normal control(65.12%,15%and 15%,respectively,P<0.05); Secondly, the protein expression of uPA were significantly higher than that in benign tumor and normal control(52.50%,20% and15 %,respectively,P<0.05), the protein expression of PAI-1 were significantly higher than that in benign tumor and normal control(67.50%,30% and25%,respectively,P<0.05); Thirdly,there was no significantly association between expression levels of uPA and PAI-1 mRNA and its histopathologic type , ascitic volume and liver metastasis; but they showed that there was significant difference with differentiated grade, clinical stage as well as residual tumor volume in ovarian carcinomas. The positive expression rate of uPAmRNA in Ⅲ~Ⅳ phase (90%)was significantly higher than inⅠ~Ⅱphase(38.46%, P<0.05)；the positive expression rate of PAI-1mRNA in Ⅲ~Ⅳ phase (76.67%)was significantly higher than inⅠ~Ⅱphase(38.46%, P<0.05).They were higher in cases with lymph node metastasis(100%,78.57%respectively)than that without(26.67%,40% respectively, P<0.05). The positive expression rate of uPAmRNA with omentum involvement was higher than that in patients without omentum involvement( P<0.05)；There is no relationship between the expression of PAI-1mRNA and omentum involvement.The levels of uPAmRNA, PAI-1mRNA in patients with residual diseases >2cm (95.24%,90.48% respectively)than that in those have none(63.64%,4.55% respectively,P<0.05).Fourthly, no significantly association was evident between protein expression levels of uPA and PAI-1 and its
histopathologic type , ascitic volume and lymph node metastasis; but they show significant difference with differentiated grade, clinical stage as well as residual tumor volume in ovarian carcinomas. The positive expression rate of uPA protein in Ⅲ~Ⅳ phase (68%)was significantly higher than inⅠ~Ⅱphase(26.67%, P<0.05)；the positive expression rate of PAI-1 protein in Ⅲ~Ⅳ phase (80%)was significantly higher than inⅠ~Ⅱphase(46.67%, P<0.05). The positive expression rate of uPA protein with omentum involvement was higher than that in patients without omentum involvement(92.86% and 30.77% respectly P<0.05)；there is no relationship between PAI-1 protein and omentum involvement. The positive expression rate of uPA protein with liver metastasis was higher than that in patients without liver metastasis (78.57% and 38.46% respectly P<0.05)；there is no relationship between PAI-1 protein and liver metastasis. The protein levels of PAI-1 in patients with residual diseases >2cm (93.75%)than that in those have none(50%,P<0.05);no significantly association was evident between expression levels of uPA protein and residual diseases. Fifthly, uPA and PAI-1 expresstion had a poorly overall survive in ovarian carcinomas; the patients with positive expression of uPA and PAI-1 had a poorly overall survive in ovarian carcinomas. Cox regression showed that uPA and PAI-1 were in independent prognostic factors affecting survival and they had close negative c
引文
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