MMP-9及TIMP-1在子宫颈鳞癌组织中的表达及临床意义

目的:探讨基质金属蛋白酶9(MMP-9)及基质金属蛋白酶组织抑制因子1(TIMP-1)在宫颈鳞癌组织中的表达,及与宫颈癌临床病理特征的关系。方法:采用免疫组织化学MaxvisioTM法,检测46例宫颈鳞癌,34例宫颈原位癌(CINⅢ)和20例癌旁正常宫颈上皮(NCE)中MMP-9及其抑制因子TIMP-1的表达,分析其表达与宫颈鳞癌的临床分期,病理类型及有无淋巴结转移的关系。结果:MMP-9在宫颈鳞癌,原位癌,NCE中的阳性表达率分别为71.7%,70.6%,25.0%;TIMP-1为54.3%,73.5%,20.0%。MMP-9在NCE组与鳞癌组及原位癌组相比差异有统计学意义(P<0.01),TIMP-1在NCE组与鳞癌组及原位癌组相比差异有统计学意义(P<0.01)。MMP-9和TIMP-1的阳性表达率与临床分期和病理类型均无明显相关性(P>0.05)。MMP-9在淋巴结转移阳性组的阳性表达率明显高于阴性组(P<0.01),而TIMP-1未发现此现象。MMP-9和TIMP-1在宫颈鳞癌中的表达呈负相关(rs=-0.381,P<0.01)。结论:MMP-9在宫颈癌组织中表达水平的上调和TIMP-1的相对弱表达在宫颈鳞癌浸润和转移中起重要的作用。     

上皮性卵巢癌中基质金属蛋白酶-2及其抑制剂的表达及意义分析

目的检测上皮性卵巢癌中基质金属蛋白酶-2(matrix metalloproteinase-2,MMP-2)及金属蛋白酶组织抑制剂-2(tissue inhibitor of metalloproteinase-2,TIMP-2)的表达水平,并分析其临床意义。方法采用免疫组化染色法检测MMP-2、TIMP-2在上皮性卵巢癌、上皮性良性卵巢肿瘤及正常卵巢组织3组对象卵巢组织中的阳性表达率,分析上皮性卵巢癌患者不同临床病理特征下MMP-2及TIMP-2的阳性表达水平。结果上皮性卵巢癌组卵巢组织MMP-2及TIMP-2的阳性表达率明显高于良性上皮性卵巢肿瘤组和正常卵巢组织组(P0.05)。MMP-2及TIMP-2在上皮性卵巢癌Ⅲ期+Ⅳ期患者中的阳性表达率明显高于Ⅰ期+Ⅱ期患者(P0.05);在低分化(G3)患者中的阳性表达率明显高于高、中分化(G1+G2)患者(P0.05);在有淋巴结转移患者中的阳性表达率明显高于无淋巴结转移患者(P0.05)。结论 MMP-2和TIMP-2的检测是否可作为早期诊断上皮性卵巢癌的生物指标,尚需进一步研究,但MMP-2及TIMP-2的表达水平与上皮性卵巢癌的临床分期、分化程度、淋巴结转移有关,可作为判断上皮性卵巢癌预后的辅助指标。     

肺癌MMP-9和VEGF表达与微血管密度的关系及其意义

[目的]探讨肺癌组织中MMP-9和VEGF的表达与肺癌血管生成的关系及其意义。[方法]采用免疫组织化学S-P法检测84例肺癌组织中MMP-9、VEGF和CD34的表达。[结果]肺癌组织MMP-9和VEGF表达显著高于癌旁正常肺组织(P﹤0.01)。小细胞肺癌和腺癌MMP-9表达高于鳞癌(P﹤0.01)。肺癌MMP-9表达有淋巴结转移者高于无淋巴结转移者(P﹤0.01),Ⅲ和Ⅳ期高于Ⅰ和Ⅱ期(P﹤0.05)。肺癌MMP-9表达阳性者微血管密度高于MMP-9表达阴性者(P﹤0.01)。肺癌VEGF表达有淋巴结转移者高于无淋巴结转移者(P﹤0.05),Ⅲ和Ⅳ期高于Ⅰ和Ⅱ期(P﹤0.05)。肺癌VEGF表达阳性者微血管密度高于肺癌VEGF表达阴性者(P﹤0.01)。肺癌MMP-9和VEGF的表达呈正相关(P﹤0.05)。[结论]MMP-9和VEGF促进肺癌血管生成,与肺癌侵袭转移密切相关。     

基质金属蛋白酶-7异常表达与子宫内膜癌发病关系的探讨

目的:探讨MMP-7与子宫内膜癌发病及转移的关系。方法:利用免疫组化的方法观察72例子宫内膜癌病变组织、64例内膜癌前病变组织和80例正常子宫内膜中MMP-7及其天然抑制物TIMP-1的表达情况。结果:在内膜癌组、内膜癌前病变组MMP-7的阳性表达分别为87.5%(63/72)、75%(48/64),明显高于正常内膜组43.8%(35/80)(P<0.01),而两组之间无显著差异。内膜癌组和癌前病变组TIMP-1的阳性表达分别为80.6%(58/72)、65.6%(42/64),也明显高于正常内膜组38.8%(31/80)(P<0.01)。随着内膜癌临床分期的增加,MMP-7的表达明显增强,Ⅱ期以上的内膜癌MMP-7表达均明显高于Ⅰ期(P<0.05)。在不同组织学分类中,组织分化程度低的内膜癌MMP-7表达明显高于组织分化程度高者。淋巴结转移阳性的内膜癌组织,MMP-7表达高于淋巴结转移阴性的内膜癌组织(P<0.01)。而TIMP-1则与上述病理学参数无显著相关性。结论:MMP-7在内膜癌发生过程中起到了重要作用,MMP-7表达增强和TIMP-1分泌相对不足,是内膜癌浸润和转移的重要促进因素。     

非小细胞肺癌中MMP-9和TIMP-1表达及意义

目的:观察血清中MMP-9和TIMP-1在非小细胞肺癌表达水平和相互关系。方法:ELISA法对44例NSCLC为观察组和28例健康人为健康对照组进行MMP-9和TIMP-1血清测定及分析。结果:MMP-9和TIMP-1在NSCLC血清表达水平显著高于健康对照组(P0.01),NSCLC中与TNM分期、淋巴结转移有相关性。NSCLC患者血清中Ⅲ+Ⅳ期MMP-9和TIMP-1高于Ⅰ+Ⅱ期患者,有淋巴结转移组高于无淋巴结转移组。结论:MMP-9和TIMP-1在NSCLC转移和侵袭中起重要作用,可作为监测NSCLC疾病发展程度的指标。     

子宫内膜癌组织中基质金属蛋白酶-2及其组织抑制因子-2的表达和意义

目的:探讨子宫内膜癌(EC)组织中基质金属蛋白酶-2(MMP-2)及其组织抑制因子-2(TIMP-2)的表达,分析其与子宫内膜癌发生发展、侵袭、转移的关系。方法:选取EC患者癌组织标本64例为EC组,选取同期子宫内膜轻、中度不典型增生20例为增生症组及内膜正常组20例作为对照。用免疫组化法检测MMP-2、TIMP-2在3组中的表达。结果:MMP-2、TIMP-2在EC组阳性表达高于正常组(P<0.05)和增生症组(P<0.05),而增生症组与正常组比较阳性表达无统计学差异(P>0.05);MMP-2表达与手术-病理分期、肌层浸润深度、组织学分级及淋巴结的转移相关(P<0.05);TIMP-2表达仅与淋巴结有无转移有关(P<0.05);EC组MMP-2表达高于TIMP-2(P<0.05),且两者表达具有一致性(P<0.05)。结论:子宫内膜癌组织中MMP-2和TIMP-2均高表达;但TIMP-2的表达却不足以抑制MMP-2高表达的活性,可能与子宫内膜癌的发生发展、浸润和转移有关。     

血管内皮生长因子和基质金属蛋白酶-9在非小细胞肺癌中的表达及临床意义

目的研究非小细胞肺癌（NSCLC）组织中血管内皮生长因子（VEGF）及基质金属蛋白酶-9（MMP-9）的表达情况,探讨VEGF及MMP-9在NSCLC侵袭和转移中的作用。方法应用免疫组织化学SABC法检测23例肺良性病变组织、30例NSCLC癌旁正常肺组织及111例NSCLC组织中VEGF及MMP-9的表达水平。结果NSCLC组织中VEGF及MMP-9的阳性表达率均高于肺良性病变组织和NSCLC癌旁正常肺组织（P〈0.05）。VEGF和MMP-9的表达随组织分化程度的降低而升高（P〈0.05）;在腺癌中MMP-9的阳性表达率高于鳞癌（P〈0.05）。VEGF和MMP-9的阳性表达率随TNM分期增高而升高（P〈0.05）,VEGF的阳性表达率随肿瘤增大而升高（P〈0.05）。有淋巴结转移者VEGF和MMP-9的阳性表达率高于无淋巴结转移者（P〈0.05）;存活1 a以内、1-3 a的患者VEGF和MMP-9的阳性表达率均高于存活3-5 a者（P〈0.05）。结论VEGF和MMP-9可能在NSCLC的侵袭和转移中发挥重要作用,可作为评估NSCLC的侵袭、转移和预后的参考指标。     

高迁移率族蛋白1及基质金属蛋白酶-9在子宫内膜癌中的阳性表达率及相关性分析

目的探讨高迁移率族蛋白1(HMGB1)及基质金属蛋白酶-9(MMP-9)在子宫内膜癌中的阳性表达率,并分析其相关性。方法选取2015年2月-2016年10月的子宫内膜癌患者60例,取其癌变组织作为子宫内膜癌组,同时取其癌旁正常组织作为癌旁组。另选取同期行子宫切除术的单纯性子宫内膜增生症患者60例作为对照组。检测3组HMGB1及MMP-9阳性表达率并进行比较,分析子宫内膜癌患者HMGB1及MMP-9阳性表达率与年龄、肿瘤直径、是否绝经、FIGO分期、淋巴结转移、分化程度、病理类型和浸润程度的关系,分析HMGB1表达及MMP-9表达的相关性。结果 3组HMGB1和MMP-9阳性率比较差异均有统计学意义(P<0.05)。子宫内膜癌组HMGB1阳性表达率显著高于癌旁组和对照组(P<0.05),子宫内膜癌组MMP-9阳性表达率显著高于癌旁组和对照组(P<0.05)。子宫内膜癌组HMGB1及MMP-9阳性表达率与年龄、肿瘤直径、是否绝经无关(P>0.05),与FIGO分期、淋巴结转移、分化程度、病理类型和浸润程度有关(P<0.05)。经Spearman统计分析,HMGB1表达及MMP-9表达在子宫内膜癌患者中呈正相关(r=0.558,P=0.021)。结论 HMGB1及MMP-9在子宫内膜癌患者中呈高表达,二者可能参与了子宫内膜癌的发生和发展。子宫内膜癌患者HMGB1及MMP-9阳性表达率与FIGO分期、淋巴结转移、分化程度、病理类型和浸润程度有关,HMGB1表达及MMP-9表达在子宫内膜癌患者中呈正相关。     

基质金属蛋白酶-9及基质金属蛋白酶组织抑制物-1与卵巢上皮性癌血管生成的关系

目的:探讨基质金属蛋白酶-9(MMP-9)及基质金属蛋白酶组织抑制物-1(TIMP-1)在卵巢上皮性癌血管生成中的作用。方法:采用免疫组织化学SP法检测45例卵巢上皮性癌组织中MMP-9和TIMP-1的表达,并检测其中微血管密度(MVD,CD34标记)。结果:卵巢癌组织和卵巢良性肿瘤中MMP-9阳性表达率明显高于正常卵巢组织(P<0.01),而TIMP-1未见升高(P>0.05),并且TIMP-1在卵巢癌组织中的阳性表达率显著低于MMP-9(P<0.01)。MMP-9在卵巢癌组织中表达与MVD显著正相关(r=0.286,P<0.05),而TIMP-1与MVD无相关性(r=0.194,P>0.05)。卵巢癌中MMP-9表达高于TIMP-1者,其MVD显著高于MMP-9表达低于TIMP-1者(P<0.05)。结论:MMP-9和TIMP-1表达失衡可能在卵巢上皮性癌血管生成中起重要作用,MMP-9表达增强而TIMP-1表达降低,其血管生成能力可能显著增强,但并非唯一决定因素。检测卵巢上皮性癌中MMP-9和TIMP-1表达对进一步了解卵巢上皮性癌局部血管生成情况有一定应用价值。     

基质金属蛋白酶-7在非小细胞肺癌中表达的意义

目的探讨基质金属蛋白酶-7(MMP-7)在非小细胞肺癌的发生、浸润及转移过程中的作用。方法采用免疫组织化学SP法,检测原发性非小细胞肺癌石蜡包埋组织80例、正常肺组织40例中MMP-7的表达水平,分析其与非小细胞肺癌的病理分化程度、手术-病理分期、淋巴结转移的相关性。结果非小细胞肺癌组MMP-7阳性率高于正常肺组织组(P=0.000)。非小细胞肺癌组TNM分期中Ⅰ、Ⅱ期合并后和Ⅲ、Ⅳ期合并后MMP-7的阳性率比较,差异有统计学意义(P=0.022);低分化癌的MMP-7的阳性率与高、中分化癌相比,差异无统计学意义(P=0.073);淋巴结转移组MMP-7的表达与无淋巴结转移组差异有统计学意义(P=0.003)。结论 MMP-7可能参与了非小细胞肺癌的发生和演进的过程;MMP-7检测可能成为判断非小细胞肺癌发生发展和评价预后的有效参考指标之一,对于非小细胞肺癌的早期预测可能具有重要的临床意义。     

基质金属蛋白酶与大骨节病

基质金属蛋白酶是参与关节软骨降解的多种酶之一，主要降解软骨胶原和蛋白囊糖。其与各种骨关节疾病包括大骨节病关系密切。从基质金属蛋白酶的结构、调控、激活及与骨关节疾病的关系等多方面阐述了近年来国内外在这一领域的研究成果，并对在大骨节病领域开展有关基质金属蛋白酶的研究提出了建议。     

基质金属蛋白酶及抑制物在胎膜早破中表达

目的 探讨基质金属蛋白酶-9、-2及其抑制因子-1、-2在胎膜早破孕妇的胎膜中的变化及与胎膜早破的关系.方法 应用免疫组织化学S-P法对上述两组胎膜组织检测基质金属蛋白酶-9、基质金属蛋白酶抑制因子-1、基质金属蛋白酶-2、基质金属蛋白酶抑制因子-2的表达.结果 胎膜早破组和对照组胎膜中基质金属蛋白酶-9、基质金属蛋白酶-2的阳性表达分别为100%、87%,差异有显著性(P＜0.01);胎膜早破组胎膜中基质金属蛋白酶抑制因子-1、基质金属蛋白酶抑制因子-2的表达较正常孕妇组低,但差异无显著性(P＞0.05).结论 基质金属蛋白酶-9、基质金属蛋白酶-2在胎膜早破孕妇胎膜中高表达,可能是胎膜早破发生的原因之一,需及时采取预防措施,防止胎膜早破的发生;人工诱导基质金属蛋白酶抑制因子-1、基质金属蛋白酶抑制因子-2或降低基质金属蛋白酶-2、基质金属蛋白酶-9的含量以防止胎膜早破的发生、发展,有望成为胎膜早破预防及治疗的辅助手段.     

Conformationally constrained analogues of endogenous tripeptide inhibitors of zinc metalloproteinases

Two diastereomeric furan-2-carbonylamino-3-oxohexahydroindolizino[8,7-b]indole carboxylates, highly constrained analogues of endogenous pyroglutamyl tripeptide inhibitors of snake venom endopeptidases, have been prepared as potential inhibitors of adamalysin II and matrix metalloproteinases. They proved to be inactive against adamalysin II and weak inhibitors of gelatinase A, gelatinase B, stromelysin 1 and human neutrophil collagenase. Evaluation of the mode of binding of the (2R,5S,11bR) isomer in the active site of adamalysin II suggests that the decrease of potency may be due to the reorientation of the acylamino chain in three of the heterocyclic nucleus, to a short contact at the entrance of the S'(1) hydrophobic cleft and to the loss of flexibility of the tetracyclic nucleus in the P'(1), P'(2) region of the inhibitor, which prevents optimal arrangement in the S'(1) specificity subsite.     

Expression of matrix metalloproteinases 9 and 12 in actinic cheilitis

AIM: To investigate the role of matrix-degrading metalloproteinases 9, 12 (MMPs), as mediators of functional connective tissue damage in actinic cheilitis.METHODS: Thirty five formalin-fixed, paraffin embedded specimens of actinic cheilitis, and twelve specimens of normal lower lip vermillion, which were obtained by the archives of the Department of Oral Medicine and Maxillofacial Pathology, were examined. From each block, 5 μm thick sections were cut and routinely stained with Hematoxylin and Eosin. Immunohistochemical studies were performed on 4-μm thick sections of formalin-fixed paraffin embedded actinic cheilitis lesions and of normal lower lip vermillion, for MMP-9 and MMP-12 in serial sections of our specimens. Appropriate positive and negative controls were performed to confirm the specificity of the staining reaction. MMP immunohistochemistry was evaluated using a semiquantitative immunoreactive score.RESULTS: Haematoxylin and eosin staining revealed in actinic cheilitis lesions atrophic stratified squamous cell epithelium, or focally and irregularly hyperplastic of variable thickness, in some areas was observed marked keratin production. Varying degrees of epithelial dysplasia were noticed with a wide spectrum of change within the same specimen. Characteristic was the appearance of chronic inflammatory infiltration, and a band of amorphous acellular, basophilic change like solar elastosis (elastin replacement of collagen). In normal lower lip specimens weak and scanty positive expression of MMP-9 and MMP-12 was observed. Anti-MMP-9 antibody showed a weak reaction, in actinic cheilitis lesions, focal in the elastotic material, in chronic inflammatory cells and mostly in macrophages and neutrophils. Strong and in some cases diffused immunohistochemical expression of MMP-12 was detected in actinic cheilitis lesions in the areas of the fragmented, distorted and thickened elastic fibers. MMP-12 was also expressed in chronic inflammatory cells and mostly macrophages. MMP-12 was significantly higher in actinic cheilitis specimens compared with the normal lower lip specimens (P = 0.0029).CONCLUSION: Our results suggest that especially MMP-12 may play an important role in remodeling events occurring in the connective tissue during long-term exposure to sunlight in the actinic cheilitis lesions.     

基质金属蛋白酶与胎膜早破

胎膜早破是一重要的产科并发症 ,但确切的病因及发病机制仍不十分明确。最近越来越多的证据表明胎膜早破与胎膜本身结构改变有关。基质金属蛋白酶是一类能水解包括胶原质等细胞外基质的蛋白水解酶 ,其分解胶原的螺旋结构 ,可调控细胞外基质含量和胎膜结构 ,与胎膜的破裂关系密切     

基质金属蛋白酶11和12在子宫颈癌中的表达及相关性研究

目的通过检测MMP-11、MMP．12在宫颈癌组织中的表达,探讨其与宫颈癌临床病理的关系,为诊治提供理论依据。方法采用免疫组化方法检测20例正常宫颈组织、36例宫颈上皮内瘤变组织（CIN）以及80例宫颈癌组织中MMP-11、MMP-12的表达情况,分析各组宫颈组织中的阳性表达与临床病理的关系。结果（1）MMP-11及MMP-12在宫颈癌组织中的阳性表达率（82．50％,81．25％）高于宫颈非典型增生组织（69．44％,61．11％）和正常宫颈组织（5．00％,0,P〈0．05）。（2）MMP．11及MMP-12的阳性表达与宫颈癌的组织学分级、临床分期、间质浸润深度、有无脉管入侵、有无淋巴结转移有关（P〈0．05）。（3）宫颈癌组织中MMP-11与MMP-12的阳性表达呈正相关（L=0．706,P〈0．05）。结论MMP-11及MMP-12在宫颈癌组织呈高表达,二者阳性表达在宫颈癌的浸润转移过程中起重要作用;联合检测MMP-11及MMP-12的表达可能对宫颈癌的早期诊断、判断肿瘤恶性程度及预后具有参考意义。     

胆囊癌组织中MMP-2和MMP-9的表达及相关性研究

目的 研究MMP-2和MMP-9在胆囊癌组织中的表达及其与胆囊癌侵袭的关系。方法 应用S—P免疫组化方法研究17例胆囊癌标本和8例胆囊腺瘤、9例慢性胆囊炎组织中MMP-2和MMP-9的表达水平及特征。结果 MMP-2、MMP-9在胆囊癌、胆囊腺瘤两种组织中的阳性表达率比较差异无统计学意义（P〉0．05），但均显著高于其在慢性胆囊炎中的表达；两种酶在胆囊组织中的表达强度呈显著正相关（γs=0．4201）；但两种酶在胆囊癌组织中的表达强度与胆囊癌的分化程度及Nevin分期无关。结论 MMP-2和MMP-9可能与胆囊癌的侵袭和转移有关。     

Regulation of metalloproteinases by nitric oxide in human trophoblast cells in culture

The process of embryo implantation requires extensive remodelling of the endometrial extracellular matrix, a function largely performed by matrix-degrading metalloproteinases (MMPs). In the present study, we used trophoblast cells isolated from human term placentas to study the regulation of MMPs by nitric oxide (NO). Using a combination of zymography, Western blot and indirect immunofluorescence, we showed that MMP-2 and MMP-9 are increased during the conversion from low-motile cytotrophoblast cells to the highly motile and differentiated syncytiotrophoblast multinucleated cells. We also observed an increase in NO production and NO synthase (NOS) expression during this cellular differentiation process. In addition, we demonstrated a positive regulatory role of NO on the activity and protein expression of MMP-2 and MMP-9, because NO donors (NOC-18 and spermine-NONOate) or the NOS substrate (L-arginine) stimulate, whereas NOS inhibitors (N(G)-nitro-L-arginine methyl ester and N(G)-monomethyl-L-arginine) reduce the expression and gelatinolytic activity of MMP-2 and MMP-9 in isolated trophoblast cells. Taken together, these results suggest that, in differentiating trophoblasts, NO regulates the induction of matrix-degrading proteases required for invasion during embryo implantation.     

胆囊癌组织中MMP-2和MMP-9的表达及相关性研究

目的研究MMP-2和MMP-9在胆囊癌组织中的表达及其与胆囊癌侵袭的关系.方法应用S-P免疫组化方法研究17例胆囊癌标本和8例胆囊腺瘤、9例慢性胆囊炎组织中MMP-2和MMP-9的表达水平及特征.结果MMP-2、MMP-9在胆囊癌、胆囊腺瘤两种组织中的阳性表达率比较差异无统计学意义(P＞0.05),但均显著高于其在慢性胆囊炎中的表达;两种酶在胆囊组织中的表达强度呈显著正相关(γs=0.4201);但两种酶在胆囊癌组织中的表达强度与胆囊癌的分化程度及Nevin分期无关.结论MMP-2和MMP-9可能与胆囊癌的侵袭和转移有关.     

Conjugated linoleic acid alters matrix metalloproteinases of metastatic mouse mammary tumor cells

Conjugated linoleic acid (CLA) is a group of linoleic acid derivatives that has been implicated in animal studies to reduce a number of components of mammary tumorigenesis. Previously, we showed that CLA could alter the latency and metastasis of the highly metastatic transplantable line 4526 mouse mammary tumor. Several possible mechanisms have been proposed for the actions of CLA, but here we assessed how CLA may act to alter the expression and activity of matrix-modifying proteins within tumors from line 4526. In vitro, highly metastatic mouse mammary tumor cells had significantly decreased invasiveness after treatment with CLA, an indication that matrix-modifying proteins may have been altered. Using these same highly metastatic cells, primary tumors were grown in mice of separate groups fed 0, 0.1, 0.5, and 1% CLA (wt:wt) and evaluated for their levels and activities of matrix-modifying enzymes, enzyme inhibitors, and enzyme activators. The addition of CLA to the diet increased steady-state levels of messenger RNA (mRNA) of the matrix metalloproteinases (MMP) -2 and -9 in primary tumors removed from mice. However, western analysis revealed that although relative levels of the proform of MMP-9 were consistent with the mRNA observations, MMP-2 proform levels were actually decreased by dietary CLA. The activity of MMP-2 was barely detectable, but gelatin zymography and an in vitro activity assay showed that MMP-9 activity was significantly decreased by CLA. The steady-state mRNA and protein levels of tissue inhibitors of metalloproteinase-1 (TIMP-1) and TIMP-2, natural inhibitors of MMP, were increased at higher dietary CLA levels relative to low or no CLA. Suppression of MMP activity, therefore, may be 1 pathway through which CLA reduces tumor invasion and spread.