MMP-2、MMP-9及其抑制因子TIMP-2、TIMP-1联合检测对宫颈癌浸润转移潜能的预测价值

目的 分析基质金属蛋白酶2（MMP-2）和MMP-9及其抑制因子2（TIMP-2）和TIMP-1联合检测对宫颈癌浸润转移潜能的预测价值.方法 选取经病理证实的宫颈浸润癌患者112例（ICC组）、宫颈上皮内瘤样病变患者56例（CIN组）;同时,选取正常宫颈组织标本30例为对照组.采用SABC法行免疫组织化学检测MMP-2、MMP-9 、TIMP-2和TIMP-1的表达情况.比较3组相关因子阳性表达率的差异,并分析ICC组各因子阳性表达率与临床病理参数的关系.结果 ICC组MMP-2和MMP-9的阳性表达率显著高于CIN组和对照组,TIMP-2和TIMP-1的阳性表达率显著低于CIN组和对照组（P＜0.05）.ICC组中,MMP-2、MMP-9、TIMP-2和TIMP-1的阳性表达率与国际妇产科联盟（FIGO）分期、组织学分级、分化程度、脉管浸润和淋巴结转移有关（P＜0.05）.结论 MMP-2、MMP-9及其抑制因子TIMP-2、TIMP-1可能与宫颈癌的发生、发展有关,其可作为评估宫颈癌侵袭转移潜能的重要指标.     

MMP9和CD44v6在食管癌组织中表达的研究

目的 探讨基质金属蛋白酶MMP9、细胞黏附因子CD44v6在食管癌表达的意义。方法 采用免疫组织化学法对60例食管癌组织进行检测及分析。结果 MMP9和CD44v6与食管癌的浸润及转移密切相关。浸润癌组织MMP9表达高于原位癌组织．淋巴结转移组明显高于无淋巴结转移组;原位癌组织CD44v6阳性表达高于浸润癌组织,而淋巴结转移组明显高于无淋巴结转移组。结论 MMP9和CD44v6的表达均与食管癌浸润转移有关,但两者的作用机制和途径不同。     

p21、p27和bcl-2在大肠癌、大肠腺瘤及正常大肠黏膜中表达的意义及相关性研究

目的：探讨p21、p27、bcl-2蛋白在大肠癌、大肠腺瘤及正常大肠黏膜中的表达及其临床意义。方法：采用免疫组化方法,分别检测20例正常大肠黏膜、22例大肠腺瘤和69例大肠癌中p21、p27、bcl-2蛋白表达情况。结果：p21、p27、bcl-2蛋白总阳性表达率分别为44．93％、50．72％、52．17％,各种蛋白的阳性表达率在大肠癌组织与对照组间存在的差异有统计学意义（p〈0．05）。其中发生淋巴结转移的大肠癌组织中p21阳性表达率高于无淋巴结转移的大肠癌组织中的阳性表达率,差异具有统计学意义（P〈0．05）;p27蛋白的表达与肿瘤分化程度呈负相关（P〈0．05）;在发生淋巴结转移的大肠癌组织中bcl-2阳性表达率低于无淋巴结转移的大肠癌组织中的阳性表达率,差异具有统计学意义（P〈0．05）,高分化、中分化腺癌与低分化腺癌相比,差异均有统计学意义（P〈0．05）,TNMⅣ期bcl-2表达率显著低于Ⅰ、Ⅱ、Ⅲ期（P〈0．05）。结论：p21、p27、bcl-2蛋白与大肠癌的发生、发展有密切关系,联合检测p21、p27、bcl-2对于临床诊断大肠癌及判断病情、预后有重要意义。     

大肠癌中MMP-2、TIMP-2基因的表达及其对预后的影响

目的研究大肠癌中MMP-2、TIMP-2基因的表达，旨在探讨其在大肠癌局部进展中的作用。方法应用流式细胞术（flow cytometry technique，FCM）测定60例大肠癌和15例正常对照组结肠标本的MMP-2、TIMP-2基因蛋白表达量，蛋白表达量以荧光指数（fluorescent index FI）表示，并将大肠癌根据临床病理分期、癌细胞分化程度、细胞学类型分组比较。其结果用统计软件包spss11．5进行统计学处理。结果大肠癌组MMP-2、TIMP_2基因蛋白的表达量与正常对照组比较有显著性差异P〈0．01；转移组大肠癌MMP-2、TIMP-2基因蛋白的表达量与未转移组比较有显著性差异，P〈0．01；大肠癌低分化腺癌与中、高分化腺癌MMP-2、TIMP-2基因蛋白FI值比较差异有显著性，P〈0．叭。结论MMP-2、TIMP-2基因的表达与大肠癌的发生和进展关系密切，值得临床注意。     

EB病毒膜潜伏蛋白LMP1和基质金属蛋白酶MMP9表达与鼻咽癌转移的关系

目的探讨EB病毒膜潜伏蛋白LMP1和基质金属蛋白酶MMP9在鼻咽癌组织表达的意义。方法采用免疫组织化学法对40例鼻咽癌组织进行标记及分析。结果鼻咽癌淋巴结转移组LMP1和MMP9阳性表达率明显高于无淋巴结转移组,二者阳性表达呈明显相关。结论 LMP1和MMP9的表达与鼻咽癌的浸润及转移密切相关,LMP1介导MMP9在鼻咽癌细胞扩散和转移起重要作用。     

MRP与LRP在大肠癌组织中的表达及临床意义

目的 探讨多药耐药相关蛋白（MRP）与肺耐药相关蛋白（LRP）在大肠癌组织中的表达特点及临床意义.方法 采集山西大同大学附属医院2008年至2013年收治的大肠癌患者共计58例,留取手术切除的新鲜癌组织制成蜡块儿.同时收集30例正常大肠组织的标本.采用免疫组化的方法检测MRP与LRP在大肠癌组织中以及正常大肠黏膜组织中的表达情况.同时检测其表达与肿瘤细胞分化程度及淋巴结转移的关系.结果 MRP与LRP在大肠癌组织中的表达均明显高于正常大肠组织（P＜0.01）.在不同分化程度的大肠癌中,MRP与LRP的表达水平不同,其中高分化腺癌组与中分化、低分化腺癌组比较均有统计学意义（P＜0.05）;中分化与低分化腺癌组比较无统计学意义（P＞0.05）.在伴有淋巴结转移的大肠癌组织中MRP与LRP的阳性表达率均较不伴有淋巴结转移者为高（P＜0.05）.结论 MRP与LRP均在大肠癌组织中有一定程度的表达,且与其肿瘤细胞分化程度、淋巴结转移情况相关.     

整合素β_1和基质金属蛋白酶-2在胃癌中的表达及临床意义

目的通过应用免疫组化方法研究胃癌患者原发灶转移及邻近非肿瘤胃黏膜等不同组织的基质金属蛋白酶-2(MMP2)和整合素β1亚单位分布特征,旨在探讨整合素β1、MMP2的表达与胃癌侵袭性的关系,并指导临床治疗及判断胃癌患者的预后。方法采用免疫组织化学通用二步法检测整合素β1和MMP2在64例胃癌原发灶及其淋巴结转移灶中的表达情况。结果整合素β1在正常胃小凹表层上皮细胞膜表面呈均质性表达,并沿基底膜呈连续性线状分布;在胃癌组织的细胞浆和细胞膜呈棕黄色表达;淋巴结转移灶中呈非均质性棕黄色表达。在胃癌组织中的阳性表达率明显高于邻近的正常黏膜组织(P<0.05);在不同的组织学类型整合素β1阳性表达也有差异,在高中分化组为40%,在低分化组中为84.6%,可见,在低分化癌明显高于高中分化癌(P<0.01);整合素β1的阳性表达率与患者的年龄、性别、肿瘤的大小无明显相关性(P>0.05)。胃癌组织中MMP2阳性主要表达于胃癌组织的细胞浆和细胞膜内,呈棕黄色。MMP2表达阳性在胃癌组织明显强于邻近正常黏膜组织(P<0.05);浸透黏膜层组中的表达强于未浸透组(P<0.05);有淋巴结转移组的阳性表达高于无淋巴结转移组;不同的组织学类型中阳性表达也有差异,在低分化癌明显高于高中分化癌(P<0.01)。MMP2在胃癌中的表达与性别、年龄、肿瘤大小无关。结论整合素β1和MMP2的表达与胃癌的分化程度、侵润程度、淋巴结转移状况等临床病理因素密切相关,而与年龄、性别、肿瘤的大小等无关,其表达的检测对评估胃癌淋巴结转移程度有重要的意义,还可以作为估计患者预后及术后治疗的生物学指标。     

大肠癌病理分型、浸润深度与淋巴结转移相关关系的研究

目的:探讨大肠癌病理分型及浸润深度与淋巴结转移的关系。方法:回顾性研究了306例大肠癌病理资料,对大肠癌的病理分型分期及浸润深度与淋巴结转移进行分析。结果:低分化腺癌、印戒细胞癌的淋巴结转移率和淋巴结转移度较高分化腺癌高;大肠癌浸润肠壁全层的淋巴结转移率和转移度较仅浸润黏膜层的高。结论:大肠癌分化程度、病变深度与淋巴结转移密切相关。     

口腔鳞癌基质金属蛋白酶-2表达分析

目的：探讨基质金属蛋白酶-2（Matrix metalloproteinase 2,MMP2）在口腔鳞癌（oral squamous cell carcinoma,OSCC）中的表达及其血管生成、浸润和转移中的作用。方法：选用正常口腔黏膜组织12例、口腔白斑12例、OSCC标本52例,采用免疫组化方法和原位杂交技术检测MMP2的表达,用CD34抗体进行血管内皮细胞的免疫组化染色,计数OSCC的微血管密度（mierovessel density,MVD）。结果：口腔白斑组织中MMP2蛋白和MMP2 mRNA阳性表达率显著高于正常口腔黏膜组织,OSCC组织中MMP2蛋白和MMP2 mRNA阳性表达率显著高于正常口腔黏膜组织和口腔白斑组织。OSCC组织Ⅲ＋Ⅳ期组、有淋巴结转移组和肌层浸润组中MMP2蛋白和mRNA阳性表达率显著高于Ⅰ＋Ⅱ期组、无淋巴结转移组和黏膜及黏膜下层浸润组。OSCC组织中MMP2蛋白、MMP2 mRNA阳性表达组织MVD水平显著高于MMP2蛋白、MMP2 mRNA阴性表达组MVD水平。结论：MMP2在OSCC组织中呈特征性高表达状态,与OSCC肿瘤血管生成、肿瘤生长、浸润和转移密切相关。     

JAB1、β-catenin与大肠癌生物学行为之间的关系

目的：通过检测大肠癌组织及相应癌旁组织中的C-Jun结合蛋白1（c-Jun activation domain binding protein 1,JAB1）和β-连环素（β-catenin）的表达,探讨JAB1和β-catenin在大肠癌组织中的表达与其生物学行为之间的关系。方法（1）应用免疫组化学方法（SP法）检测94例大肠癌及相应癌旁组织中JAB1和β-catenin的表达情况。（2）分析JAB1和β-catenin的表达与大肠癌的发生、发展、分化程度、临床分期及淋巴结转移等之间的关系。结果（1） JAB1在大肠癌组织中的表达率明显高于癌旁组织（χ2＝86．686, P＜0．001）,JAB1在低分化型大肠癌中的阳性表达率为94．3％,高于中、高分化型中的79．7％（χ2＝5．634,P＝0．018）;在淋巴结转移阳性的病例中表达率为94．6％,高于淋巴结转移阴性的病例中的73．7％（χ2＝8．344,P＝0．004）;在Dukes 分期C期＋D期中的阳性表达率为93．2％,在A期＋B期中阳性表达率为70．0％,差异具有统计学意义（χ2＝8．124,P＝0．004）;JAB1的表达与患者性别、年龄、肿瘤大小无明显统计学意义（P＞0．05）;（2）在94例大肠癌组织中β-catenin异常表达数为61例（64．9％）,癌旁组织异常表达数为26例（27．7％）,二者差别有明显统计学意义（χ2＝26．209,P＜0．001）,β-catenin在低分化型大肠癌中的异常表达率为91．4％,高于中、高分化型中的72．9％（χ2＝4．686,P＝0．030）;在淋巴结转移阳性的病例中异常表达率为98．2％,高于淋巴结转移阴性的病例的76．3％（ P＝0．001）;在Dukes 分期C期＋D期中的异常表达率为90．9％,在A期＋B期中异常表达率为64．0％,差异具有统计学意义（χ2＝9．454,P＝0．002）。β-catenin的表达与患者性别、年龄、肿瘤大小无明显统计学意义（P＞0．05）。结论（1）JAB1、β-catenin 参与大肠癌的发生及发展;（2） JAB1?     

RT-PCR expression profiling of matrix metalloproteinases and their specific inhibitors in cell lines and fresh biopsies of squamous cell carcinomas of the head and neck

The expressions of MMP2, -7, -9, -13 and TIMP1, -2, -3 were examined in biopsies and cell lines of head and neck squamous cell carcinomas (HNSCC) to determine the association between the expression profile and TNM-staging of the primary. The expressions of MMP2, -7, -9, -13 and TIMP1, -2, -3 were analyzed in 30 HNSCC biopsies, 7 HNSCC cell lines and 1 keratinocyte cell line using RT-PCR. Negative correlation was determined between N-status and MMP13-RNA expression [Kendall-tau-b -0.404 (p = 0.016), Spearman-rho -0.448 (p = 0.014)], histological grading [Kendall-tau-b -0.291 (p = 0.049), Spearman-rho -0,333 (p = 0.048)], and MMP7 and TIMP2 expression [Kendall-tau-b -0.318 (p = 0.045); Spearman-rho -0.353 (p = 0.045)]. Positive correlation was determined between M-status and MMP9-RNA expression [Kendall-tau-b 0.341 (p = 0.025), Spearman-rho 0.377 (p = 0.024)] and MMP13 and TIMP2 expression [Kendall-tau-b 0.727 (p = 0.037), Spearman-rho 0.850 (p = 0.016)]. The results point to a role of the tested MMPs and TIMPs in the metastatic spread of HNSCC.     

Matrix metalloproteinases contribute to endotoxin and interleukin-1beta induced vascular dysfunction

BACKGROUND AND PURPOSE: The acute vascular inflammatory dysfunction associated with endotoxaemia may reflect an imbalance between matrix metalloproteinases (MMPs) and their natural inhibitors (TIMPs), induced by the endotoxin. This possibility was tested in rat aortic tissue. EXPERIMENTAL APPROACHES: Tone induced by phenylephrine in aortic rings was measured after exposure in vitro to ambient lipopolysaccharide (LPS) or the proinflammatory cytokine interleukin-1beta (IL-1beta) for 6h, with or without MMP inhibitors (doxycycline or GM6001). Gelatinase and MMP activities, TIMP proteins and contractility were measured in aortae taken from rats 6h after receiving LPS in vivo. KEY RESULTS: Inhibition of MMP prevented the loss of phenylephrine-induced tone in aortic rings after LPS or IL-1beta. IL-1beta also increased release of MMP-2 activity from aortic tissue. In aortae exposed in vivo to LPS, net gelatinase, MMP-9 activities and TIMP-1 protein levels were increased, whereas TIMP-4 was reduced. These aortae were hypocontractile to both phenylephrine and KCl. Hypocontractility was partially reversed by doxycycline ex vivo. CONCLUSIONS AND IMPLICATIONS:MMP inhibitors ameliorate vascular hyporeactivity induced by either LPS or IL-1beta in vitro. LPS in vivo alters the balance between MMPs and TIMPs, contributing to vascular dysfunction which is partially reversed by MMP inhibitors. Vascular MMPs are activated as a result of LPS or IL-1beta-induced stress and contribute to the hyporeactivity of blood vessels to vasoconstrictors.     

Targeting matrix metalloproteinases in heart disease: Lessons from endogenous inhibitors

Basic pharmacological/transgenic studies have clearly demonstrated a cause–effect relationship between the induction and activation of matrix metalloproteinases (MMPs) and adverse changes in the structure and function of the left ventricle (LV). Thus, regulation of MMP induction and/or activation would appear to be a potential therapeutic target in the context of cardiovascular disease, such as following myocardial infarction (MI). However, pharmacological approaches to inhibit MMPs have yet to be realized for clinical applications. The endogenous inhibitors of the MMPs (TIMPs) constitute a set of 4 small molecules with unique functionality and specificity. Thus, improved understanding on the function and roles of individual TIMPs may provide important insight into the design and targets for pharmacological applications in LV remodeling processes, such as MI. Therefore, the purpose of this review will be to briefly examine biological functions and relevance of the individual TIMPs in terms of adverse LV remodeling post-MI. Second is to examine the past outcomes and issues surrounding clinical trials targeting MMPs in the post MI context and how new insights into TIMP biology may provide new pharmacological targets. This review will put forward the case that initial pharmacological attempts at MMP inhibition were over-simplistic and that future strategies must recognize the diversity of this matrix proteolytic system and that lessons from TIMP biology may lead to future therapeutic strategies.     

Expression of matrix metalloproteinase,tissue inhibitors of metalloproteinase and adhesion molecules in silicotic mice with lung tumor metastasis

The number of metastatic foci in silicotic mice is approximately 1.5-fold that in normal mice and in mice treated with TiO2 as inert particles. Expression of matrix metalloproteinases (MMPs) tissue inhibitors of metalloproteinases (TIMPs) and selectins was investigated in silicotic mice with lung tumor metastasis. Expression of MMP-9 and P-selectin mRNA, but not MMP-2 and E-selectin, increased significantly, showing decreases of the ratio of expression in TIMPs/MMP-9 in tumor-bearing silicotic mice compared with the tumor-bearing normal mice and mice treated with TiO2. Pretreatment with anti-P-selectin antibody inhibited number of metastatic foci significantly in silicotic mice, while pretreatment of animals with anti MMP-9 antibody showed slight decrease of metastatic foci. This evidence indicated that up-regulation of P-selectin expression contributed to enhanced rate of tumor metastasis in lung with silicosis.     

Section Review Biologicals & Immunologicals: Matrix metalloproteinases and malignant disease: Recent developments

One important proteolytic event during metastasis and angiogenesis appears to be the degradation of basement membrane components. A specific class of extracellular matrix (ECM) degrading metallo-enzymes, the matrix metalloproteinases (MMPs), also known as the matrixins, are thought to have a critical role in the creation of the proteolytic defect in basement membrane type IV collagen that allows tumour cells to escape from their primary site. The expression of matrixin proteases has been linked with many physiologic and pathologic processes involving ECM turnover. A number of correlative and functional studies suggest that the action of MMPs is required during tumour invasion and progression, as well as angiogenesis. The correlative studies have demonstrated overexpression of MMPs in many human cancer tissues at both the protein (immunoperoxidase) and mRNA (in situ hybridisation) levels. Functional studies have used endogenous inhibitors (Tissue Inhibitors of Metalloproteinases, TIMPs) or synthetic MMP inhibitors to block tumour cell invasion or metastasis formation. MMPs have also been implicated in the cell-surface proteolysis that modulates the adhesive behaviour of neoplastic cells. Therefore, targeting the activity of MMPs may provide a clinically useful mechanism for blocking local invasion and the metastatic spread of cancer cells. Results from a variety of studies indicate that mechanism-based inhibitors for MMPs can be developed and exploited in the clinical setting. This strategy has been utilised for the development of MMP inhibitors as substrate analogues have been modified to target selectively reactive moieties at the active site of MMPs.     

Introduction: MMPs, ADAMs/ADAMTSs research products to achieve big dream

Matrix metalloproteinases (MMPs) are known to participate in cancer invasion and metastasis. Copious research on MMPs and their inhibitors has promoted the understanding of the mechanisms of cancer invasion and metastasis as well as the development of effective drugs for cancer treatment. This review discusses the classification of MMPs and tissue inhibitors of metalloproteinases (TIMPs) in relation to tumor growth and invasion mechanisms via signal transduction, followed by the possibilities for cancer treatment. The review focuses especially on the development of anti-cancer agents in the field of MMP science.     

Matrix metalloproteinases in cancer invasion, metastasis and angiogenesis

Matrix metalloproteinases (MMPs) are a family of proteinases that play an important role in cancer as well as in numerous other diseases. In this article, we summarize the current views on the role of MMPs in cancer with respect to invasion, metastasis and angiogenesis. A positive correlation between tumor progression and the expression of multiple MMP family members in tumor tissues has been demonstrated in numerous human and animal studies. It has been assumed that cancer cells are responsible for producing the MMPs in human tumors. However, recent evidence suggests that tumor cells have docking sites that bind stromal-cell-secreted MMPs. Furthermore, the role of MMPs produced by endothelial cells, especially MMP-2 and MT1-MMP, appear to be crucial for tumor angiogenesis, which is a requirement for cancer growth and dissemination.     

Protective effects of Phyllanthus amarus on fibrotic markers during alcohol and polyunsaturated fatty acid-induced toxicity

Alcoholic liver disease (ALD) remains a major problem, with significant morbidity and mortality worldwide. One of the serious consequences of ALD is hepatic fibrosis. This happens when the matrix synthesis rate exceeds that of matrix degradation. Matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) play a key role in matrix remodeling. Disruption of MMP/TIMP balance can lead to excessive accumulation of extracellular matrix components resulting in severe liver injury. The focus of the present study is to analyze the effect of Phyllanthus amarus on MMP and TIMPs activity in alcohol and thermally oxidized polyunsaturated fatty acid (PUFA)-induced hepatic fibrosis. Male albino Wistar rats were used for the study. The matrix metalloproteinase expression was found to be significantly decreased and the levels of TIMPs and the collagen were significantly increased in alcohol + thermally oxidized PUFA-treated rats. Administration of Phyllanthus amarus extract significantly decreased the levels of collagen and TIMPs; and positively modulated the expression of MMPs. From this study, we conclude that Phyllanthus amarus effectively modifies alcohol + thermally oxidized PUFA-induced fibrosis.     

Matrix metalloproteinase expression and activity in human airway smooth muscle cells

Airway remodelling is a feature of chronic asthma comprising smooth muscle hypertrophy and deposition of extracellular matrix (ECM) proteins. Matrix metalloproteinases (MMPs) breakdown ECM, are involved in tissue remodelling and have been implicated in airway remodelling. Although mesenchymal cells are an important source of MMPs, little data are available on airway smooth muscle (ASM) derived MMPs. We therefore investigated MMP and tissue inhibitor of metalloproteinase (TIMP) production and activity in human ASM cells. MMPs and TIMPs were examined using quantitative real-time RT-PCR, Western blotting, zymography and a quench fluorescence (QF) assay of total MMP activity. The most abundant MMPs were pro-MMP-2, pro- MMP-3, active MMP-3 and MT1-MMP. TIMP-1 and TIMP-2 expression was low in cell lysates but high in conditioned medium. High TIMP secretion was confirmed by the ability of ASM-conditioned medium to inhibit recombinant MMP-2 in a QF assay. Thrombin increased MMP activity by activation of pro-MMP-2 independent of the conventional smooth muscle thrombin receptors PAR 1 and 4. In conclusion, ASM cells express pro-MMP-2, pro and active MMP-3, MMP-9 and MT1-MMP. Unstimulated cells secrete excess TIMP 1 and 2, preventing proteolytic activity. MMP-2 can be activated by thrombin which may contribute to airway remodelling.