基质金属蛋白酶-2和-9在食管鳞状细胞癌中的过表达

目的 探讨人食管鳞癌组织中基质金属蛋白酶(MMP)-2、-9的表达及其临床意义.方法 采用免疫组织化学法,检测57例食管鳞癌及10例食管正常黏膜石蜡标本中MMP-2、-9蛋白的表达情况.结果 食管鳞癌组织中MMP-2及MMP-9阳性表达率(40.3%,61.4%)显著高于正常组织(0.0%,10.0%)(P＜0.05).食管鳞癌组织中MMP-2及MMP-9阳性表达与淋巴结转移和癌组织浸润深度有显著相关性(P＜0.05),而与患者的性别、年龄和组织分化程度无显著相关性(P＞0.05).结论 MMP-2和MMP-9在食管癌中显著高表达,与食管癌的转移及侵袭有关,其异常表达可能共同参与食管癌的发生、发展过程,检测MMP-2、-9可作为食管癌病理学特点的参考指标.     

食管鳞癌组织中巨噬细胞移动抑制因子、金属蛋白酶-9和血管内皮生长因子的表达意义

目的探讨食管鳞癌组织中巨噬细胞移动抑制因子(MIF)、基质金属蛋白酶(MMP)-9和血管内皮生长因子(VEGF)表达情况及临床意义。方法选择自2008年9月至2012年7月62例资料完整的食管鳞癌患者的病理切片,另选取相同病理癌变旁边正常组织作为对照组,采用Eli Vision TM免疫组织化学法检测MIF、MMP-9和VEGF在食管鳞癌组织中的表达,与食管鳞癌临床参数进行统计分析,并分析三者之间的相关性。结果食管鳞癌组织中MIF、MMP-9及VEGF的阳性表达率明显高于对照组(P0.05)。MIF、MMP-9及VEGF在食管鳞癌组织中的表达与分化程度、淋巴道转移、病理分期(c TNM)及浸润深度有关(P0.05)。MIF与MMP-9及VEGF在食管鳞癌组织中的表达均呈正相关(P均0.05)。结论MIF、MMP-9和VEGF在食管鳞癌组织中高表达,并且三个因子之间具有显著的线性关系,可以通过检测三个因子的表达来诊断食管鳞癌。     

胃肠安方对胃癌基质金属蛋白酶9及基质金属蛋白酶抑制因子1/2蛋白表达的影响

[目的]观察胃肠安方对人胃癌裸鼠原位移植瘤转移的抑制作用及其对基质金属蛋白酶9 (matrix metalloproteinase-9,MMP-9)、基质金属蛋白酶抑制因子(matrix metalloproteinases tissue inhibitor,TIMP)-1、TIMP-2蛋白表达的影响.[方法]建立裸小鼠胃原位癌模型,分为胃肠安方组及模型组,观察裸小鼠胃癌种植后肿瘤转移灶情况以及与肿瘤生长与转移密切相关的MMP-9、TIMP-1、TIMP-2的影响.[结果]胃肠安方能够抑制胃癌生长与转移,与模型组比较,差异具有统计学意义(P＜0.05).胃肠安方组MMP-9蛋白阳性表达明显弱于模型组,TIMP-1及TIMP-2蛋白阳性表达明显强于模型组.[结论]胃肠安方具有抑制人胃癌裸鼠原位移植瘤转移作用,其抑制胃癌转移的部分作用机制与抑制MMP-9蛋白表达及上调TIMP-1、TIMP-2蛋白表达有关.     

基质金属蛋白酶-2及其抑制物在慢性肝炎和肝硬化肝组织中的表达

为进一步探讨基质金属蛋白酶-2（MMP-2）和基质金属蛋白酶-2组织抑制因子（TIMP-2）在肝纤维化发生，发展过程中的作用，用免疫组织化学方法检测慢性肝炎和肝硬化肝组织中MMP-2和TIMP-2的表达及分布状态，并作定位及半定量分析。     

基质金属蛋白酶-9与脑血管病

基质金属蛋白酶-9(matrix metalloproteinase,MMP-9)可降解细胞外基质中的Ⅳ型胶原,在脑基底膜的降解中起主要作用.组织金属蛋白酶抑制剂-1(tissue inhibitor of metalloproteinase,TIMP-1)是天然的MMP-9特异性抑制剂.MMP-9与TIMP-1平衡关系的失调与缺血性和出血性脑损伤有关,与动脉瘤、动脉粥样硬化等的形成和发展也有关.因此,人为地调节MMP-9与TIMP之间的平衡,有可能成为治疗脑血管病的新途径.     

基质金属蛋白酶在心房颤动犬心房结构重构中的作用

目的 探讨基质金属蛋白酶-9（MMP-9）和组织型基质金属蛋白酶抑制因子-1（TIMP-1）在快速起搏心房颤动（房颤）动物模型心房结构重构中的作用和Ca^2＋超载对MMP-9激活的影响。方法 14只犬随机分为房颤组（n=8）和对照组（n=6），右心房快速起搏（350～450次／min）8周建立房颤动物模型。取左心房组织，采用半定量逆转录聚合酶链反应（RT-PCR）和免疫组织化学法检测MMP-9和TIMP-1 mRNA和蛋白质表达，采用Masson染色测定心房肌组织胶原含量，采用超声心动图测量左心房内径，同时还测定心房肌组织Ca^2＋浓度。结果 与对照组比较，房颤组心房肌胶原含量、Ca^2＋浓度和左心房内径增加（P〈0．05）；房颤组左心房心肌组织MMP-9 mRNA表达升高45％（P〈0．01），蛋白质水平表达增加19．5％（P〈0．001）；TIMP-1 mRNA表达增加46．67％（P〈0．01），TIMP-1蛋白质水平表达下调8．33％（P〈0．01）；MMP-9 mRNA表达与左心房内径、Ca^2＋浓度和心肌胶原含量正相关（P〈0．05）；TIMP-1 mRNA表达与左心房内径、心肌胶原含量和MMP-9 mRNA表达正相关（P〈0．05）。结论 MMP-9／TIMP-1平衡失调可能是慢性房颤心房肌细胞外基质重构和心房扩大的重要分子机制，细胞内Ca^2＋超载可能是MMPs的重要激活途径。     

食管鳞癌中基质金属蛋白酶-7的表达及意义

目的:研究基质金属蛋白酶-7(MMP-7)在食管鳞癌中的表达情况及其与肿瘤浸润和淋巴结转移的关系。方法:用免疫组织化学法检测75例食管鳞癌组织及其相应正常粘膜中MMP-7的表达。结果:食管鳞癌组织MMP-7基因表达(59/75,78.7％)高于正常组织(P<0.01)。浸润到外膜层食管鳞癌(37/45,82.2％)与浸润至粘膜下层鳞癌(5/10,50.0％)之间MMP-7的高表达有显著性差异(P<0.05),淋巴结转移组MMP-7高表达(27/29,93.1％)高于淋巴结未转移组(P<0.05)。结论:MMP-7的高表达与食管鳞癌浸润深度和淋巴结转移有关,可能成为食管鳞癌恶性生物学行为的指标。     

基质金属蛋白酶-1和基质金属蛋白酶-9及其抑制剂-1对心房颤动患者心房结构重构的影响

目的研究心房颤动患者心房组织基质金属蛋白酶-1和基质金属蛋白酶-9(MMP-1,MMP-9)及其组织型基质金属蛋白酶抑制因子-1(TIMP-1)的基因表达,并探讨其与心房结构重构的关系。方法将28例风湿性心脏病接受换瓣手术患者的右心耳标本分为3组,窦性心律组8例,阵发性房颤组8例,持续性房颤组12例,采用半定量逆转录-聚合酶链反应(RT-PCR)技术检测心房组织中MMP-1、MMP-9和TIMP-1基因表达。结果(1)与窦性心律组比较,阵发性房颤组MMP-1的mRNA表达虽有增加,但无显著性差异,而持续性房颤组MMP-1的mRNA表达显著增加(P<0.05);(2)MMP-9的mRNA表达在窦性心律组、阵发性房颤组和持续性房颤组心房组织的表达逐渐增加(P<0.05)。MMP-9的mRNA水平与房颤持续的时间、左心房的内径成显著的正相关(r=0.509,0.543,P<0.01);(3)与窦性心律组比较,阵发性房颤组和持续性房颤组TIMP-1的mR-NA水平明显下降(P<0.05,P<0.01)。TIMP-1的mRNA水平与房颤持续的时间、左心房的内径成显著的负相关(r=-0.43,-0.387,P<0.05)。结论房颤患者的MMP-1、MMP-9和TIMP-1相互间的作用失衡可能与慢性房颤时的心房结构重构有关。     

基质金属蛋白酶9在大肠癌中表达的研究

目的 探讨基质金属蛋白酶9（MMP-9）在大肠癌中的表达及临床意义。方法 采用免疫组织化学SP法检测216例大肠癌组织中MMP-9的表达。结果 216例大肠癌组织MMP-9阳性表达率为76．9％（166／216），高表达率为65．3％（141／216）。MMP-9高表达与大肠癌的分化程度、Dukes分期、生存期、淋巴结转移和器官转移密切相关（P〈0．05或0．01）。结论 MMP-9高表达在大肠癌的侵袭和转移中发挥重要作用。     

系统性红斑狼疮外周血单个核细胞基质金属蛋白酶-9的表达研究

系统性红斑狼疮（SLE）是一种病因未明的自身免疫性疾病，其复杂多变的临床表现源于其基本病理改变—一血管炎。近年来研究表明，基质金属蛋白酶-9（matrix metailoproteinase-9．MMP-9）参与介导自身免疫性炎症反应。MMP-9及金属蛋白酶组织抑制因子-1（TIMP-1）有可能涉及SLE的病理损伤过程。本研究采用反转录聚合酶链反应（RT—PeR）方法检测SLE患者和健康人群外周血单个核细胞（pefipheral blood nuclearceils，PBMCs）MMP-9及TIMP-1 mRNA的表达水平．探讨其在SLE发病中的作用。     

基质金属蛋白酶及其组织抑制剂与食管癌浸润转移的关系

目的:研究基质金属蛋白酶-9(MMP-9)及其相应的组织金属蛋白酶抑制剂-1(TIMP-1)在食管癌组织上的表达及其在细胞浸润转移过程中所起的重要作用。方法:采用免疫组织化学链霉素抗生物素蛋白-过氧化物酶(SP)法检测的50例食管癌组织中MMP-9及TIMP-1的表达。结果:MMP-9在食管癌组织的阳性表达率为76％,其表达与淋巴结转移呈正相关(Pearson列联系数0.343,P<0.05)。TIMP-1在食管癌组织表达的阳性率为30％,其表达与淋巴转移呈负棚关(Pearson列联系数为O.333,P<0.05)。结论:MMP-9阳性表达与食管癌浸润转移呈正相关,TIMP-1阳性表达与食管癌浸润转移呈负相关,二者在食管癌浸润转移中的关系表现为MMP-9促进肿瘤转移,TIMP-1对食管癌有独立的抑制作用。通过检测食管癌组织中的MMP-9及TIMP-1的表达,对预后的评价有一定价值。     

Imbalance between expression of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in invasiveness and metastasis of human gastric carcinoma

AIM: The expressive balance between matrix metalloproteinase-9 (MMP-9) and its tissue inhibitor of metalloproteinase-1 (TIMP-1) plays a critical role in maintaining the degradation and synthesis of extracellular matrix. Loss of such balance is associated with invasion and metastasis of tumors. This study aimed to determine the expression of MMP-9 and TIMP-1 in gastric carcinoma, and the association of the expressive imbalance between MMP9 and TIMP-1 with the invasion and metastasis and prognosis of gastric carcinoma.METHODS: We used immunohistochemistry to determine the expressions of MMP-9, TTMP-1 and proliferating cell nuclear antigen Ki-67 in the gastric specimens taken from 256 patients with primary gastric carcinoma. The patients were followed-up for up to 96 months.RESULTS: No association between the expression of MMP9 and TIMP-1 and patients' sex and age, tumor size and location of gastric carcinoma was observed. The incidence of the positive expression of MMP-9 in cases with tumors invasion to muscularis propria and visceral peritoneum (70.13% and 69.09%, respectively) was significantly higher than that in cases with tumor invasion only to lamina propria or submucosa (42.50 %, P=0.0162). The positive correlation between MMP-9 expression and the depth of tumor invasion was observed (Pearson correlation coefficient=0.2129,P=0.016). Along with the increase of the metastatic station of lymph nodes, the incidence of the MMP-9 expression was increased by degrees; a positive correlation between them was observed (Pearson correlation coefficient=0.2910,P=0.0001). There was also a significant correlation between MMP-9 expression and the TNM stage in gastric carcinoma (Pearson correlation coefficient=0.3027, P＜0.0001). The incidence of MMP-9 expression in stage Ⅱ and Ⅲ/Ⅳ (75.00%and 76.15%, respectively) was significantly higher than those in stage Ⅰ (46.15 %, P＜0.0001). A negative correlation between TIMP-1 immunoreactivity and the depth of invasion,status of lymph node metastasis and TNM stage was observed (Pearson correlation coefficient =-0.1688, -0.3556and -0.3004, P=0.023, ＜0.0001 and ＜0.0001, respectively).Four types of co-expression of MMP-9 and TIMP-1 were observed; i.e. MMP-9 positive but T IMP-1 negative (n=115),both positive (n=52), both negative (n=62) and MMP-9negative but TIMP-1 positive (n=27). The frequency of serosal invasiveness was significant higher in patients with MMP-9 but without TIMP-1 expression than those with other types of the co-expression (P=0.0303). The incidence of lymph node metastasis was highest in patients with MMP-9but without TIMP-1 expression, and lowest in those with TIMP-1 but without MMP-9 expression (P＜0.0001). The survival rate in patients with MMP-9 but without TIMP-1expression was lower than that in those with TIMP-1 but without MMP-9 expression (P=0.0014).CONCLUSION: Our results in gastric carcinoma demonstrated a significant positive association of MMP-9 over-expression with proliferation of tumor cells, the depth of invasiveness,lymph node metastasis and TNM stage, suggesting MMP-9can serve as a molecular marker of tumor invasion and metastasis. We also demonstrate a significant negative relationship of TIMP-1 expression with the depth of invasiveness and lymph node metastasis, which provide a new idea in the tumor biological and genetic treatment.The interaction between MMP-9 and TIMP-1 in the processes of tumor invasion and metastasis is that MMP-9 mainly promotes tumor invasion and metastasis and TIMP-1 inhibits functions of MMP-9. The imbalance between MMP-9 and TIMP-1 expression may suggest the occurrence of tumor invasion and metastasis, predict poor prognosis. For patients with imbalanced MMP-9 and TIMP-1 expression, the optimal treatment scheme needs to be selected.     

Usefulness of MMP-9/TIMP-1 in Predicting Tumor Recurrence in Patients Undergoing Curative Surgical Resection for Gastric Carcinoma

Degradation of the extracellular matrix is an essential step in tumor invasion and metastasis. It involves the actions of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). We evaluated the expression of MMP-9 and TIMP-1 in gastric carcinomas and the relationship between this expression and tumor recurrence. Eighty patients who had undergone curative surgical resection for gastric carcinoma were included. Resected gastric tissue samples were stained immunohistochemically to evaluate the expression of MMP-9 and TIMP-1. TIMP-1 expression was related to the depth of tumor invasion and lymph node metastasis. The proportion of tumors larger than 5 cm, or displaying muscle layer invasion, and the cumulative incidence of tumor recurrence were significantly elevated in patients with tumors expressing TIMP-1. Furthermore, these measures were lowest in patients with no TIMP-1 expression and highest in patients who only expressed TIMP-1. In conclusion, TIMP-1 expression and the balance between expression of MMP-9 and expression of TIMP-1 may be important indicators of tumor progression and predictors of tumor recurrence.     

DNA ploidy analysis and expression of MMP-9, TIMP-2, and E-cadherin in gastric carcinoma

AIM: To investigate DNA ploidy and expression of MMP-9, TIMP-2, and E-cadherin in gastric carcinoma and to explore the mechanism of invasion and metastasis of gastric carcinoma. METHODS: Immunohistochemical methods were used to detect the expressions of MMP-9, TIMP-2, and E-cadherin in 156 cases, including 99 cases of gastric carcinoma, 16 cases of adjacent noncancerous mucosa, 16 cases of distant metastases and 25 cases of metastatic lymph node (LN) from gastric carcinoma. Flow cytometry DNA ploidy and S-phase fraction (SPF) analysis were performed on 57 cases, including 47 cases of gastric cancer, 6 cases of adjacent noncancerous mucosa, and 4 cases of distant metastatic cancer. RESULTS: The expression of MMP-9 was significantly correlated with Lauren's classification, Borrmann's classification, LN metastasis, tumor metastasis, and TNM stage, as well as depth of invasion (all P<0.05). The positive rate was lower in noncarcinoma than in carcinoma (31.3% vs66.7%, P<0.01). The expression of TIMP-2 was significantly correlated with Borrmann's classification, LN metastasis, and the depth of invasion (all P<0.05), The expression of E-cadherin was significantly correlated with differentiation, Lauren's classification, Borrmann's classification, and LN metastasis, as well as the depth of invasion (P<0,01 or P<0.05). E-cadherin was less expressed in carcinoma than in noncarcinoma (42.4% vs87.5%, P<0.01). There was a positive correlation between MMP-9 and TIMP-2 and a negative correlation between MMP-9 and E-cadherin, but no correlation between TIMP-2 and E-cadherin. Also there was a positive correlation between DNA aneuploid rate and differentiation and LN metastasis. SPF that was higher than 15% was positively correlated with tumor size, differentiation and LN metastasis. And there was a significant difference between carcinoma and noncarcinoma in DNA aneuploid rate and SPF. CONCLUSION: With tumor progression and development of heterogeneity, the abnormal expressions of MMP-9, TIMP-2, and E-cadherin or DNA aneuploid rate or high SPF gradually increases, suggesting that they play a crucial role in gastric carcinoma progression.     

Matrix metalloproteinase-2 and tissue inhibitor of metallo-proteinase-2 in colorectal carcinoma invasion and metastasis

AIM: To explore the relationship between matrix metallopr- oteinase-2 (MMP-2) and tissue inhibitor of metallopr- oteinase-2 (TIMP-2) in the development of colorectal carcinoma and to provide a valuable marker for clinical diagnosis. METHODS: Twenty-five patients with colorectal carcinoma underwent surgical resection. Samples were taken from tumor sites and normal tissues. MMP-2 activity was determined by gelatin zymography. Western blot and ABC immunohist-ochemical staining were used to detect the expression levels of MMP-2 and TIMP-2 in normal and colorectal carcinoma tissues. Statistical analyses were performed using the Student's t test and one-way ANOVA. P<0.05 was considered statistically .significant. All the statistical analyses were performed using SPSS 10.0 software. RESULTS: MMP-2 activity could be detected in both normal and colorectal carcinoma tissues. MMP-2 activity in colorectal carcinoma tissues was much higher than that in normal tissues (P<0.05, t=3.916,4.227). MMP-2 activity was positively related to the colorectal carcinoma invasion depth, lymph node metastasis and Duke's stage. Western blot and ABC immunohistochemical staining demonstrated that the expression level of MMP-2 in colorectal carcinoma tissues was much higher than that in normal tissues (P<0.05, t = 9.429), but the expression level of TIMP-2 in colorectal carcinoma tissues was much lower than that in normal tissues (P<0.05, t = 7.329). The MMP-2/TIMP-2 ratio of colorectal carcinoma was much higher than that of normal tissues. With the progression of invasion depth, lymph node metastasis and tumor Duke's stage, the activity and expression level of MMP-2 and TIMP-2 gradually increased, but the MMP-2/TIMP-2 ratio gradually decreased. CONCLUSION: The balance between MMP-2 and TIMP-2 plays a crucial role in the process of colorectal carcinoma invasion and metastasis.     

Overexpression of MMP‐2 and MMP‐9 in esophageal squamous cell carcinoma

Matrix metalloproteinases (MMPs) are known to play important roles in extracellular matrix remodeling during the process of tumor invasion and metastasis. However, little is known about their role in esophageal squamous cell carcinoma (ESCC). Expression of MMP‐2 and MMP‐9 in ESCC was detected in our research. Tissue microarray chip was prepared, consisting of 58 cases of ESCC and corresponding esophageal epithelium tissues. MMP‐2 and MMP‐9 were examined by immunohistochemistry. Overexpression of MMP‐2 and MMP‐9 was found in ESCC (42.1 and 60.3%, respectively), compared with paired distal normal esophageal tissues (22.9 and 8.9%, respectively). Expression of MMP‐2 in ESCC was significantly associated with the tumor invasion depth, tumor‐node‐metastasis stages, and lymph node metastasis. MMP‐2 and MMP‐9 may play important roles in carcinogenesis, and MMP‐2 may act as a biological marker of invasion and lymph node metastasis in ESCC.     

BMP7 Expression in Esophageal Squamous Cell Carcinoma and Its Potential Role in Modulating Metastasis

Background

Our previous study showed that BMP7 revealed significantly higher levels in esophageal squamous cell carcinoma (ESCC) tissues with lymph node metastasis compared with non-lymph node metastasis, using gene expression profiling assays. The roles of BMP7 in ESCC is not fully understood.

Aim

The aim of this study was to investigate the effect of BMP7 on lymph node metastasis of ESCC and to explore its potential mechanism.

Methods

Expression of BMP7 in ESCC tissues was evaluated by immunohistochemistry. BMP7 were down-regulated by RNA interference. The protein and mRNA levels of BMP7 were detected by western blot and RT-PCR, respectively. High content screening and transwell assay were used to identify the metastatic ability of tumor cells.

Results

Positivity of BMP7 staining was 57.5 % in the tissues of primary carcinoma with lymph node metastasis compared to tissues without lymph node metastasis, and expression of BMP7 was significantly higher in the cell lines with highly metastatic capacity than that in the cell lines without metastatic ability. Suppression of endogenous BMP7 expression by siRNA in the highly metastatic cell lines resulted in significant reduction in ability of cell migration and invasion in both in vitro and in vivo studies. In addition, inhibition of BMP7 by siRNA also leads to up-regulation of E-cadherin and down-regulation of MMP-9 in the highly metastatic cell lines.

Conclusions

These findings indicate that BMP7 modulates the expression of E-cadherin and MMP-9, and by which mechanism it may regulate cell migration and metastasis of ESCCs.     

Clinical significance of matrix metalloproteinase-9 expression in esophageal squamous cell carcinoma

AIM: To evaluate the expression of matrix metalloproteinase-9 (MMP-9) and its clinical significance in esophageal squamous cell carcinoma (ESCC). METHODS: The expression of MMP-9 in 208 cases of ESCC was detected by immunohistochemistry (IHC) and its clinical significance in ESCC especially the relationship with the clinicopathological parameters was analyzed. RESULTS: The percentage of positive cases for MMP-9 detected by IHC was 49.0%. MMP-9 was mainly expressed in the cytoplasm of cancer cells especially in the invasive front. Only weak expression was detected in the stromal cells and no expression in non-cancerous mucosa. The expression of MMP-9 was positively correlated with poorer differentiation (P= 0.001<0.01), existence of vessel permeation (P= 0.027<0.05) and lymph node metastasis (P=0.027<0.05). CONCLUSION: The expression of MMP-9 correlates with the cancer cell differentiation, vessel permeation and lymph node metastasis. It may be a novel biomarker for the diagnosis and treatment of ESCC.