MMP-9及TIMP-1在卵巢上皮性肿瘤中的表达

目的 :探讨MMP 9和TIMP 1在卵巢上皮性肿瘤中的表达。方法 :采用免疫组化方法检测 12 5例卵巢上皮性肿瘤及 7例正常卵巢组织中MMP 9和TIMP 1的表达。结果 :MMP 9在交界性 (5 .4 0± 2 .2 8)和恶性卵巢上皮性肿瘤 (6.88± 2 .0 9)中的表达显著高于良性卵巢上皮性肿瘤 (3.80± 1.5 6)和正常卵巢组织 (2 .69± 1.19) (P <0 .0 1) ;TIMP 1在正常卵巢组织、良性、交界性和恶性卵巢上皮性肿瘤中的表达分别为 1.86± 1.10、3.89± 1.11、3.97± 0 .98和 4 .99± 1.70 ,差异有显著性 (P <0 .0 1)。结论 :MMP 9可能参与卵巢上皮性肿瘤的发生和侵袭 ,TIMP 1在卵巢肿瘤的演化过程中除可抑制肿瘤的侵袭和转移外 ,可能还有非MMP 9抑制活性的作用     

基质金属蛋白酶-2在卵巢上皮性肿瘤组织中的表达及意义

目的基质金属蛋白酶-2(MMP-2)mRNA和蛋白在卵巢上皮性肿瘤组织中的表达以及与临床病理特征和预后的关系.方法用半定量逆转录聚合酶链反应技术、链霉菌抗生物素蛋白-过氧化物酶连接法对41例卵巢上皮性癌及26例卵巢良性肿瘤组织中MMP-2mRNA及蛋白的表达分别进行定量和定位分析;应用蛋白印迹法定性检测MMP-2酶原和活性MMP-2在卵巢上皮性肿瘤组织中的表达.结果良、恶性卵巢肿瘤组织中MMP-2mRNA表达分别为0.68±0.48和0.97±1.00,MMP-2蛋白表达阳性率分别为54%和76%,两者分别比较,差异无显著性(P＞0.05).卵巢上皮性癌组织中的活性MMP-2表达阳性率为71%,显著高于卵巢良性肿瘤组织的42%(P＜0.05).手术病理分期为Ⅲ～Ⅳ期卵巢癌患者的活性MMP-2表达阳性率为81%,显著高于Ⅰ～Ⅱ期患者的9例中3例(P=0.01).病情进展患者的活性MMP-2表达阳性率为86%,明显高于无进展患者的19例中10例(P=0.02).结论卵巢上皮性肿瘤普遍存在MMP-2mRNA及蛋白表达,活性MMP-2表达与卵巢上皮性癌侵袭、转移密切相关,是卵巢上皮性癌的一项预后监测指标.     

卵巢上皮性肿瘤组织中KiSS-1、基质金属蛋白酶9和核因子κBp65蛋白的表达及其相关性

目的 探讨KiSS-1、基质金属蛋白酶9（MMP-9）、核因子κB（NF-κB）p65蛋白3者在卵巢上皮性肿瘤组织中的表达及其相关性。方法 采用免疫组化方法检测50份卵巢上皮性癌（卵巢癌）、20份卵巢交界性肿瘤、20份卵巢良性肿瘤和10份正常卵巢组织中KiSS-1、MMP-9、NF-κBp65蛋白的表达,并分析其临床意义及3者间的相关性。结果 KiSS-1蛋白在卵巢癌组织中的阳性表达率（80％）明显高于良性肿瘤组织及正常卵巢组织（分别为35％、10％;P〈0．05）;在卵巢交界性肿瘤组织中阳性表达率（65％）明显高于正常卵巢组织（P〈0．05）。在卵巢癌组织中,KiSS-1蛋白阳性表达率与淋巴结转移有关（P〈0．05）,与手术病理分期、病理类型及病理分级均无关（P〉0．05）;MMP-9蛋白阳性表达率与手术病理分期及淋巴结转移有关（P〈0．05）,而与病理类型及病理分级均无关（P〉0．05）;NF-KBp65蛋白阳性表达率与手术病理分期、病理分级及淋巴结转移有关（P〈0．05）,而与病理类型无关（P〉0．05）。在卵巢癌组织中,KiSS-1与MMP-9、NF．KBp65蛋白表达呈显著负相关关系（rs=-0．547,P〈0．05;rs=-0．414,P〈0．05）;MMP-9与NF-κBp65蛋白表达呈显著正相关关系（rs=0．695,P〈0．05）。结论 KiSS-1基因可能对卵巢癌的转移起一定的抑制作用;KiSS-1基因可能通过抑制MMP-9、NF-κB基因,从而发挥抑制卵巢癌转移的作用。     

Expression of matrix metalloproteinases and related tissue inhibitors in the cyst fluids of ovarian mucinous neoplasms

OBJECTIVES AND METHODS: The growth of an ovarian cystic neoplasm often involves its invasion into and destruction of the extracellular matrix. We examined neoplastic cysts of ovarian mucinous tumors for the presence of matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) using zymography (in situ zymography, gelatin zymography, and casein zymography) and enzyme-linked immunosorbent assay. RESULTS: Matriolytic activity was detected within the cystic contents and cytoplasm of the lining epithelial cells of the cyst by in situ zymography. This intracystic matriolytic activity was thought to originate mainly in the epithelial cells. The activated form of MMP-9 was seen in all carcinoma and borderline fluids and in 7 of 15 adenomas. The concentration of MMP-9 was higher in carcinoma fluids than in borderline and adenoma fluids (P < 0.05). TIMP-1, which specifically binds to MMP-9, was also higher in carcinoma and borderline fluids than in adenoma fluids (P < 0.05). MMP-2 activity was nearly ubiquitously present in all cyst fluids, irrespective of the fluid's histologic category. The amount of MMP-2 was highest in the carcinoma category, although not to a statistically significant degree. TIMP-2, a specific inhibitor for MMP-2, was significantly lower in the borderline category than in the adenoma category. The molar ratios of TIMP-1/MMP-9 (not significant) and TIMP-2/MMP-2 (P < 0.05) were higher in the adenoma category. Expressions of trypsin, MMP-7, and MMP-9 were generally higher in carcinoma and borderline fluids than in adenoma fluids. CONCLUSIONS: These observations indicate the importance of ovarian cystic fluids for analyzing tumor-associated matriolytic activities. The findings suggest that these matriolytic enzymes, together with the presence of their inhibitors, play an important role in the growth of ovarian mucinous tumors.     

Prognostic value of matrix metalloproteinase-9 (gelatinase-B) expression in epithelial ovarian tumors

PURPOSE OF INVESTIGATION: To determine the expression of matrix metalloproteinase-9 (MMP-9) expression in malignant and borderline ovarian tumors and its correlation to prognosis. METHODS: Forty-five patients with primary epithelial ovarian tumors were enrolled in this retrospective study from 1988 to 2002. Only malignant (n = 30) and borderline (n = 15) ovarian tumors constituted the study group. All cases were surgically staged according to FIGO criteria. Patient characteristics and clinico-pathological findings were obtained from hospital records. Paraffin-embedded tissue blocks were treated with MMP-9 immunohistochemical stain. The percentage of the total number of tumors staining positively was categorised and awarded a score of 0 to 4: < 5% as 0, < or = 6-25% as 1, 26-50% as 2, 51-75% as 3 and 76-100% as 4. The intensity of immunostaining was scored on a 3-point scale: 1, weak; 2, moderate and 3, intense. A weighed score for each tumor specimen was produced by multiplying the percentage score with the intensity score and was defined as the 'epithelial MMP-9 score'. Stromal staining was also assessed as weak, moderate and intense. Cases with final epithelial MMP-9 scores < or = 6 and > 6 were then recategorised into two groups, accordingly. Based on degree of stromal staining, cases were recategorised into two final groups as mildly stained and intense or moderately stained. Tumor stages were regrouped as early (Stage I-II) and late (Stage III-IV), respectively. RESULTS: Mean ages of cases with malignant and borderline ovarian tumors were 57.2 +/- 3.1 and 49.7 +/- 2.1 years, respectively. Epithelial MMP-9 scores were higher in malignant tumors compared to borderline tumors (p = 0.014). However, with regard to stromal MMP-9 staining, no significant difference was observed among malignant and borderline tumors (p = 0.113). Among malignant ovarian tumors, epithelial MMP-9 scores did not differ between early versus late-staged and well versus poorly differentiated tumors. Median survival time of cases with epithelial MMP-9 scores < or = 6 and > 6 were 24 months and 32 months, respectively (log-rank: 0.93, p = 0.335). Cases with weak stromal MMP-9 staining had a longer median survival (48 months) compared to cases with moderate or intense stromal MMP-9 staining (24 months, log-rank: 4.46, p = 0.03). CONCLUSION: Epithelial MMP-9 expression generally appears in the malignant form of ovarian tumors compared to borderline tumors. MMP-9 expression in the stroma but not in the epithelium contributes to poor survival in ovarian cancers.     

Expression of matrix metalloproteinase-26 and tissue inhibitors of metalloproteinases TIMP-3 and -4 in benign endometrium and endometrial cancer

OBJECTIVE: Matrix metalloproteinases (MMPs) and their physiological inhibitors, the tissue inhibitors of MMPs (TIMPs), play a key role in tumor cell invasion, angiogenesis, and growth. The aim of this study was to determine the expression and cellular distribution of MMP-26, TIMP-3, and TIMP-4 in endometrial cancers and benign endometrium throughout the menstrual cycle and the correlation with tumor histological subtype, stage, and grade. METHODS: Immunohistochemical analysis using polyclonal antibodies generated against pro- and active MMP-26, and mono- and polyclonal antibodies specific to TIMP-3 and TIMP-4, respectively, was performed. RESULTS: MMP-26, TIMP-3, and TIMP-4 are expressed in endometrial carcinomas (N = 86) and benign endometrium (N = 50) from various stages of the menstrual cycle. Semi-quantitative analysis of staining intensity indicated that endometrial carcinomas expressed more MMP-26, TIMP-3, and TIMP-4 compared to benign endometrium from the postmenopausal period, but not from the secretory phase of the menstrual cycle. The highest staining intensity was associated with endometrial epithelial cells, followed by vascular endothelial cells, myometrial smooth muscle cells, and endometrial stromal cells. Increased staining intensity of MMP-26 and TIMP-3 correlated with grade III tumors and MMP-26 and TIMP-4 with the depth of myometrial invasion in tumors histologically characterized as endometrioid adenocarcinoma, clear-cell, and papillary serous carcinoma staged/graded based on FIGO criteria. CONCLUSION: MMP-26 and TIMP-4 are expressed in endometrium and endometrial carcinoma and their elevated expression and correlation with myometrial invasion suggests that MMP-26 and TIMP-4 may play a key role in endometrial tumor progression.     

Expression of matrix metalloproteinase-9 in squamous cell carcinoma of the uterine cervix-clinicopathologic study using immunohistochemistry and mRNA in situ hybridization

OBJECTIVE: Invasion of the extracellular matrix and blood vessels by malignant neoplasms, with subsequent distant dissemination, is a key event in tumor progression. This process appears to be mediated largely through the action of matrix metalloproteinases (MMPs), a family of proteolytic enzymes produced by both stromal and tumor cells. The role of gelatinases (MMP-2 and MMP-9) in basement membrane and matrix degradation was described in various tumors. We studied MMP-9 protein expression in cervical intraepithelial neoplasia (CIN) and squamous cell carcinoma using immunohistochemistry and detected MMP-9 mRNA using in situ hybridization. METHODS: Fifty squamous cell carcinomas, 10 cases of CIN II-III, and 10 normal cervices were stained for MMP-9, using a monoclonal antibody. The presence of MMP-9 mRNA was studied using in situ hybridization. Results were correlated with patient survival during a follow-up period of up to 167 months (average, 41 months). RESULTS: Immunohistochemical staining of tumor cells for MMP-9 was noted in 36/50 (72%) carcinomas and 5/10 (50%) CIN lesions, but was uniformly absent from the nonneoplastic epithelium adjacent to tumors and from control cervices. Peritumoral staining of stromal cells was observed in 27/50 (54%) carcinomas, but only in 3/10 (30%) CIN lesions and 1/10 (10%) control cervices. The presence of MMP-9 mRNA was detected in tumor cells in 39 (78%) carcinomas and 8 (80%) CIN lesions, but only in 4 (40%) control cervices. An intense signal for MMP-9 mRNA was observed most frequently in carcinomas. MMP-9 mRNA was detected in stromal cells in the majority of cases. However, an intense signal was observed only in stromal cells around invasive tumors. In survival analysis, age (P = 0.016), grade (P = 0. 016), and stage (P = 0.001) showed independent correlation with poor survival. Neither MMP-9 protein expression nor an intense signal for MMP-9 mRNA was associated with poor survival, although the latter was observed more frequently in neoplastic cells of lethal tumors (8/14 tumors vs 11/36 nonlethal tumors). CONCLUSIONS: MMP-9 mRNA and protein expression are elevated in tumor and stromal cells of both high-grade CIN and invasive squamous cell carcinoma of the uterine cervix. Thus, MMP-9 is possibly an early marker of tumor progression in squamous lesions of the cervix. An intense stromal signal for MMP-9 mRNA characterizes some invasive carcinomas. Expression of MMP-9 in cervical carcinoma cells is present in both lethal and nonlethal tumors, consistent with the key role of this proteolytic enzyme in invasion, and does not appear to predict disease outcome.     

Expression of matrix metalloproteinase-26 and tissue inhibitors of metalloproteinase-3 and -4 in normal ovary and ovarian carcinoma

The objective of this study was to determine the spatial expression of matrix metalloproteinases (MMPs) and their physiologic inhibitors, the tissue inhibitor of MMP (TIMP)-3 and TIMP-4, in ovarian carcinoma compared to normal ovaries. Immunohistochemistry was carried out in this study. Tissue sections prepared from normal ovarian tissues from throughout the menstrual cycle (N = 20) and ovarian carcinomas (N = 45) characterized as stage I (N = 5), stage III/IV (N = 40) were immunostained using polyclonal antibodies to the latent and the active form of MMP-26, TIMP-3, and a monoclonal antibody to TIMP-4. Immunoreactive MMP-26, TIMP-3, and TIMP-4 were detected in all the ovarian cell types in normal and tumor tissues. In normal ovarian tissues, theca externa and luteal cells immunostained with high intensity for MMP-26 and TIMPs while theca/granulosa cell staining intensity increased as lutenization progressed. There was low immunostaining of the ovarian stromal and surface epithelial cells for MMP-26, with moderate staining for TIMPs. In the carcinoma specimens, cancer cells and vascular endothelial cells displayed the highest staining intensity compared to adjacent nontumor areas. The immunostaining intensity of MMP-26 and TIMP-3 increased with stage of tumor with the invading tumor cells displaying the strongest immunostaining. MMP-26, TIMP-3, and TIMP-4 are expressed in normal ovarian as well as ovarian tumors with elevated expression in the invasive tumor cells suggesting a potential role for MMP-26 in normal ovary and ovarian cancer biologic function.     

血清基质金属蛋白酶-9测定在诊断卵巢肿瘤和评估预后中的价值

目的 :探讨测定血清基质金属蛋白酶 - 9(MMP - 9)的含量对诊断卵巢上皮癌的价值及它与患者预后的关系。方法 :将卵巢上皮癌 (OEC) 43例 ,卵巢交界性肿瘤(BOT) 12例及卵巢良性肿瘤 (OBT) 2 4例分为 3个研究组 ,2 0例正常妇女为对照组 ,用ELISA法测定各组术前血清中的MMP - 9含量。结果 :(1)OEC、OBT、BOT及对照组血清MMP - 9的中位数分别为 534.6 0、2 79.19、2 0 0 .54、55.56ng L ,上述各组的范围分别为 111.18～ 176 6 .12ng L、16 .38～ 874 .34ng L、2 5.10～ 4 2 3.2 9ng L、11.0 1～ 2 0 1.6 3ng L。OEC组血清MMP - 9水平高于OBT、BOT及对照组 ,差异有显著性 (P <0 .0 5) ;(2 )OEC患者按临床分期、病理分级、组织学类型、淋巴或大网膜转移等影响患者预后的因素分组 ,各组间血清MMP - 9水平无显著性差异。结论 :患者血清MMP - 9水平与卵巢肿瘤的恶性行为有关 ,对诊断有一定的价值 ,但用于判断患者预后的价值有限     

c-Met和MMP-2在卵巢上皮癌中的表达及相关性研究

目的探讨肝细胞生长因子受体(c-Met)和基质金属蛋白酶-2(MMP-2)在卵巢上皮癌中的表达特点及生物学行为关系。方法应用免疫组化S-P法检测50例卵巢上皮癌、15例交界性卵巢上皮肿瘤、20例良性卵巢上皮肿瘤及20例正常卵巢组织中c-Met和MMP-2的表达情况。结果 c-Met和MMP-2在卵巢上皮癌中的阳性表达率分别为84.0%和86.0%,与卵巢上皮癌的组织分化和临床分期有关,而与组织类型无关。c-Met和MMP-2表达具有正相关性(P0.05)。结论 c-Met和MMP-2的表达可能与卵巢上皮癌的发生发展有关,c-Met和MMP-2表达呈正相关,二者可成为观察卵巢上皮癌侵袭进展、转移和预后的指标。     

Arsenic trioxide (As(2)O(3)) inhibits peritoneal invasion of ovarian carcinoma cells in vitro and in vivo

OBJECTIVES: To study the role of arsenic trioxide (As(2)O(3)) in regulating peritoneal invasive activity of ovarian carcinoma cells in vitro and in vivo. METHODS: The effects of As(2)O(3) on human ovarian cancer cell lines (3AO, SW626 and HO-8910PM) migration, invasion and adhesion with tumor cells and human peritoneal mesothelial cells (HPMC) were observed by means of cell migration test, cell invasion test and cell adhesion test. The effects of As(2)O(3) on MMP-2, MMP-9, TIMP-1 and TIMP-2 gene expressions and protein expressions of tumor cells were determined by RT-PCR and ELISA, respectively. In animal experiments, ovarian tumor cells were implanted into abdominal cavity of nude mice and then the nude mice were treated by intraperitoneal injection of different doses As(2)O(3). The foci on the surface of peritoneum were counted. RESULTS: As(2)O(3) inhibited tumor cells migration, invasion and adhesion with HPMC in a dose-dependent manner, while the same treatment enhanced tumor cell-tumor cell interactions. As(2)O(3) inhibited mRNA and protein expressions of MMP-2, MMP-9 and TIMP-2 of tumor cells. In contrast, As(2)O(3) increased mRNA and protein expressions of TIMP-1. As(2)O(3) could reduce tumor cells peritoneal metastasis in nude mice. CONCLUSION: As(2)O(3) inhibits in vitro and in vivo peritoneal invasive activity of ovarian carcinoma cells in a dose-dependent manner. Its anti-invasive activity may be the results of reduced cell motility, inhibited attachment of tumor cells to HPMC and enhanced tumor cell-tumor cell interaction, as well as down-regulation of MMP-2 and MMP-9 levels and up-regulation of TIMP-1 level.     

基质金属蛋白酶及其组织抑制因子在子宫内膜癌中的表达及其意义

目的　研究基质金属蛋白酶 (matrixmetalloproteinases,MMPs) 2、9及其组织抑制因子(tissueinhibitorofmetalloproteinases ,TIMPs) 1、2在子宫内膜癌中的表达 ,探讨其与子宫内膜癌浸润转移的关系。方法　应用链霉菌抗生物素蛋白 过氧化物酶免疫组织化学方法和明胶酶谱法对 37例内膜癌及 7例绝经期妇女子宫内膜组织中MMP 2、MMP 9、TIMP 1、TIMP 2蛋白及其活性进行检测。结果　MMP 2、MMP 9及TIMP 1、TIMP 2蛋白主要分布在内膜癌细胞、血管内皮细胞及绝经期子宫内膜腺上皮细胞中 ,在间质细胞中也有少量表达。内膜癌细胞中 ,MMP 2、MMP 9及TIMP 1蛋白的表达 ,病理分级为G3内膜癌的强阳性率分别为 73%、2 0 %及 6 7% ,高于G2 (13%、0及 2 7% )、G1 者 (均为 0 ,P<0 0 5 ) ;深肌层浸润内膜癌的强阳性率分别为 6 3%、16 %及 6 8% ,高于浅肌层浸润的 8%、0及 0 (P<0 0 1) ;有淋巴结转移者的强阳性率分别为 4例中 4例、4例中 3例及 4例中 4例 ,高于无淋巴结转移者的 2 5 %、0及 2 5 % (P <0 0 5 ) ;手术病理分期为Ⅲ～Ⅳ期者强阳性率分别为 5例中 5例、5例中 3例及 5例中 5例 ,高于Ⅰ～Ⅱ期者的 30 %、0及 30 % (P <0 0 5 ) ;TIMP 2蛋白在不同病理分级、肌层浸润、淋巴结转移和手术病理分期的内膜癌细     

Prognostic significance of stromal metalloproteinase-2 in ovarian adenocarcinoma and its relation to carcinoma progression

OBJECTIVES: MMP-2 expression in ovarian cancer cells has been correlated with poor prognosis. This study attempts to assess the prognostic importance of stromal MMP-2 in patients with ovarian endometrioid and serous adenocarcinoma. METHODS: MMP-2, MMP-2 activator, MT1-MMP, and its inhibitor (TIMP-2) were immunostained in 84 primary epithelial ovarian carcinomas (EOCs) (35 endometrioid adenocarcinomas [ECs] and 49 serous adenocarcinomas [SCs]). Results were correlated to pathological subtypes, tumor stage, grade, size, and to recurrence-free and cancer-specific survival. RESULTS: MMP-2 and stromal MMP-2 were detected in all carcinoma cells of 22.2% of EC and 77.8% of SC tumors. MT1-MMP co-localized with MMP-2. TIMP-2 staining was weak and cytoplasmically distributed in all tumors. Univariant analysis showed expression of stromal MMP-2 significantly associated with advanced stage (P = 0.018), higher grade (P = 0.005), serous subtype (P = 0.02), smaller tumor size at operation (P = 0.001), and higher incidence of recurrence (P = 0.042), but not with the rate of death due to cancer. By multiple Cox proportional hazard regression analysis, patient survival and disease-free survival were significantly related to the presence of stromal MMP-2 in EC but not SC patients (P < 0.05). However, after multivariant analysis, the associations with patient age, tumor stage, grade, and size no longer existed. In stepwise selection, tumor stage remained the most important predictor of patient survival and disease-free survival in ovarian EC and SC, but stromal MMP-2 remained the most important predictor of recurrence-free survival in patients with EC. CONCLUSIONS: Stromal MMP-2 occurs early and may play a role early in EOC invasion. Tumor stage and stromal MMP-2 are important predictors of disease-free survival.     

基质金属蛋白酶-9及基质金属蛋白酶组织抑制物-1表达失衡与宫颈癌局部肿瘤血管生成的关系

目的 :探讨基质金属蛋白酶 - 9(MMP 9)和基质金属蛋白酶组织抑制物 - 1(TIMP 1)在宫颈癌局部肿瘤血管生成中的作用。方法 :采用免疫组织化学SP法检测 75例早期宫颈癌 (ICC)、18例宫颈上皮内瘤样病变 (CIN)和 15例癌旁正常宫颈上皮 (NCE)中MMP 9和TIMP 1的表达情况 ,并检测其中微血管密度 (MVD ,CD3 4 标记 )。结果 :从NCE组到CIN组再到ICC组 ,MMP 9的阳性表达率显著升高 (P <0 0 5 )而TIMP 1未见升高 (P >0 0 5 ) ,并且TIMP 1在ICC组的阳性表达率显著低于MMP 9(P <0 0 1)。MMP 9在ICC组中表达与MVD显著正相关 (r =0 2 87,P <0 0 5 ) ,而TIMP 1与MVD无显著相关性 (r=0 195 ,P >0 0 5 )。宫颈癌中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 0 5 )。结论 :MMP 9和TIMP 1表达失衡可能在宫颈癌局部肿瘤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。检测宫颈癌中MMP 9和TIMP 1表达对进一步了解宫颈癌局部血管生成情况有一定的应用价值。     

MMP-2 and TIMP-2 expression correlates with poor prognosis in cervical carcinoma--a clinicopathologic study using immunohistochemistry and mRNA in situ hybridization.

OBJECTIVE: The spread of malignant neoplasms is closely associated with matrix and basement membrane degradation, mediated by various classes of proteolytic enzymes. Matrix metalloproteinases (MMP) appear to have a key role in the sequence of events that lead to local invasion and metastasis. The present study evaluated the role of matrix metalloproteinase-2 (MMP-2), tissue inhibitor of metalloproteinases-2 (TIMP-2), and membrane-type metalloproteinase (MT1-MMP) in cervical neoplasia. METHODS: We have analyzed 49 uterine cervical squamous cell carcinomas, 10 cases of high-grade cervical intraepithelial neoplasia (CIN II-III), and 10 control cervices for the presence of MMP-2, TIMP-2, and MT1-MMP using in situ hybridization. MMP-2 protein expression was evaluated using immunohistochemistry. Results were analyzed for possible correlation with disease outcome. RESULTS: MMP-2, TIMP-2, and MT1-MMP mRNA were localized to both stromal and tumor cells. However, an intense signal for MMP-2 was detected almost exclusively in tumor cells and was uniformly absent from CIN lesions and control cervices. Conversely, intense signals for TIMP-2 and MT1-MMP were detected in both stromal and tumor cells of invasive carcinomas, more often for the former. As with MMP-2, they were absent from CIN lesions. MMP-2 protein expression was enhanced in tumor cells compared to CIN cases and controls, significantly compared to the latter (P = 0.01). The presence of both MMP-2 and TIMP-2 mRNA in tumor cells correlated with advanced stage (P = 0.003 for MMP-2, P = 0.002 for TIMP-2) and with poor survival (P = 0.003 for MMP-2, P = 0.002 for TIMP-2) in univariate analysis. In addition, their presence in tumor cells intercorrelated (P = 0.002). In multivariate survival analysis, MMP-2 presence retained its association with survival (P = 0.004), in addition to patient age (P = 0.027) and advanced stage (P = 0. 0002). CONCLUSIONS: Both MMP-2 and TIMP-2 have a key role in extracellular matrix invasion in cervical carcinoma, largely through their elaboration by tumor cells. The presence of mRNA for both proteins is interrelated and is associated with poor survival.     

Matrix metalloproteinase-9 expression correlates with prognosis and involved in ovarian cancer cell invasion

Purpose

One of the most important characteristics of ovarian cancer is invasion and metastasis. Matrix metalloproteinases (MMPs) are known to play an important role in cancer cell invasion by mediating the degradation of extracellular matrix (ECM). The activities of MMPs are regulated by tissue inhibitors of metalloproteinases (TIMPs). In this study, we investigated the clinical significance of MMP-2, -7 and -9 and TIMP-1, -2 and -3 expression and MMP-9 functional role in cell invasion and adhesion in ovarian cancer.

Methods

RT-PCR was used to determine mRNA expression of MMP-2, -7 and -9 and TIMP-1, -2 and -3 in ovarian tissues; ELISA was used to detect the serum level of MMP-9; RNA interference (RNAi) was performed to determine the function of MMP-9 in cell invasion and adhesion in ovarian cancer cells.

Results

mRNA expression of MMP-2, MMP-7, MMP-9, TIMP-2 and TIMP-3 and serum level of MMP-9 were significantly high in patients with ovarian cancer. MMP-9 expression was significantly high in patients with advanced ovarian cancer and correlated with poor prognosis. The ability of cells for invasion and adhesion was significantly reduced by treatment of cells with MMP-9 siRNA.

Conclusions

Our results suggest that MMP-9 is a potential prognostic factor for ovarian cancer and could be a novel treatment target in ovarian cancer patients.     

Expression of latent matrix metalloproteinase 9 (MMP-9) predicts survival in advanced ovarian cancer

OBJECTIVE: Matrix metalloproteinases (MMPs) are frequently expressed in malignant tumors and play an important role in tumor invasion and metastasis. MMP-2 and MMP-9 expression has been correlated with poor survival in some tumors, but data for ovarian cancer are lacking, despite clinical trials with MMP inhibitors. The aim of this study was to assess activity of MMP-2 and MMP-9 and correlate it to prognosis in ovarian cancer. METHODS: MMP-2 and MMP-9 gelatinolytic activity was analyzed in 84 patients with advanced ovarian cancer FIGO stage III and 19 benign ovarian tumors by gelatin zymography. MMP-9 immunoreactivity was detected by immunohistochemistry and gelatinolytic activity was localized in ovarian cancer tissue by in situ zymography. RESULTS: were correlated with patient survival, with a median follow-up period of 55 months. Results. Median pro-MMP-9 activity was at 0.00 U/microg protein in benign ovarian tissues and 4.82 U/microg protein in ovarian cancer (P = 0.001); activated MMP-9 was not detected. Pro-MMP-2 expression in benign ovarian tissue did not differ from that of malignant ovarian tissue, whereas active MMP-2 was present in 52% of ovarian cancers, but absent in benign ovarian tissues. Analyzing all patients high pro-MMP-9 activity was associated with short overall survival (P = 0.019) while pro-MMP-2 and activated MMP-2 did not predict overall survival. When analyzing the subgroups of patients with and without residual tumor mass at the time of surgery, pro-MMP-9 was of prognostic value only in the subgroup of patients with no residual tumor mass. In univariate analysis pro-MMP-9 activity, residual tumor mass, age, ascites volume, and grading were of prognostic significance for overall survival. However, in multivariate analyses, including all biological and clinicopathologic variables, only pro-MMP-9 and residual disease remained statistically independent prognostic factors. In situ zymography localized gelatinolytic activity predominantly to the tumor cell nests displaying MMP-9 immunoreactivity. CONCLUSIONS: Pro-MMP-9 gelatinolytic activity, but not active MMP-2 or MMP-9, serves as a useful statistically independent prognostic factor in ovarian cancer FIGO stage III, thus helping to identify ovarian cancer patients with an aggressive form of the disease.     

AQP4,5在卵巢上皮性肿瘤的表达及意义

目的:探讨水通道蛋白4,5(AQP4,5)在卵巢上皮性肿瘤的表达及意义。方法:原位杂交和免疫组化染色检测AQP4 mRNA及蛋白在10例正常卵巢组织、15例卵巢良性上皮性肿瘤、15例卵巢交界性上皮性肿瘤及50例卵巢恶性上皮性肿瘤的分布和表达。结果:AQP4,5 mRNA及蛋白主要于交界性及恶性上皮性肿瘤细胞的胞质和胞膜表达。AQP4,5在恶性及交界性上皮性肿瘤的表达量明显高于良性上皮性肿瘤及正常卵巢组织(P0.05),良性上皮性肿瘤与正常卵巢组织间的表达差异无统计学意义(P0.05)。卵巢癌有腹水者AQP4,5表达量明显高于无腹水者(P0.05)。组织学分级为G2、G3的卵巢癌组织中AQP4,5表达高于G1;Ⅲ、Ⅳ期卵巢癌AQP4表达明显高于Ⅰ、Ⅱ期(P0.05);伴淋巴转移者AQP4明显高于无淋巴转移者(P0.05)。AQP4,5蛋白及mR-NA表达有相关性(P0.05,r=0.487)。结论:AQP4,5高表达可能通过增加肿瘤细胞对水的通透性,在卵巢上皮性肿瘤的发生及进展中起重要作用,并且可能参与卵巢癌腹水的形成。