基质金属蛋白酶MMP-9及其组织抑制剂TIMP-1在卵巢肿瘤中的表达及意义

目的　研究基质金属蛋白酶MMP - 9及组织抑制剂TIMP - 1在卵巢肿瘤中的mRNA表达及与卵巢癌临床病理特征和预后的关系。方法　应用RT -PCR方法检测 4 8例卵巢癌、 2 1例良性卵巢肿瘤及 2 2例正常卵巢组织中MMP - 9及TIMP - 1mRNA的表达情况 ,进行阳性率及半定量的比较 ,并将其结果与临床及病理学资料进行统计学分析。结果　MMP - 9在卵巢癌中表达的阳性率及半定量明显高于正常卵巢组织 ,其表达水平与卵巢癌的手术病理分期及预后有关 ,在Ⅲ -Ⅳ期患者中的表达显著高于Ⅰ -Ⅱ期患者 (P <0 0 5 )。MMP - 9阳性患者累积生存率明显低于阴性者。TIMP - 1的表达在卵巢癌中无明显增高 ,且与临床病理无相关性。MMP - 9/TIMP- 1在卵巢癌中的比值明显高于正常卵巢组织。结论　MMP - 9及MMP - 9与TIMP - 1的平衡失调与卵巢癌的浸润转移密切相关 ,MMP - 9可作为监测晚期卵巢癌患者预后的一个指标。     

细胞外基质金属蛋白酶诱导因子在绒毛和胎盘组织中的表达

目的 探讨细胞外基质金属蛋白酶诱导因子(EMMPRIN)在绒毛及胎盘组织中的表达以及表达部位。方法 分别取36例妊娠6～9周妇女的早孕绒毛组织、7例因病理指征行中期引产妇女的胎盘组织和11例足月妊娠妇女的胎盘组织,免疫组化方法检测绒毛组织和胎盘组织中EMMPRIN的表达部位变化特点。结果 (1)表达部位：EMMPRIN在早孕绒毛组织、中期和足月妊娠的胎盘组织中均有高度表达。在早孕绒毛组织中的表达部位主要集中在绒毛内细胞滋养细胞、合体滋养细胞及细胞滋养层柱细胞;在中期和足月妊娠的胎盘组织中,主要表达于底蜕膜的绒毛外细胞滋养细胞。(2)表达特点：在早孕绒毛组织中细胞滋养细胞、合体滋养细胞和细胞滋养层柱细胞的。EMMPRIN阳性率随妊娠进展逐渐下降。在妊娠中期的胎盘组织中,细胞滋养细胞、合体滋养细胞和细胞滋养层柱细胞的EMMPRIN阳性率分别为5／7、3／7、5／7;在足月妊娠的胎盘组织中,细胞滋养细胞、合体滋养细胞和细胞滋养层柱细胞的EMMPRIN阳性率分别为73％、18％和82％。在中期和足月妊娠的底蜕膜中的EMMPRIN阳性率较弱,且趋于稳定。而早期妊娠阶段,侵入到底蜕膜的绒毛外细胞滋养细胞中。EMMPRIN阳性表达则随孕周进展逐渐增强。结论 EMMPRIN在妊娠早期与胚胎植入有关,在妊娠的中晚期则可能参与妊娠维持。     

Conservative surgery of ovarian endometriosis in infertility

53 patients attending the infertility clinic were operated for ovarian endometriosis. The overall pregnancy rate was 53%. The major benefit of the surgery was that 79% of the pregnancies occurred within the year following the operation.     

子宫内膜异位症中膜型1-基质金属蛋白酶和基质金属蛋白酶组织抑制因子-1表达的研究

目的探讨膜型1-基质金属蛋白酶（MT1-MMP）和基质金属蛋白酶组织抑制因子-1（TIMP-1）在子宫内膜异位症发生中的作用.方法皖南医学院附属弋矶山医院2003-07-2004-04采用免疫组化SP方法研究25例子宫内膜异位症患者的异位内膜组织和22例正常子宫内膜组织中的MT1-MMP和TIMP-1蛋白的表达情况.结果子宫内膜异位症组中的MT1-MMP蛋白表达水平明显高于对照组（P＜0.05）,TIMP-1蛋白表达水平在两组之间比较差异无显著性意义.结论MT1-MMP在子宫内膜异位症的发生发展中起一定的作用.     

卵巢子宫内膜异位症与卵巢恶性肿瘤的相关性分析

目的卵巢子宫内膜异位症（EM）是常见的妇科良性疾病,具有潜在的恶变可能。本研究通过对卵巢EM恶变、合并EM及未合并EM的卵巢恶性肿瘤病例的分析,了解卵巢EM恶变与卵巢恶性肿瘤的关系。方法 回顾性分析新疆医科大学第一附属医院2003年1月至2010年12月经病理确诊的原发性卵巢恶性肿瘤患者共362例,根据卵巢EM恶变诊断标准及病理结果,将EM恶变的17例患者分为A组,其他仅合并卵巢EM的卵巢恶性肿瘤16例患者分为B组,未合并卵巢EM的卵巢恶性肿瘤329例为C组,从卵巢恶性肿瘤的临床病理资料对三组进行对照分析。同期在本院经手术确诊的卵巢EM患者共1 946例。结果A、B组临床症状多以腹痛为主,其次为盆腔包块;从临床分期来看,A、B组以Ⅱ期居多,分别占70.6%、56.5%,C组以Ⅲ期为多,占47.7%;从组织类型来看,A、B组多为透明细胞癌（分别为70.6%、56.2%）,而C组则以浆液性腺癌（50.2%）为主。三组在一般特征、临床分期及病理组织分类的分布差异均有统计学意义。结论卵巢EM恶变的临床症状以腹痛为多,其次为盆腔包块,肿块直径超过9 cm,且CA125水平多在200 U/ml以上;卵巢EM恶变及卵巢恶性肿瘤合并EM病例中早期患者比例较高,具有年轻化（尤其是卵巢内异症恶变患者）的特点,且多为卵巢透明细胞癌和子宫内膜样癌;卵巢EM恶变的诊断与组织病灶程度、临床分期可能有关,卵巢EM病灶恶变可能来源于透明细胞癌和子宫内膜样癌,因此卵巢EM可被认为是卵巢恶性肿瘤的危险因素。     

基质金属蛋白酶MMP-2 MMP-9及其抑制因子TIMP-1TIMP-2在子宫内膜异位症中的表达及意义

目的　研究基质金属蛋白酶MMP 2、9和组织抑制因子TIMP 1、2在子宫内膜异位症中的表达及意义。方法　 2 0 0 0年 3月至 2 0 0 2年 4月应用免疫组化S P法检测卵巢巧克力囊肿 4 5例的异位内膜和其中 2 0例在位内膜 ,以及 2 2例正常子宫内膜中MMP 2、9及TIMP 1、2的表达。结果　异位内膜组织中MMP 2、9和TIMP 1、2的表达均显著高于在位内膜和正常内膜 (P <0 0 1)。在位内膜和正常子宫内膜组织细胞中的表达率比较 ,差异无显著性 (P >0 0 5 )。子宫内膜异位症组织中MMP 2、9的表达与侵袭程度正相关。TIMP 1、2的表达则与侵袭程度呈负相关。结论　MMP 2、9是检测子宫内膜异位症较好的分子标志 ,人工诱导TIMP 1、2或阻断MMP 2、9的表达可能抑制内异症的发生发展 ,有望成为子宫内膜异位症治疗新的辅助手段     

The role of extracellular inducer of matrix metalloproteinases in premature rupture of membranes

Objective: To investigate the role of matrix metalloproteinases (MMP-2, MMP-9) and their inducer (CD147) in premature rupture of membranes (PROM) at term labor.

Methods: In a cross-sectional study, 24 women aged 19–39, with 37–40-week pregnancy, and no clinical and histological signs of chorioamnionitis, were divided into two groups with and without PROM. The histological and immunohistochemical study of the fetal membranes was performed with polyclonal rabbit antibodies to MMP-2/MMP-9 and monoclonal rabbit antibodies to CD147.

Results: The analysis of MMP revealed the increase of MMP-9 expression in the amniotic epithelium during premature membrane rupture both in rupture area, and beyond it, and increased MMR-2 expression in the mesodermal cells. We also found high level of CD147 in the amniotic epithelium in PROM group. The above-mentioned changes were found in all areas of fetal membranes, regardless of the rupture localization.

Conclusions: The study results demonstrate the increased expression of MMR-2 and MMR-9, which regulate the catabolism of fetal membrane extracellular matrix proteins, in amniotic membranes of women with PROM at term labor. The increased expression of CD147 may be one of the mechanisms triggering PROM in the absence of infection.     

子宫内膜异位症相关性卵巢癌的研究现状及展望

子宫内膜异位症(内异症)是最常见的妇科疾病之一。内异症恶变与卵巢透明细胞癌和卵巢子宫内膜样癌存在密切联系,甚至被认为是后者的癌前病变。既往临床研究显示内异症相关性卵巢癌(endometriosis associated ovarian carcinoma,EAOC)患者有某些特殊的临床病理特点,预后相对较好;基础研究发现某些特殊的基因异常表达与其相关。后续研究应着重于从EAOC发现新的分子分型靶点,以便指导临床筛选内异症恶变高危人群、预测疾病进展、实现此类卵巢癌的精准分型和分层管理。     

A clinicopathologic study on the association of endometriosis and carcinoma of the ovary using a scoring system

Two-hundred and thirty-five cases of epithelial ovarian carcinoma were studied with a newly devised scoring system for endometriosis consisting of both clinical and histopathologic findings, in order to evaluate the association with endometriosis. Fifty cases (21.3%) of all carcinomas evaluated were judged to be associated with endometriosis. The patients with endometriosis were younger and their clinical stage was significantly earlier than those without endometriosis. The predominant histologic subtype was clear cell carcinoma and the histologic grade was mostly 1 or 2 in the tumors with endometriosis. No prognostic difference was noted between the cases associated with endometriosis and those without endometriosis in stage 1 and 2 disease. In conclusion, the actual frequency of the association of endometriosis with ovarian carcinoma is higher than supposed and almost half of clear cell carcinomas are definitely related to endometriosis, and the cases of ovarian carcinoma associated with endometriosis occur in younger patients, and are of earlier stage and lower histologic grade, but the association of endometriosis does not seem to otherwise influence prognosis.     

Expression of apoptosis-related proteins in peritoneal, ovarian and colorectal endometriosis

Endometriosis is defined as the presence of endometrial glands and stroma outside the uterus. Apoptosis, a physiological process by which multicellular organisms eliminate superfluous cells, is altered in tumor tissue. Here we studied the expression of the apoptosis-related proteins p53, bcl-2, bax, p21 and fas in proliferative (n = 9) and secretory (n = 9) endometrium, and in peritoneal (n = 11), ovarian (n = 20) and colorectal (n = 20) endometriosis, by qualitative and semi-quantitative immunohistochemical methods using the percentage of positive cells and HSCORE analysis.

In endometrium, p53, p21 and fas expression was low, whereas bax and bcl-2 expression was elevated. Using HSCORE analysis, only bcl-2 expression varied during the menstrual cycle (48.9 ± 34.2% in the proliferative phase, 11.5 ± 24.7% in the secretory phase, p = 0.01).

Using HSCORE analysis, p53 expression was higher in ovarian endometriosis than in peritoneal (p < 0.0001) and colorectal endometriosis (p = 0.03). P21 expression was higher in ovarian endometriosis than in peritoneal (p = 0.01) and colorectal endometriosis (p = 0.01). Bcl-2 expression was lower in ovarian endometriosis than in peritoneal (p = 0.0002) and colorectal endometriosis (p < 0.0001). Fas expression was higher in peritoneal endometriosis than in ovarian (p = 0.02) and colorectal endometriosis (p = 0.008).

In conclusion, these results confirm the involvement of apoptosis in the pathogenesis of endometriosis. Moreover, expression of apoptosis-related proteins varies according to the location of endometriosis suggesting the involvement of different apoptotic pathways.     

上皮性卵巢肿瘤细胞外基质的表达及意义

目的 :探讨上皮性卵巢肿瘤细胞外基质重要成分纤连蛋白、层粘蛋白和IV型胶原蛋白成分表达及改变的意义。方法 :采用免疫组化S P法分别研究在良性卵巢上皮瘤、交界性卵巢上皮瘤及上皮性卵巢癌中纤连蛋白、层粘蛋白和IV型胶原蛋白的表达。结果 :1.良性卵巢上皮瘤、交界性卵巢上皮瘤及上皮性卵巢癌中 ,这 3种成分表达呈由高向低的趋势 ,呈连续线形、间断线形、碎片状及缺失表达 (P <0 .0 5 ) ;2 .上皮性卵巢癌纤连蛋白、层粘蛋白和IV型胶原蛋白表达与临床分期、病理分级、转移及预后有关 (P <0 .0 5 ) ,三者表达与病理类型无关 (P >0 .0 5 ) ;3.上皮性卵巢癌中纤连蛋白、层粘蛋白和IV型胶原蛋白表达呈一致性 (P <0 .0 5 )。结论 :纤连蛋白、层粘蛋白和IV型胶原蛋白的改变与上皮性卵巢癌的病理分级、临床分期、转移和预后有关 ,三者对肿瘤细胞均有屏障作用 ,其阳性表达减低或缺失表达表明基膜受损严重 ,预后差 ,可作为判断预后的指标之一。     

子宫内膜异位症诊治中有争议的几个问题

子宫内膜异位症(EM)是一种雌激素依赖的慢性疾病,在育龄期女性中发病率达10％～15％.其病因不明,保守治疗后容易复发,难以根治,有恶变的风险.因此,EM需要长期管理. 国内外EM诊治指南中的很多建议都是基于专家共识[1],缺乏高质量的证据支撑.在EM患者的诊治中,很多问题还存在争议,需进一步明确.     

卵巢癌合并子宫内膜异位症病例分析

目的分析卵巢癌病例中子宫内膜异位症的发生情况及其相互关系。方法 对210例原发性卵巢恶性肿瘤中合并有子宫内膜异位症的患者进行回顾性分析。结果 原发性卵巢恶性肿瘤合并子宫内膜异位症25例，发生率为11．9％，其中内膜样癌12例，透明细胞癌6例，黏液性4例，浆液性2例，其他类型1例。结论子宫内膜异位症与卵巢内膜样癌和透明细胞癌关系密切，内膜异位症病灶恶变可能是这两型卵巢癌的来源之一。     

Matrilysin (matrix metalloproteinase 7) in parturition, premature rupture of membranes, and intrauterine infection

OBJECTIVE: Matrix metalloproteinases are enzymes capable of degrading extracellular matrix components. Matrilysin (matrix metalloproteinase 7), a novel member of this family, degrades fibronectin and proteoglycans. The objective of this study was to determine whether parturition (either term or preterm), premature rupture of the membranes, and microbial invasion of the amniotic cavity are associated with changes in the amniotic fluid concentration of matrilysin. STUDY DESIGN: A cross-sectional study was conducted with 275 women in the following categories: (1) second trimester, (2) term not in labor, (3) term in labor, (4) term with microbial invasion of the amniotic cavity, (5) preterm labor with intact membranes without microbial invasion of the amniotic cavity who delivered at term, (6) preterm labor without microbial invasion of the amniotic cavity who delivered preterm, (7) preterm labor with microbial invasion of the amniotic cavity, (8) preterm premature rupture of membranes with and without microbial invasion of the amniotic cavity, and (9) term premature rupture of membranes not in labor and without microbial invasion of the amniotic cavity. Matrilysin concentrations were measured with a sensitive specific immunoassay that was validated for amniotic fluid. RESULTS: Matrilysin was detectable in 97.4% (268/275) of the samples. The concentration of matrilysin increased with advancing gestational age (r = 0.8; P <.001). Parturition at term was not associated with a significant increase in amniotic fluid concentration of matrilysin. Preterm parturition in the absence of microbial invasion of the amniotic cavity was associated with a significant increase in amniotic fluid concentration of matrilysin (preterm labor with preterm delivery: median, 1.7 ng/mL; range, 0.45-21.6 mg/mL; vs preterm labor with term delivery: median, 1.2 ng/mL; range, 0.17-42. 1 ng/mL; P <.05). Premature rupture of membranes without microbial invasion of the amniotic cavity (either term or preterm) was not associated with a significant change in the amniotic fluid matrilysin concentration. Intra-amniotic infection was associated with a significant increase in amniotic fluid matrilysin among both patients with preterm labor and patients with preterm premature rupture of membranes (preterm labor with microbial invasion of the amniotic cavity: median, 3.2 ng/mL; range, 0.16-21.9 ng/mL; vs preterm labor and delivery without microbial invasion of the amniotic cavity: median, 1.7 ng/mL; range, 0.45-21.6 ng/mL; vs preterm labor with term delivery: median, 1.2 ng/mL; range, 0.17-42. 1 ng/mL; P <.01 for each comparison; and preterm premature rupture of membranes without microbial invasion of the amniotic cavity: median, 1.7 ng/mL; range, 0.29-13.9 ng/mL; vs preterm premature rupture of membranes with microbial invasion of the amniotic cavity: median, 3.6 ng/mL; range, 0.59-20.3 ng/mL; P <.01). CONCLUSION: Matrilysin is a physiologic constituent of amniotic fluid, and its concentration increases with advancing gestational age. Microbial invasion of the amniotic cavity in preterm gestations was associated with a significant increase in amniotic fluid concentration of matrilysin. Matrilysin therefore may play a role in the host defense mechanism.     

Significance of matrix metalloproteinases in the pathophysiology of the ovary and uterus

Matrix metalloproteinases (MMP) are capable of degrading a variety of extracellular matrix (ECM) proteins and are also involved in the processing of a number of bioactive molecules. Our findings indicate that the functions of MMP in the ovary and uterus are organ-specific and time-dependently vary during the reproductive cycle. Prolactin induces structural luteolysis indicated by loss of luteal weight, protein and DNA within 36 h after pretreatment with ergot alkaloid. MMP activation appears crucial for the selective depletion of protein during luteal involution, which entails loss of ECM accompanied by apoptosis. During GnRHagonist-induced luteolysis, this response was also associated with marked increases in MMP-2, which degraded collagen type IV, and MT1-MMP, which in addition to activating MMP-2 also degrades collagen type I, III and V. We also found that the level of MT1-MMP and MMP-2 expression in the human CL is greater during the late luteal phase than during either the early mid luteal phases or during gestation, respectively. That dehydroepiandrosterone (DHEA) treatment caused the formation of cysts from antral follicles in the ovaries of immature rats while depressing MMP-2 collagenolytic activity and enhancing lysyl oxidase expression highlights the importance of collagen degradation in the process of ovulation and suggests that changes in the activities of these enzymes play a key role in ovarian cystogenesis in polycystic ovary syndrome patients. Furthermore, immunohistochemical analyses showed that MT1-MMP and FasL co-localize with TdT-mediated dUTP-biotin nick endlabeling (TUNEL)-positive apoptotic granulosa cells in rats treated with DHEA, that the Fas/FasL/Caspase-8 (death receptor-dependent) pathway is pivotal for follicular atresia and that increased levels of MT1-MMP likely play an important role in tissue remodeling during follicular atresia. After parturition, the uterus undergoes involution, a conspicuous feature characterized by a rapid reduction in the collagen content mediated by degradation of extracellular collagen bundles. Our findings strongly suggest that MT1-MMP, MMP-2 and MMP-9 are each time-dependently regulated and play important roles in tissue remodeling during postpartum uterine involution.