基质金属蛋白酶在卵巢癌侵袭转移中的研究进展

侵袭和转移是卵巢癌患者死亡的直接原因.基质金属蛋白酶(MMPs)通过降解细胞外基质(ECM)在卵巢癌侵袭转移中发挥重要作用,深入研究MMPs降解ECM的机制,选择针对MMPs的抑制物来治疗卵巢癌的转移是一个很有希望的目标.     

基质金属蛋白酶在卵巢癌侵袭转移中的研究进展

侵袭和转移是卵巢癌患者死亡的直接原因,基质金属蛋白酶（MMPs）通过降解细胞外基质（ECM）在卵巢癌侵袭转移中发挥重要作用,深入研究MMPs降解ECM的机制,选择针对MMPs的抑制物来治疗卵巢癌转移是一个很有希望的目标。     

基质金属蛋白酶与宫颈癌

基底膜(BM)、细胞外基质(ECM)的降解是肿瘤侵蚀正常组织和开始转移的信号.基质金属蛋白酶(MMPs)是人体内一组降解ECM的关键酶系,通过探讨MMPs在肿瘤演进中的功能和相互调控及对MMPs与宫颈癌的相关研究,提出检测MMPs将成为宫颈癌预防、早期诊断、判断预后和寻找早期终止疾病方法的新指针.     

基质金属蛋白酶与宫颈癌

基底膜(BM)、细胞外基质(ECM)的降解是肿瘤侵蚀正常组织和开始转移的信号。基质金属蛋白酶(MMPs)是人体内一组降解ECM的关键酶系，通过探讨MMPs在肿瘤演进中的功能和相互调控及对MMPs与宫颈癌的相关研究，提出检测MMPs将成为宫颈癌预防、早期诊断、判断预后和寻找早期终止疾病方法的新指针。     

基质金属蛋白酶及其组织抑制物与卵巢癌的侵袭和转移

卵巢癌是最常见的女性恶性肿瘤之一，5年存活率低，与其侵袭和转移的特性有关。细胞外基质(extracellular matrix，ECM)在肿瘤的侵袭和转移中起了关键性的作用，ECM的降解主要依靠蛋白水解酶，基质金属蛋白酶是较为重要的一类。大量实验表明基质金属蛋白酶(matrix metalloproteinases，MMPs)介导的细胞外基质的降解对肿瘤的侵袭起着极为重要的作用，而基质金属蛋白酶的组织抑制剂(tissue inhibitor of matrx metalloproteinases,TIMPs)可抑制MMPs的活性，MMPs和TIMPs的平衡失衡可导致肿瘤的浸润转移。本文就近年来有关MMPs的TIMPs在卵巢癌浸润和转移中的作用作一综述如下。     

基质金属蛋白酶及其组织抑制物与妇科肿瘤的侵袭和转移

细胞外基质的降解是肿瘤侵袭、转移的重要信号和途径,基质金属蛋白酶(MMPs)是溶解基质的一组重要酶类,金属蛋白酶组织抑制物(TIMPs)是MMPs的特异性抑制物.两者的表达、代谢平衡调节与宫颈癌、卵巢癌、子宫内膜癌浸润转移、生理病理和临床预后有密切关系.MMPs-TIMPs调节失衡、细胞外基质降解,以及基底膜消失,均可促进妇科恶性肿瘤发生浸润转移.MMPs、TIMPs表达量的检测可作为早期诊断、监测妇科恶性肿瘤的理想标志物,并可针对其平衡采取相应的肿瘤治疗措施.     

基质金属蛋白酶及其组织抑制物与妇科肿瘤的侵袭和转移

细胞外基质的降解是肿瘤侵袭、转移的重要信号和途径，基质金属蛋白酶（MMPs)是溶解基质的一组重要酶类，金属蛋白酶组织抑制物（TIMPs)是MMPs的特异性抑制物。两者的表达、代谢平衡调节与宫颈癌、卵巢癌、子宫内膜癌浸润转移、生理病理和临床预后有密切关系。MMPs-TIMPs调节失衡、细胞外基质降解，以及基底膜消失，均可促进妇科恶性肿瘤发生浸润转移。MMPs、TIMPs表达量的检测可作为早期诊断、监测妇科恶性肿瘤的理想标志物，并可针对其平衡采取相应的肿瘤治疗措施。     

基质金属蛋白酶在生殖系统中的研究现状

基质金属蛋白酶(matrix metalloproteinase,MMPs)在生殖系统中大量表达,通过对细胞外基质(extracellular matrix,ECM)的降解作用精密调控子宫内膜的脱落、排卵过程及胚胎种植等,最新研究显示其与辅助生殖技术控制性超排卵(COH)中内膜容受性降低有关,同时可能参与多囊卵巢综合症(PCOS)的发生、发展。     

肿瘤坏死因子α对子宫内膜细胞基质金属蛋白酶9及其组织抑制物3蛋白表达的调控

基质金属蛋白酶（MMP）及其组织抑制物（TIMP）,是调控细胞外基质降解的主要酶类之一,可能是参与胚胎着床过程中细胞外基质降解的重要调节因素.有研究表明,肿瘤坏死因子α（TNF-α）对胚胎着床有重要的调节作用,但是否能调控子宫内膜细胞MMP及TIMP蛋白的表达,目前尚不明确.本研究通过检测不同浓度TNF-α作用于离体的子宫内膜后,子宫内膜细胞MMP-9及TIMP-3蛋白表达的变化,探讨在胚胎着床过程中,TNF-α调控MMP及TIMP蛋白作用的可能因素.     

妊娠期尿液基质金属蛋白酶9的变化分析

基质金属蛋白酶(matrix metalloproteinases, MMPs)参与细胞外基质降解,导致宫颈成熟、扩张及胎膜破裂.MMP-9是妊娠宫颈组织、胎盘、胎膜的主要MMPs.MMP-9在妊娠末期由羊膜、滋养细胞和蜕膜细胞选择性表达,并且是分娩过程中表达最主要的MMPs.MMP-9时间上选择性的表达,使其成为最有潜力的分娩启动的生化指标.本研究通过测定妊娠不同时期妇女尿液MMP-9的浓度,探讨了MMP-9在妊娠期的变化规律.     

Molecular mediators of implantation.

Because cytotrophoblastic cells (CTB) from first-trimester placenta form columns of invasive CTB they have been considered as a model for blastocyst implantation. This invasive behaviour is due to the ability of CTB to secret matrix metalloproteinases (MMPs) because tissue inhibitor of MMP (TIMP) inhibits their invasiveness. Although CTB behave like metastatic cells, in vivo they are only transiently invasive (first trimester) and their invasion is normally limited only to the endometrium and to the proximal third of the myometrium. This temporal and spatial regulation of trophoblast invasion is believed to be mediated in an autocrine way by trophoblastic factors and in a paracrine way by uterine factors. Several types of regulators have been investigated: hormones, extracellular matrix (ECM) glycoproteins and cytokines or growth factors. This review is not intended to be an exhaustive catalogue of all the potential regulators but is aimed at describing the mechanism of action of certain factors relevant in trophoblast-endometrial interactions.     

基质金属蛋白酶9在正常及病理妊娠中的作用

基质金属蛋白酶(MMPs)是一种分解细胞外基质(ECM)组分的锌依赖性蛋白酶,其活性受金属蛋白酶组织抑制剂(TIMPs)的抑制。MMPs通过降解ECM参与众多组织重塑过程。妊娠过程的顺利进行有赖于滋养细胞侵入子宫内膜并将胚胎植入宫腔内,通过侵入血管内皮使血管重塑,满足胎盘血流供应。MMP-9通过发挥蛋白酶的功能降解ECM,在滋养细胞侵入、胎盘血管重塑以及分娩过程中发挥重要作用。MMP-9与其抑制剂TIMP-1调节失衡与早期自然流产、早产、妊娠期高血压疾病、妊娠期糖尿病等病理妊娠过程有关。综述MMP-9在正常及病理妊娠中的研究进展,明确ECM蛋白酶领域的最新知识将有利于为干预病理妊娠过程提供创新性思路。     

蜕膜基质细胞条件培养液对滋养细胞浸润功能的影响

目的:探讨蜕膜基质细胞条件培养液(DSCM)对滋养细胞浸润力的影响。方法:体外培养人早孕正常蜕膜基质细胞,收集DSCM处理早孕滋养细胞系(B6Tert)。应用浸润实验分析B6Tert细胞浸润力的改变,采用RT-PCR与明胶酶谱技术检测B6Tert细胞中基质金属蛋白酶(MMPs)的表达变化。结果:DSCM浓度较低时(占细胞培养液5%),可促进B6Tert细胞的浸润力与该细胞MMP-2mRNA及pro-MMP-2的表达;反之,高浓度的DSCM(20%)则抑制滋养细胞的浸润力与MMP-2的表达,差异有统计学意义(P<0.05)。DSCM不影响B6Tert细胞中MMP-9的表达。结论:早孕DSCM可能通过调节滋养细胞中MMP-2的表达影响滋养细胞的浸润能力。     

CXCR2 is decreased in preeclamptic placentas and promotes human trophoblast invasion through the Akt signaling pathway

IntroductionCXCR2, the receptor of the CXC chemokines, plays a critical role in cell migration and invasion in many types of cancer. It is unclear what impact CXCR2 may have on Preeclampsia (PE), a pregnancy-specific disease, which is related to insufficient trophoblast invasion. The aim of this study was to investigate the expression pattern of CXCR2 in the placentas of healthy and PE pregnancies, and to investigate the molecular mechanism of CXCR2 involvement in the development of PE.MethodsCXCR2 expression levels in newly delivered placentas from 38 pregnant women with PE and 21 healthy pregnant women were detected using quantitative real-time PCR, immunohistochemistry and Western blot assays. The effect of CXCR2 on trophoblast invasion and the underlying mechanisms were examined in two trophoblast cell lines (HTR-8/SVneo and TEV-1 cells).ResultsCXCR2 mRNA and protein expression levels were significantly decreased in preeclamptic placentas than normal control. The invasive abilities of the two trophoblast cell lines were significantly inhibited when CXCR2 was silenced, but that CXCR2 overexpression promoted trophoblast cells invasion. In addition, silencing CXCR2 reduced the expression of matrix metalloproteinase 2 and 9 (MMP2 and MMP9) and phosphorylated Akt (p-Akt). Furthermore, an Akt inhibitor suppressed the expression of MMP-2 and MMP-9.DiscussionOur results suggest that the decreased CXCR2 may contribute to the development of preeclampsia through impairing trophoblast invasion by down-regulating MMP-2 and MMP-9 via the Akt signaling pathway.     

Factors regulating trophoblast invasion

Implantation in the human is unique. This uniqueness is characterized on the maternal side by a spontaneous and massive decidualization of the endometrium and on the embryonic side by an almost unlimited invasive potential. Human embryos express an intrinsic invasive potential, which allows them to implant almost anywhere except in the endometrium because it protects itself from implantation. Human implantation is thus only possible during a limited period of time known as the implantation window. This mini review stresses the importance of studying trophoblast invasion into the endometrium as a model for human implantation. Cytotrophoblastic cells (CTB) can easily be isolated from first-trimester legal abortions and retain their invasive behavior when cultured in vitro. This model shows that matrix metalloproteinases (MMPs) are produced by CTB and are instrumental to their invasive behavior. Embryo implantation and tumor invasion use these same biochemical mediators for invasion. However, in contrast to tumor invasion, trophoblast invasion is limited both in time and space: it occurs during the first trimester of pregnancy and invasion does not go beyond the proximal third of the myometrium. Factors regulating MMP expression are of maternal and fetal origin.     

Influences of extracellular matrix and of conditioned media on differentiation and invasiveness of trophoblast stem cells

Embryo implantation in the human and rodents relies on the trophoblast's ability to invade into the uterine stroma, partly depending on proteinases degrading components of basement membrane and underlying extracellular matrix (ECM). We have utilized mouse trophoblast stem (TS) cells (Science, 1998, 282:2072) to study trophoblast invasion and trophoblast-ECM interactions in vitro. On plastic in fibroblast-conditioned medium containing fibroblast growth factor (FGF)-4 and heparin, the cells remain proliferative but display increased differentiation in media without these components. Marker gene expression (Eomes, Pl-1, Tpbp) and invasion assays showed that TS cells exhibit increased invasive capacity when differentiating into giant cells and spongiotrophoblasts in unconditioned media without FGF-4 and heparin. Concomitantly, an up-regulation of matrix metalloproteinases (MMP)-9 and -14 was observed. Culture on gels of the basement membrane-like Matrigel resulted in striking changes in morphology and gene expression. Differentiating TS cells invaded into this ECM in a three-dimensional culture, while in turn ECM contact enhanced differentiation of TS cells and up-regulated the expression of MMP-9 and its tissue inhibitor (TIMP)-3. These findings implicate that the TS cell culture system used in this study can be utilized as a model for studying the regulation of trophoblast-ECM interactions, differentiation, and invasion in vitro.     

The proprotein convertase furin in human trophoblast: Possible role in promoting trophoblast cell migration and invasion

Furin, a proprotein convertase (PC), is ubiquitously expressed and implicated in many physiological and pathological processes. This study is aimed to identify the role of furin in human trophoblast invasion and migration. Furin was found to be highly expressed in placental villi of both rhesus monkeys and human beings during early pregnancy. Specifically, furin was found in trophoblast column and trophoblast shell, regions where highly invasive cytotrophoblast cells invade the maternal decidua during human placentation. To determine whether furin plays any role in trophoblast invasion and migration, we employed human extravillous HTR8/SVneo cells in Matrigel invasion and transwell migration assays. Knocking-down furin expression by siRNA significantly inhibited invasion and migration of HTR8/SVneo cells (P < 0.01), with corresponding decrease of matrix metalloproteinase-9 (MMP-9) activities. In contrast, over-expression of furin markedly increased cell invasion and migration (P < 0.01), accompanied by significant increase of MMP-9 activities. Furthermore, furin siRNA significantly increased the levels of both tissue inhibitors of MMPs (TIMP)-1 and -2. Our results suggest that furin may play an important role in the invasion and migration of human trophoblast cells during early pregnancy.     

Metalloproteinases and human placental invasiveness

Matrix metalloproteinases (MMPs) are the main mediators of extracellular matrix degradation. This confers an important role to these enzymes in the invasion of the trophoblast cells where their expression are spatiotemporally regulated. The regulation of MMPs activity is complex and is established at different levels. Their expressions depend on various cis-elements in their gene promoter, and are induced or repressed by various soluble factors. After expression and secretion, the proMMPs must be activated through an activation network. Then, the enzyme activity is regulated by inhibition or stabilization. In this review, we shall focus on the expression, the role in invasion and the regulation of MMPs in the human placenta.     

Expression of Gadd45α in human early placenta and its role in trophoblast invasion

Objectives

Well-controlled trophoblast migration and invasion at the maternal–foetal interface are crucial events for normal placentation and successful pregnancy. Growing evidence has revealed that growth arrest and DNA damage-inducible 45 alpha (Gadd45α) participates in tumour migration and invasion as a tumour suppressor. However, the expression and function of Gadd45α in trophoblasts is unknown. This study aimed to determine the Gadd45α expression and function in the human first trimester placenta and identify the underlying mechanisms.

Methods

The expression of Gadd45α in human first trimester placenta was determined using immunohistochemistry. HTR8/SVneo cell line was used to investigate the effects of Gadd45α on proliferation, apoptosis, migration/invasion, matrix metalloproteinase (MMP)2/9 activities, and tissue inhibitor of metalloproteinase (TIMP)1/2 expression using cell proliferation assays, flow cytometric analysis, transwell migration/invasion assays, gelatin gel zymography, and western blotting, respectively. Moreover, a placental villous explant model was employed to verify its functions in placentation.

Results

Gadd45α was strongly expressed in syncytiotrophoblasts and trophoblast columns of human placental villi, extravillous trophoblast cells and glandular epithelium within the maternal decidua. Gadd45α knockdown significantly promoted migration and invasion of HTR8/SVneo cells, whereas it did not affect cell proliferation or apoptosis. Silencing Gadd45α also enhanced trophoblast outgrowth and migration in placental explants. These effects were related to increased activities of MMP2/9 and the decreased expression of TIMP1/2.

Discussion and conclusion

Gadd45α may be involved in human trophoblast migration and invasion and may function as an important negative regulator at the foetal–maternal interface during early pregnancy by directly or indirectly regulating MMP2/9 activities.