基质金属蛋白酶基因多态性及表达在子宫内膜异位症发病机制中作用的研究
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摘要
子宫内膜异位症是一种良性但具有侵袭与转移生物学行为的妇科疾病。调查表明,30~40岁妇女的患病率据保守估计为25%,且近年来呈明显上升趋势,其中30%~50%合并不孕。尽管有包括手术在内的多种方法可以治疗子宫内膜异位症,但结果却并不满意,无论经过何种治疗,其5年内的复发率均在40%以上。究其原因,乃是该疾病的病因学和病理发生学尚未完全阐明,治疗的针对性不强。
由于子宫内膜异位症在组织学上表现为异位内膜组织可以出现在子宫以外的全身多处,与恶性生物学行为相似,因而,子宫内膜异位症发生的关键因素可能与恶性肿瘤相似。目前普遍认为子宫内膜细胞在盆腔种植生长需经历三个主要阶段:细胞黏附→细胞外基质重建→血管生成,相似于肿瘤的侵袭转移过程。基质金属蛋白酶(Matrix metalloproteinases,MMPs)在细胞外基质重建中起重要作用。
MMPs是一个高度保守的依赖于锌离子的内切蛋白水解酶家族,可降解细胞外基质的大多数蛋白。在生理条件下,MMPs即存在于多种正常细胞中,但表达量极少,而在炎性细胞因子、激素、生长因子刺激下和细胞转化过程,其表达量上升,此过程涉及人体多种生理和病理过程,如炎症、胚胎发生、血管形成、肿瘤侵袭转移等。在人的正常子宫内膜组织中,不同的MMPs在月经周期中的表达不同,子宫内膜间质可表达数种MMPs,这些酶可能参与子宫内膜重建、囊胚种植及滋养层浸润。但研究发现在子宫内膜异位症患者的异位内膜中也表达多种MMPs蛋白,且部分MMPs在异位内膜中表达水平明显高于在位内膜组织,并不受月经周期的影响。MMPs在子宫内膜异位症的发生发展中起重要作用。迄今为止,MMPs在子宫内膜异位症患者异位内膜中过度表达的机制尚不十分明确。目前真核生物的基因表达调控研究主要以研究转录调控为主,研究其表达调控,从分子水平上阐明疾病的发生机理和细胞的重要功能,为疾病的防治提供理论依据。越来越多的研究表明基因多态性在基因的转录调控中起重要作用,可能与一些疾病的易感性相关。因此本课题选择了与基因转录活性调控相关的4个MMPs基因的多态性位点,研究基因多态性和其表达与子宫内膜异位症发病的关系。我们的研究内容包括:(1)比较MMP-1、3、7、9在子宫内膜异位症患者在位子宫内膜和异位内膜组织中表达的差异。(2)分析存在于MMP-1、3、7、9基因启动子区的单核苷酸多态性(single nucleotide polymorphism,SNP)与子宫内膜异位症发病风险的关系。(3)分析与子宫内膜异位症发病相关的基因多态性与其mRNA、蛋白在患者在位内膜组织中表达的关系。
通过以上研究探讨MMP-1、3、7、9四种基因在子宫内膜异位症发病中的作用,从遗传差异上阐明该病的发生机制,寻找子宫内膜异位症可能的MMPs遗传易感基因。
第一部分子宫内膜异位症患者在位子宫内膜和异位子宫内膜MMP表达的比较研究
目的:检测子宫内膜异位症患者在位宫内膜和异位组织中MMP-1、3、7、9表达的差异,探讨MMP蛋白表达在子宫内膜异位症发生和发展中的作用。
方法:采用流式细胞检测技术检测20例子宫内膜异位症患者在位宫内膜和40例异位组织MMP-1、3、7、9基因表达。t检验分析在位宫内膜与异位组织4种MMPs基因的表达差异。
结果:1)子宫内膜异位症患者在位宫内膜组织MMP-1蛋白表达量为1.00±0.13,异位组织MMP-1蛋白表达量为1.09±0.16,两者相比具有统计学差异(P<0.05)。2)子宫内膜异位症患者在位子宫内膜组织MMP-3蛋白表达量为1.00±0.22,异位组织MMP-3蛋白表达量为1.29±0.23,两者相比具有统计学差异(P<0.05)。3)子宫内膜异位症患者在位子宫内膜组织MMP-7蛋白表达量为1.00±0.16,异位组织MMP-7蛋白表达量为0.94±0.20,两者相比无统计学意义(P>0.05)。4)子宫内膜异位症患者在位子宫内膜组织MMP-9蛋白表达量为1.00±0.13,异位组织MMP-9蛋白表达量为1.04±0.11,两者相比无统计学意义(P>0.05)。
结论:首次采用流式细胞检测方法分析了子宫内膜异位症患者在位宫内膜和异位组织的MMP-1、3、7、9的蛋白表达,结果表明:1)子宫内膜异位症患者的异位内膜中MMP-1和MMP-3蛋白表达明显高于在位内膜,表明MMP-1、3蛋白的异常表达可能与子宫内膜异位症的发生和发展有关。MMP-1为胶原酶,MMP-3为间质溶素,二者的高表达均可增加细胞外基质的降解能力,所以异位组织中MMP-1、3的高表达可能表明细胞降解细胞外基质的能力增强,与组织的重建、出血及种植有关。2)子宫内膜异位症患者的在位和异位内膜中MMP-7和MMP-9蛋白表达无明显差异。
第二部分基质金属蛋白酶基因多态性与子宫内膜异位症发病风险关系的研究
目的:通过分析子宫内膜异位症患者和对照组妇女人群MMPs基因多态性位点基因型频率和等位基因频率的差异,探讨MMPs基因多态性与子宫内膜异位症发病风险的关系。
方法:采用病例-对照研究方法,以外周血白细胞DNA为实验材料,通过聚合酶链反应-限制内切酶片段长度多态性(PCR-RFLP)技术分析了143例子宫内膜异位症患者和160位健康妇女对照的MMP-1基因启动子区-1607 1G/2G、MMP-3基因启动子区-1171 5A/6A、MMP-7基因启动子区-181 A/G和MMP-9基因启动子区-1562 C/T多态性位点的基因型频率分布情况。t检验分析病例及对照组年龄差异;χ2检验分析两组人群MMP-1、3、7、9等位基因及基因型频率分布的差异,以非条件Logistic回归方法计算表示相对风险度的比值比(odds ratio,OR)及其95%可信区间(confidence interval,CI)。EH软件分析基因多态性单体型频率。2LD软件分析等位基因连锁不平衡状态。
结果:1)子宫内膜异位症患者MMP-1中2G等位基因频率(79%)明显高于对照组(66.9%)(P<0.05);子宫内膜异位症患者组1G/1G、1G/2G、2G/2G三种基因型频率分别为7%、28%和65%,与正常对照组16.6%、32.7%和50.7%相比也有显著差异(P<0.05);患者组2G纯合子的基因型频率明显高于对照组(P<0.05)。与1G/1G基因型相比,单独的2G/2G基因型或2G/2G+1G/2G基因型均能增加子宫内膜异位症患者的发病风险,校正的风险值分别为3.65(95%CI=1.41~9.43)和3.25(95%CI=1.29~8.23)。2)MMP-3中5A、6A等位基因频率在子宫内膜异位症患者和健康对照组中分别为14%、86%和20.3%、79.7%,两组之间分布无差别(P>0.05);5A/5A、5A/6A、6A/6A基因型频率分布在两组间也无显著差异(P>0.05);与6A/6A基因型相比,5A/5A或5A/5A+5A/6A基因型均未增加子宫内膜异位症的发病风险,校正的风险值为2.51(95%CI=0.25~25)和1.63(95%CI=0.92~2.98)。3)将MMP-1和MMP-3基因多态性联合分析结果显示,2G纯合子和6A纯合子同时存在于个体时,子宫内膜异位症发病风险增加了4倍,校正的风险值为4.13 (95%CI=1.55~10.99)。4)子宫内膜异位症患者MMP-7中G等位基因频率(7.3%)明显高于对照组(2.8%)(P<0.05);子宫内膜异位症患者A/A、A/G、G/G三种基因型频率分别为86.0%、13.3%和0.7%,正常对照组则分别为94.4%、5.6%和0,两者有显著差异(P<0.05);与A/A基因型相比,携带G等位基因能明显增加子宫内膜异位症的发病风险,经年龄校正的OR值为2.71(95%CI=1.19~6.16)。5)MMP-9中C和T等位基因频率在病例组和对照组分别为88.8%、11.2%及91.9 %、8.1%,两组差异无统计学意义(P>0.05);病例组C/C、C/T和T/T基因型频率分别为78.3%、21%和0.7%,对照组则分别为83.8%、16.2%和0,两者差异亦无统计学意义(P>0.05)。与C/C基因型相比,携带T等位基因未能明显增加子宫内膜异位症的发病风险,经年龄校正的OR值为1.41(95%CI=0.79~2.52)。
结论:在国内外首次研究报道了MMPs基因启动子区单核苷酸多态性与子宫内膜异位症发病风险的关系,其研究结果如下:1)MMP-1基因启动子区-1607 1G/2G与子宫内膜异位症发病风险相关,即2G等位基因的携带者可能明显增加子宫内膜异位症发病风险。2)MMP-3基因启动子区-1171 5A/6A虽然不能作为独立检测子宫内膜异位症发病风险的分层标记,但6A/6A基因型可能与MMP-1 2G/2G基因型成为联合分层标记。3)MMP-7基因启动子区-181 A/G多态与子宫内膜异位症发病存在关联。即G等位基因的携带者可能明显增加子宫内膜异位症的发病风险。4)未发现MMP-9基因启动子区-1562 C/T多态性与子宫内膜异位症发病存在关联。5)某些存在于MMPs基因上的多态性位点可能成为检测子宫内膜异位症发病风险的独立分子标志物。
第三部分子宫内膜异位症患者子宫内膜组织MMP-1和MMP-7基因mRNA和蛋白表达与基因多态之间的关系
目的:探讨MMP-1和MMP-7基因启动子区多态性与基因mRNA和蛋白表达水平之间的关系。
方法:采用反转录聚合酶链反应(RT-PCR)检测30例携带MMP-1、MMP-3不同基因型的子宫内膜异位症患者的在位内膜组织2种基因mRNA的转录活性。采用免疫组织化学方法检测了MMP-1、MMP-3不同基因型的子宫内膜异位症患者的在位内膜组织2种基因蛋白表达水平。秩和检验比较不同基因型的在位内膜组织mRNA和蛋白表达差异。
结果:1)MMP-1基因1G/1G基因型携带者的子宫内膜异位症患者在位子宫内膜mRNA相对表达量为0.33±0.10,1G/2G基因型携带者的子宫内膜异位症患者在位子宫内膜mRNA相对表达量为0.43±0.16,2G/2G基因型携带者的子宫内膜异位症患者在位子宫内膜mRNA相对表达量为0.54±0.24,三组相比具有统计学差异(P=0.04)。2)MMP-7基因A/A基因型携带者的子宫内膜异位症患者在位子宫内膜mRNA相对表达量为0.37±0.26,G等位基因携带者(A/G+G/G)的子宫内膜异位症患者在位子宫内膜mRNA相对表达量为0.37±0.26,两组相比具有统计学差异(P=0.01)。3)MMP-1蛋白主要表达于在位内膜的间质细胞中,2G/2G基因型携带者的子宫内膜异位症患者在位子宫内膜蛋白表达明显高于1G/1G基因型携带者(P=0.047)和1G/1G+1G/2G基因型的携带者(P=0.019)。4)MMP-7蛋白主要表达于在位内膜的上皮细胞中,与携带A/A基因型的子宫内膜异位症患者在位内膜相比,A/G基因型携带者的在位内膜的MMP-7蛋白表达明显增高(P=0.016)。
结论:首次研究证实MMP不同基因型携带者的妇女宫内膜组织相关基因转录活性和蛋白的表达可能不同,其结果可能导致不同个体在位内膜的差异,从而造成发病风险的不同。1)携带MMP-1基因1G/2G多态位点不同基因型的子宫内膜异位症患者在位子宫内膜组织MMP-1 mRNA和蛋白的表达强度不同,即2G/2G基因型的携带者MMP-1基因mRNA和蛋白的表达明显高于其它基因型(1G/1G和1G/2G)的携带者,表明MMP-1 2G等位基因可能通过增加基因的转录活性导致在位子宫内膜MMP-1蛋白表达的增加。2)携带MMP-7基因A/G多态位点不同基因型的子宫内膜异位症患者在位子宫内膜组织MMP-7 mRNA和蛋白的表达强度不同,即G等位基因的携带者在位子宫内膜组织MMP-7 mRNA和蛋白的表达明显增强,说明MMP-7的G等位基因可能通过增加基因的转录活性导致在位子宫内膜MMP-7蛋白表达的增加。
总之,通过本课题的研究我们进一步证实了MMPs基因在子宫内膜异位症的发生和发展中起重要作用。且推测不同的MMPs基因在子宫内膜异位症发生和发展的不同阶段作用不同,MMP-1基因的遗传差异所导致的个体差异与子宫内膜异位症发病风险的个体差异相关,其蛋白的异常表达还可能与子宫内膜异位症的进展相关;MMP-3基因的异常表达在子宫内膜异位症的发展中起重要作用;MMP-7作为一个上皮性表达的蛋白,可能对子宫内膜异位症的发生起重要作用,带有MMP-7高表达的在位子宫内膜细胞更易在经血逆流中“异位”种植,增加个体子宫内膜异位症的发病风险;MMP-9虽然在本研究中没有被证实与子宫内膜异位症的发生和发展有相关性,但鉴于其它相关研究,有待于从其它方法证实MMP-9在子宫内膜异位症进展中的作用。
Endometriosis (EMs) is a kind of benign but invasive and metastatic gynaecological disease. It is conservatively estimated that the incidence rate can be as high as 25% among women aged 30 to 40 years old, and the rate has increased in recent years. 30% to 50% of women with EMs are suffering from infertility. Although there are various methods to cure EMs such as surgical operation, the result is unsatisfactory, and the 5-year relapse rate is above 40% due to the fact that its aetiology and pathogenesis is not completely understood.
EMs is a malignant disease because its’ectopic endometrium may be found in many other organs besides the uterine cavity in histology. Therefore, the key step of EMs occurrence is similar to nicious tumor. As it is known that the implantation and development of endometrium in cavitas pelvis have three main stages such as cell adhesion, extracellular matrix (ECM) remolding and blood vessel forming, which is similar to invasive and metastatic process of tumor. Matrix metalloproteinases (MMPs) play an important role in the ECM remolding.
The MMPs are a highly conservative zinc-dependen family of endopeptidases and may degrade most proteins of ECM. Under physiological condition, the expression of MMPs, which exist in various kinds of normal cell, is very rare. However, the expression would increase in the stimulated cytokines, hormones, growth factors and process of cellular transformation, which is implicated in various physiologic and pathologic processes, such as inflammation, embryo occurrence, blood vessel formation, invasion and metastasis of tumor and so on. The expression of MMPs in eutopic endometrium is different in menstrual cycle, and different kinds of MMPs could be found in endometrium stroma, which may play a role in endometrium remolding, blastula implantation and trophoblast invasion. Researches showed that different types of MMPs could be found in ectopic endometrium for endometriosis patients. In addition, the expression of some MMPs in ectopic endometrium was significantly higher than that in eutopic endometrium, which would not be affected by menstrual cycle. MMPs play a very important role in the development of endometriosis. But so far, the mechanism of MMPs over-expression in ectopic endometrium for endometriosis patients is still unclear. Recently, researches of eukaryotic gene expression regulating are largely focused on the transcriptional regulation to study the expression regulation, which illuminates the pathogenesis of diseases and cellular function from the molecular level, and supplies knowledge of prevention and cure for diseases. More and more researches showed that the polymorphisms play an important role in transcriptional regulation and are associated with the susceptibility of some diseases. Thus, we choose MMPs as target gene, which is confirmed to have correlation with MMPs abnormal expression and development of some tumors, and study the association of the polymorphism and expression of MMPs with the risk of endometriosis. Our study includes: (1) comparing the difference of MMP-1, 3, 7 and 9 expressions in eutopic and ectopic endometrium of endometriosis patients. (2) Analyzing the association of single nucleotide polymorphism (SNP) in the promoter regions of the MMP-1, 3, 7, 9 with the risk of endometriosis. (3) Analyzing the relation between polymorphisms about EMs and the expression of mRNA and protein in eutopic endometrium.
All in all, by studying the role of four genes (MMP-1, 3, 7, 9) in the development of EMs, we illuminate the pathogenesis by genetic difference and search the possible MMPs susceptible gene of EMs genetically.
PartI Comparatiev study of MMPs expression in eutopic and ectopic endometrium of endometriosis patients
Objective: To examine the difference of MMPs expression in eutopic and ectopic endometrium of endometriosis patients and investigate the role of MMPs abnormal expression in the development of EMs.
Methods: The MMP-1, 3, 7 and 9 expressions were detected by flow cytometry in eutopic endometrium (n=20) and ectopic endometrium (n=40) for endometriosis patients. Using the t-test to examine the differences of four MMPs expression in eutopic and ectopic endometrium.
Results: 1) There was a significant difference in the expression of MMP-1 protein between eutopic and ectopic endometrium of endometriosis patients (P<0.05), the differences were 1.00±0.13 and 1.09±0.16, respectively. 2) The expression of MMP-3 protein in eutopic endometrium (1.00±0.22) was significantly lower than that in ectopic endometrium (1.29±0.23) (P<0.05). 3) There was not a significant difference in the expression of MMP-7 protein between eutopic endometrium and ectopic endometrium of endometriosis patients (P>0.05), which were 1.00±0.16 and 0.94±0.20, respectively. 4) Compared wth ectopic endometrium (1.04±0.11), the expression of MMP-9 protein showed no significant difference in eutopic endometrium (1.00±0.13) (P>0.05).
Conclusion: This study is the first to analyze the expression of MMP-1, 3, 7, 9 in eutopic and ectopic endometrium for endometriosis patients by flow cytometry, and the result showed 1) The expression of MMP-1 and MMP-3 protein in ectopic endometrium was significantly higher than that in eutopic endometrium for endometriosis patients, which showed there was a association between abnormal expression of MMPs (MMP-1 and MMP-3) protein and the development of EMs. The over-expression of MMP-1 and MMP-3, known as collagenase and mesenchymal lysine respectively, could increase the activity of ECM degradation, thus the over-expression of MMP-1 and MMP-3 in ectopic endometrium could show puissant activity of ECM degradation and have relation with tissular remolding, hemorrhage and implantation. 2) The expression of MMP-7 and MMP-9 protein showed no significant difference between eutopic and ectopic endometrium of endometriosis patients.
PartII Study on the association of polymorphisms of theMMPs with the risk of EMs
Objective: By analyzing the differences of MMPs allele and genotype frequencies in endometriosis patients and unrelated healthy women, we attempted to investigate the association of polymorphisms of the MMPs with the risk of EMs.
Methods: The genotype frequencies of four polymorphisms in MMPs promoter (MMP-1 -1607 1G/2G, MMP-3 -1171 5A/6A, MMP-7 -181 A/G and MMP-9 -1562 C/T) were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and using case- control study in 143 endometriosis patients and 160 unrelated healthy women. The peripheral blood DNA was used as experimental materials. The age difference of case and matched control was analyzed by the t-test. The difference of the MMP-1, 3, 7, 9 allele and genotype distributions in two study groups was tested by the Chi-square test. The odds ratio (OR) and 95% confidence interval (CI) were calculated using an unconditional logistic regression model. The haplotype frequencies and linkage disequilibrium coefficient were estimated with the EH and 2ld linkage software respectively.
Results: 1) The frequency of the MMP-1 2G allele among endometriosis patients (79%) was significantly higher than those in the healthy controls (66.9%) (P<0.05); The frequencies of the 2G/2G, 1G/2G and 1G/1G genotypes among endometriosis patients (7%, 28% and 65%, respectively) were significantly different from those in healthy controls (16.6%, 32.7% and 50.7%, respectively) (P<0.05); The frequency of the 2G homozygote in endometriosis was significantly higher than in the controls (P<0.05); Compared with the 1G/1G genotype, the 2G/2G or 2G/2G+1G/2G genotype significantly increased the risk of developing endometriosis, the adjusted odds ratios were 3.65 ( 95%CI=1.41~9.43 ) and 3.25 ( 95%CI=1.29~8.23), respectively. 2) The frequencies of the MMP-3 5A and 6A allele among endometriosis patients and healthy controls were 14%, 86% and 20.3%, 79.7%, respectively; No significant difference in the MMP-3 allele distribution was shown between the case and controls (P>0.05); There was no significant difference in 5A/5A, 5A/6A and 6A/6A genotypes distribution between endometriosis patients and healthy women (P>0.05); Compared with the 6A/6A genotype, either the 5A/5A or the 5A/5A + 5A/6A genotype significantly modified the risk of developing endometriosis, the adjusted odds ratio were 2.51(95%CI=0.25~25)and 1.63(95%CI=0.92~2.98), respectively. 3) The combined effect of the MMP-1 and MMP-3 SNP showed that it increased 4-fold higher risk of developing endometriosis, as the 2G and 6A homozygotes were found in the subject at the same time, the adjusted odds ratio was 4.13(95%CI=1.55~10.99). 4) The frequency of the MMP-7 G allele among endometriosis patients (7.3%) was significantly higher than in the healthy controls (2.8%) (P<0.05); The frequencies of the A/A, A/G and G/G genotypes among endometriosis patients (86.0%, 13.3% and 0.7%, respectively) were significantly different from those in healthy controls (94.4%, 5.6% and 0, respectively) (P<0.05); Compared with the A/A genotype, the subjects with G allele significantly increased the risk of developing endometriosis, the odds ratios was 2.71 (95%CI=1.19~6.16). 5 ) The frequencies of the MMP-9 C and T allele among endometriosis patients and healthy controls were 88.8%, 11.2% and 91.9%, 8.1%, respectively; No significant difference in the MMP3 allele distribution was shown between the case and controls (P>0.05); The frequencies of the C/C, C/T and T/T genotypes among endometriosis patients (78.3%, 21% and 0.7%, respectively) were not significantly different from those in healthy controls (83.8%, 16.2% and 0, respectively) (P>0.05); Compared with the C/C genotype, the T allele did not significantly increase the risk of developing endometriosis, the adjusted odds ratio was 1.41(95%CI=0.79~2.52).
Conclusion: This study is the first to investigate the relation between MMPs promoter SNPs and the risk of EMs all over the world. Our result showed 1) There was the association of the MMP-1 promoter -1607 1G/2G with the risk of endometriosis, in other words, 2G allele could significantly increase susceptibility to endometriosis. 2) Although the MMP-3 promoter -1171 5A/6A could not be a layering marking to detect the risk of endometriosis, the 6A/6A and MMP-1 2G/2G genotype could be the conjunctive layering marking. 3) Our data suggest an association of the MMP-7 promoter -181 A/G with the risk of endometriosis, G allele could increase susceptibility to endometriosis. 4) It was not found to the association of the MMP-9 promoter -1562 C/T with the risk of endometriosis. 5) Some polymorphisms in MMPs could be the independent molecule marking to detect the risk of endometriosis.
PartIII Association of the mRNA and the protein expression of MMP-1 and MMP-7 with SNPs
Objective: To investigate the relation between polymorphisms at MMPs promoter region and the mRNA and protein expression.
Methods: The transcriptional activity and protein expression of the MMPs in eutopic endometrium for endometriosis patients, which took with the different genotypes of the MMP-1 and MMP-7, were analyzed by reverse transcription-polymerase chain raction (RT-PCR) and immunohistochemistry, respectively. Wilcoxon signed-rank test was used to measure the difference of mMRA and protein expression in eutopic endometrium with the different genotypes.
Results: 1) The relative expression of mMRA in eutopic endometrium for endometriosis patients with the MMP-1 1G/1G, 1G/2G and 2G/2G genotypes was 0.33±0.10, 0.43±0.16 and 0.54±0.24, respectively. The significant difference in the MMP-1 mMRA expression was shown among those (P=0.04). 2) There was significant difference in the relative expression of MMP-7 mMRA in eutopic endometrium for endometriosis patients with G allele (A/G+G/G) (0.37±0.26) and A/A genotype (0.37±0.26) (P=0.01). 3) The MMP-1 protein was mainly expressed in the stromal cells of eutopic endometrium, the expression of MMP-1 protein in eutopic endometrium for endometriosis patients with 2G/2G genotype was significantly higher than those with 1G/1G (P=0.047) and 1G/1G + 1G/2G genotypes (P=0.019). 4) The MMP-7 protein expressed primarily in endothelial cells of eutopic endometrium, compared with A/A genotype, the expression of MMP-7 protein in eutopic endometrium for endometriosis patients with A/G genotype was significantly high (P=0.016).
Conclusion: Our study is the first to confirm different transcriptive activity and protein expression for subjects with different genotypes, which result in the difference of eutopic endometrium for different subject, further cause different risk of EMs. 1) There was significant difference in the mMRA and protein expression of MMP-1 in eutopic endometrium for endometriosis patients with the different MMP-1 genotypes, in other words, the mMRA and protein expression of MMP-1 for ones with the 2G/2G genotypes was significantly higher than the others, which show the 2G allele could result in the increasing expression of MMP-1 protein in eutopic endometrium by enhancing gene transcriptional activity. 2) The mMRA and protein expression of MMP-7 in eutopic endometrium for ones with the different MMP-7 genotypes had significant difference, that was to say the subjects with G allele could significantly increase the mMRA and protein expression of MMP-7 in eutopic endometrium, which show the G allele could enhance gene transcriptional activity to result in the increasing expression of MMP-7 protein in eutopic endometrium.
In conclusion, our study confirms further that MMPs could play an important role in the development of EMs. In addition, we presume that the role of different MMPs is distinct in various stages of EMs development. The difference of subjects which is resulted by the genetic difference of MMP-1 has the association with the risk of EMs, and the abnormal expression of protein may have relation with the development of EMs; The abnormal expression of MMP-3 has a very important role in the development of EMs; As a protein of endothelial expression, MMP-7 may participate in the development of EMs, endometrial cells with high-expression MMP-7 easily take place ectopic implantation in the blood of menstruate countercurrented and increase the risk of EMs; It is not confirmed in our study that there are the association of MMP-9 with the risk of EMs, but in view of other study, we will further evaluate the role of MMP-9 in the development of EMs.
由于子宫内膜异位症在组织学上表现为异位内膜组织可以出现在子宫以外的全身多处,与恶性生物学行为相似,因而,子宫内膜异位症发生的关键因素可能与恶性肿瘤相似。目前普遍认为子宫内膜细胞在盆腔种植生长需经历三个主要阶段:细胞黏附→细胞外基质重建→血管生成,相似于肿瘤的侵袭转移过程。基质金属蛋白酶(Matrix metalloproteinases,MMPs)在细胞外基质重建中起重要作用。
MMPs是一个高度保守的依赖于锌离子的内切蛋白水解酶家族,可降解细胞外基质的大多数蛋白。在生理条件下,MMPs即存在于多种正常细胞中,但表达量极少,而在炎性细胞因子、激素、生长因子刺激下和细胞转化过程,其表达量上升,此过程涉及人体多种生理和病理过程,如炎症、胚胎发生、血管形成、肿瘤侵袭转移等。在人的正常子宫内膜组织中,不同的MMPs在月经周期中的表达不同,子宫内膜间质可表达数种MMPs,这些酶可能参与子宫内膜重建、囊胚种植及滋养层浸润。但研究发现在子宫内膜异位症患者的异位内膜中也表达多种MMPs蛋白,且部分MMPs在异位内膜中表达水平明显高于在位内膜组织,并不受月经周期的影响。MMPs在子宫内膜异位症的发生发展中起重要作用。迄今为止,MMPs在子宫内膜异位症患者异位内膜中过度表达的机制尚不十分明确。目前真核生物的基因表达调控研究主要以研究转录调控为主,研究其表达调控,从分子水平上阐明疾病的发生机理和细胞的重要功能,为疾病的防治提供理论依据。越来越多的研究表明基因多态性在基因的转录调控中起重要作用,可能与一些疾病的易感性相关。因此本课题选择了与基因转录活性调控相关的4个MMPs基因的多态性位点,研究基因多态性和其表达与子宫内膜异位症发病的关系。我们的研究内容包括:(1)比较MMP-1、3、7、9在子宫内膜异位症患者在位子宫内膜和异位内膜组织中表达的差异。(2)分析存在于MMP-1、3、7、9基因启动子区的单核苷酸多态性(single nucleotide polymorphism,SNP)与子宫内膜异位症发病风险的关系。(3)分析与子宫内膜异位症发病相关的基因多态性与其mRNA、蛋白在患者在位内膜组织中表达的关系。
通过以上研究探讨MMP-1、3、7、9四种基因在子宫内膜异位症发病中的作用,从遗传差异上阐明该病的发生机制,寻找子宫内膜异位症可能的MMPs遗传易感基因。
第一部分子宫内膜异位症患者在位子宫内膜和异位子宫内膜MMP表达的比较研究
目的:检测子宫内膜异位症患者在位宫内膜和异位组织中MMP-1、3、7、9表达的差异,探讨MMP蛋白表达在子宫内膜异位症发生和发展中的作用。
方法:采用流式细胞检测技术检测20例子宫内膜异位症患者在位宫内膜和40例异位组织MMP-1、3、7、9基因表达。t检验分析在位宫内膜与异位组织4种MMPs基因的表达差异。
结果:1)子宫内膜异位症患者在位宫内膜组织MMP-1蛋白表达量为1.00±0.13,异位组织MMP-1蛋白表达量为1.09±0.16,两者相比具有统计学差异(P<0.05)。2)子宫内膜异位症患者在位子宫内膜组织MMP-3蛋白表达量为1.00±0.22,异位组织MMP-3蛋白表达量为1.29±0.23,两者相比具有统计学差异(P<0.05)。3)子宫内膜异位症患者在位子宫内膜组织MMP-7蛋白表达量为1.00±0.16,异位组织MMP-7蛋白表达量为0.94±0.20,两者相比无统计学意义(P>0.05)。4)子宫内膜异位症患者在位子宫内膜组织MMP-9蛋白表达量为1.00±0.13,异位组织MMP-9蛋白表达量为1.04±0.11,两者相比无统计学意义(P>0.05)。
结论:首次采用流式细胞检测方法分析了子宫内膜异位症患者在位宫内膜和异位组织的MMP-1、3、7、9的蛋白表达,结果表明:1)子宫内膜异位症患者的异位内膜中MMP-1和MMP-3蛋白表达明显高于在位内膜,表明MMP-1、3蛋白的异常表达可能与子宫内膜异位症的发生和发展有关。MMP-1为胶原酶,MMP-3为间质溶素,二者的高表达均可增加细胞外基质的降解能力,所以异位组织中MMP-1、3的高表达可能表明细胞降解细胞外基质的能力增强,与组织的重建、出血及种植有关。2)子宫内膜异位症患者的在位和异位内膜中MMP-7和MMP-9蛋白表达无明显差异。
第二部分基质金属蛋白酶基因多态性与子宫内膜异位症发病风险关系的研究
目的:通过分析子宫内膜异位症患者和对照组妇女人群MMPs基因多态性位点基因型频率和等位基因频率的差异,探讨MMPs基因多态性与子宫内膜异位症发病风险的关系。
方法:采用病例-对照研究方法,以外周血白细胞DNA为实验材料,通过聚合酶链反应-限制内切酶片段长度多态性(PCR-RFLP)技术分析了143例子宫内膜异位症患者和160位健康妇女对照的MMP-1基因启动子区-1607 1G/2G、MMP-3基因启动子区-1171 5A/6A、MMP-7基因启动子区-181 A/G和MMP-9基因启动子区-1562 C/T多态性位点的基因型频率分布情况。t检验分析病例及对照组年龄差异;χ2检验分析两组人群MMP-1、3、7、9等位基因及基因型频率分布的差异,以非条件Logistic回归方法计算表示相对风险度的比值比(odds ratio,OR)及其95%可信区间(confidence interval,CI)。EH软件分析基因多态性单体型频率。2LD软件分析等位基因连锁不平衡状态。
结果:1)子宫内膜异位症患者MMP-1中2G等位基因频率(79%)明显高于对照组(66.9%)(P<0.05);子宫内膜异位症患者组1G/1G、1G/2G、2G/2G三种基因型频率分别为7%、28%和65%,与正常对照组16.6%、32.7%和50.7%相比也有显著差异(P<0.05);患者组2G纯合子的基因型频率明显高于对照组(P<0.05)。与1G/1G基因型相比,单独的2G/2G基因型或2G/2G+1G/2G基因型均能增加子宫内膜异位症患者的发病风险,校正的风险值分别为3.65(95%CI=1.41~9.43)和3.25(95%CI=1.29~8.23)。2)MMP-3中5A、6A等位基因频率在子宫内膜异位症患者和健康对照组中分别为14%、86%和20.3%、79.7%,两组之间分布无差别(P>0.05);5A/5A、5A/6A、6A/6A基因型频率分布在两组间也无显著差异(P>0.05);与6A/6A基因型相比,5A/5A或5A/5A+5A/6A基因型均未增加子宫内膜异位症的发病风险,校正的风险值为2.51(95%CI=0.25~25)和1.63(95%CI=0.92~2.98)。3)将MMP-1和MMP-3基因多态性联合分析结果显示,2G纯合子和6A纯合子同时存在于个体时,子宫内膜异位症发病风险增加了4倍,校正的风险值为4.13 (95%CI=1.55~10.99)。4)子宫内膜异位症患者MMP-7中G等位基因频率(7.3%)明显高于对照组(2.8%)(P<0.05);子宫内膜异位症患者A/A、A/G、G/G三种基因型频率分别为86.0%、13.3%和0.7%,正常对照组则分别为94.4%、5.6%和0,两者有显著差异(P<0.05);与A/A基因型相比,携带G等位基因能明显增加子宫内膜异位症的发病风险,经年龄校正的OR值为2.71(95%CI=1.19~6.16)。5)MMP-9中C和T等位基因频率在病例组和对照组分别为88.8%、11.2%及91.9 %、8.1%,两组差异无统计学意义(P>0.05);病例组C/C、C/T和T/T基因型频率分别为78.3%、21%和0.7%,对照组则分别为83.8%、16.2%和0,两者差异亦无统计学意义(P>0.05)。与C/C基因型相比,携带T等位基因未能明显增加子宫内膜异位症的发病风险,经年龄校正的OR值为1.41(95%CI=0.79~2.52)。
结论:在国内外首次研究报道了MMPs基因启动子区单核苷酸多态性与子宫内膜异位症发病风险的关系,其研究结果如下:1)MMP-1基因启动子区-1607 1G/2G与子宫内膜异位症发病风险相关,即2G等位基因的携带者可能明显增加子宫内膜异位症发病风险。2)MMP-3基因启动子区-1171 5A/6A虽然不能作为独立检测子宫内膜异位症发病风险的分层标记,但6A/6A基因型可能与MMP-1 2G/2G基因型成为联合分层标记。3)MMP-7基因启动子区-181 A/G多态与子宫内膜异位症发病存在关联。即G等位基因的携带者可能明显增加子宫内膜异位症的发病风险。4)未发现MMP-9基因启动子区-1562 C/T多态性与子宫内膜异位症发病存在关联。5)某些存在于MMPs基因上的多态性位点可能成为检测子宫内膜异位症发病风险的独立分子标志物。
第三部分子宫内膜异位症患者子宫内膜组织MMP-1和MMP-7基因mRNA和蛋白表达与基因多态之间的关系
目的:探讨MMP-1和MMP-7基因启动子区多态性与基因mRNA和蛋白表达水平之间的关系。
方法:采用反转录聚合酶链反应(RT-PCR)检测30例携带MMP-1、MMP-3不同基因型的子宫内膜异位症患者的在位内膜组织2种基因mRNA的转录活性。采用免疫组织化学方法检测了MMP-1、MMP-3不同基因型的子宫内膜异位症患者的在位内膜组织2种基因蛋白表达水平。秩和检验比较不同基因型的在位内膜组织mRNA和蛋白表达差异。
结果:1)MMP-1基因1G/1G基因型携带者的子宫内膜异位症患者在位子宫内膜mRNA相对表达量为0.33±0.10,1G/2G基因型携带者的子宫内膜异位症患者在位子宫内膜mRNA相对表达量为0.43±0.16,2G/2G基因型携带者的子宫内膜异位症患者在位子宫内膜mRNA相对表达量为0.54±0.24,三组相比具有统计学差异(P=0.04)。2)MMP-7基因A/A基因型携带者的子宫内膜异位症患者在位子宫内膜mRNA相对表达量为0.37±0.26,G等位基因携带者(A/G+G/G)的子宫内膜异位症患者在位子宫内膜mRNA相对表达量为0.37±0.26,两组相比具有统计学差异(P=0.01)。3)MMP-1蛋白主要表达于在位内膜的间质细胞中,2G/2G基因型携带者的子宫内膜异位症患者在位子宫内膜蛋白表达明显高于1G/1G基因型携带者(P=0.047)和1G/1G+1G/2G基因型的携带者(P=0.019)。4)MMP-7蛋白主要表达于在位内膜的上皮细胞中,与携带A/A基因型的子宫内膜异位症患者在位内膜相比,A/G基因型携带者的在位内膜的MMP-7蛋白表达明显增高(P=0.016)。
结论:首次研究证实MMP不同基因型携带者的妇女宫内膜组织相关基因转录活性和蛋白的表达可能不同,其结果可能导致不同个体在位内膜的差异,从而造成发病风险的不同。1)携带MMP-1基因1G/2G多态位点不同基因型的子宫内膜异位症患者在位子宫内膜组织MMP-1 mRNA和蛋白的表达强度不同,即2G/2G基因型的携带者MMP-1基因mRNA和蛋白的表达明显高于其它基因型(1G/1G和1G/2G)的携带者,表明MMP-1 2G等位基因可能通过增加基因的转录活性导致在位子宫内膜MMP-1蛋白表达的增加。2)携带MMP-7基因A/G多态位点不同基因型的子宫内膜异位症患者在位子宫内膜组织MMP-7 mRNA和蛋白的表达强度不同,即G等位基因的携带者在位子宫内膜组织MMP-7 mRNA和蛋白的表达明显增强,说明MMP-7的G等位基因可能通过增加基因的转录活性导致在位子宫内膜MMP-7蛋白表达的增加。
总之,通过本课题的研究我们进一步证实了MMPs基因在子宫内膜异位症的发生和发展中起重要作用。且推测不同的MMPs基因在子宫内膜异位症发生和发展的不同阶段作用不同,MMP-1基因的遗传差异所导致的个体差异与子宫内膜异位症发病风险的个体差异相关,其蛋白的异常表达还可能与子宫内膜异位症的进展相关;MMP-3基因的异常表达在子宫内膜异位症的发展中起重要作用;MMP-7作为一个上皮性表达的蛋白,可能对子宫内膜异位症的发生起重要作用,带有MMP-7高表达的在位子宫内膜细胞更易在经血逆流中“异位”种植,增加个体子宫内膜异位症的发病风险;MMP-9虽然在本研究中没有被证实与子宫内膜异位症的发生和发展有相关性,但鉴于其它相关研究,有待于从其它方法证实MMP-9在子宫内膜异位症进展中的作用。
Endometriosis (EMs) is a kind of benign but invasive and metastatic gynaecological disease. It is conservatively estimated that the incidence rate can be as high as 25% among women aged 30 to 40 years old, and the rate has increased in recent years. 30% to 50% of women with EMs are suffering from infertility. Although there are various methods to cure EMs such as surgical operation, the result is unsatisfactory, and the 5-year relapse rate is above 40% due to the fact that its aetiology and pathogenesis is not completely understood.
EMs is a malignant disease because its’ectopic endometrium may be found in many other organs besides the uterine cavity in histology. Therefore, the key step of EMs occurrence is similar to nicious tumor. As it is known that the implantation and development of endometrium in cavitas pelvis have three main stages such as cell adhesion, extracellular matrix (ECM) remolding and blood vessel forming, which is similar to invasive and metastatic process of tumor. Matrix metalloproteinases (MMPs) play an important role in the ECM remolding.
The MMPs are a highly conservative zinc-dependen family of endopeptidases and may degrade most proteins of ECM. Under physiological condition, the expression of MMPs, which exist in various kinds of normal cell, is very rare. However, the expression would increase in the stimulated cytokines, hormones, growth factors and process of cellular transformation, which is implicated in various physiologic and pathologic processes, such as inflammation, embryo occurrence, blood vessel formation, invasion and metastasis of tumor and so on. The expression of MMPs in eutopic endometrium is different in menstrual cycle, and different kinds of MMPs could be found in endometrium stroma, which may play a role in endometrium remolding, blastula implantation and trophoblast invasion. Researches showed that different types of MMPs could be found in ectopic endometrium for endometriosis patients. In addition, the expression of some MMPs in ectopic endometrium was significantly higher than that in eutopic endometrium, which would not be affected by menstrual cycle. MMPs play a very important role in the development of endometriosis. But so far, the mechanism of MMPs over-expression in ectopic endometrium for endometriosis patients is still unclear. Recently, researches of eukaryotic gene expression regulating are largely focused on the transcriptional regulation to study the expression regulation, which illuminates the pathogenesis of diseases and cellular function from the molecular level, and supplies knowledge of prevention and cure for diseases. More and more researches showed that the polymorphisms play an important role in transcriptional regulation and are associated with the susceptibility of some diseases. Thus, we choose MMPs as target gene, which is confirmed to have correlation with MMPs abnormal expression and development of some tumors, and study the association of the polymorphism and expression of MMPs with the risk of endometriosis. Our study includes: (1) comparing the difference of MMP-1, 3, 7 and 9 expressions in eutopic and ectopic endometrium of endometriosis patients. (2) Analyzing the association of single nucleotide polymorphism (SNP) in the promoter regions of the MMP-1, 3, 7, 9 with the risk of endometriosis. (3) Analyzing the relation between polymorphisms about EMs and the expression of mRNA and protein in eutopic endometrium.
All in all, by studying the role of four genes (MMP-1, 3, 7, 9) in the development of EMs, we illuminate the pathogenesis by genetic difference and search the possible MMPs susceptible gene of EMs genetically.
PartI Comparatiev study of MMPs expression in eutopic and ectopic endometrium of endometriosis patients
Objective: To examine the difference of MMPs expression in eutopic and ectopic endometrium of endometriosis patients and investigate the role of MMPs abnormal expression in the development of EMs.
Methods: The MMP-1, 3, 7 and 9 expressions were detected by flow cytometry in eutopic endometrium (n=20) and ectopic endometrium (n=40) for endometriosis patients. Using the t-test to examine the differences of four MMPs expression in eutopic and ectopic endometrium.
Results: 1) There was a significant difference in the expression of MMP-1 protein between eutopic and ectopic endometrium of endometriosis patients (P<0.05), the differences were 1.00±0.13 and 1.09±0.16, respectively. 2) The expression of MMP-3 protein in eutopic endometrium (1.00±0.22) was significantly lower than that in ectopic endometrium (1.29±0.23) (P<0.05). 3) There was not a significant difference in the expression of MMP-7 protein between eutopic endometrium and ectopic endometrium of endometriosis patients (P>0.05), which were 1.00±0.16 and 0.94±0.20, respectively. 4) Compared wth ectopic endometrium (1.04±0.11), the expression of MMP-9 protein showed no significant difference in eutopic endometrium (1.00±0.13) (P>0.05).
Conclusion: This study is the first to analyze the expression of MMP-1, 3, 7, 9 in eutopic and ectopic endometrium for endometriosis patients by flow cytometry, and the result showed 1) The expression of MMP-1 and MMP-3 protein in ectopic endometrium was significantly higher than that in eutopic endometrium for endometriosis patients, which showed there was a association between abnormal expression of MMPs (MMP-1 and MMP-3) protein and the development of EMs. The over-expression of MMP-1 and MMP-3, known as collagenase and mesenchymal lysine respectively, could increase the activity of ECM degradation, thus the over-expression of MMP-1 and MMP-3 in ectopic endometrium could show puissant activity of ECM degradation and have relation with tissular remolding, hemorrhage and implantation. 2) The expression of MMP-7 and MMP-9 protein showed no significant difference between eutopic and ectopic endometrium of endometriosis patients.
PartII Study on the association of polymorphisms of theMMPs with the risk of EMs
Objective: By analyzing the differences of MMPs allele and genotype frequencies in endometriosis patients and unrelated healthy women, we attempted to investigate the association of polymorphisms of the MMPs with the risk of EMs.
Methods: The genotype frequencies of four polymorphisms in MMPs promoter (MMP-1 -1607 1G/2G, MMP-3 -1171 5A/6A, MMP-7 -181 A/G and MMP-9 -1562 C/T) were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and using case- control study in 143 endometriosis patients and 160 unrelated healthy women. The peripheral blood DNA was used as experimental materials. The age difference of case and matched control was analyzed by the t-test. The difference of the MMP-1, 3, 7, 9 allele and genotype distributions in two study groups was tested by the Chi-square test. The odds ratio (OR) and 95% confidence interval (CI) were calculated using an unconditional logistic regression model. The haplotype frequencies and linkage disequilibrium coefficient were estimated with the EH and 2ld linkage software respectively.
Results: 1) The frequency of the MMP-1 2G allele among endometriosis patients (79%) was significantly higher than those in the healthy controls (66.9%) (P<0.05); The frequencies of the 2G/2G, 1G/2G and 1G/1G genotypes among endometriosis patients (7%, 28% and 65%, respectively) were significantly different from those in healthy controls (16.6%, 32.7% and 50.7%, respectively) (P<0.05); The frequency of the 2G homozygote in endometriosis was significantly higher than in the controls (P<0.05); Compared with the 1G/1G genotype, the 2G/2G or 2G/2G+1G/2G genotype significantly increased the risk of developing endometriosis, the adjusted odds ratios were 3.65 ( 95%CI=1.41~9.43 ) and 3.25 ( 95%CI=1.29~8.23), respectively. 2) The frequencies of the MMP-3 5A and 6A allele among endometriosis patients and healthy controls were 14%, 86% and 20.3%, 79.7%, respectively; No significant difference in the MMP-3 allele distribution was shown between the case and controls (P>0.05); There was no significant difference in 5A/5A, 5A/6A and 6A/6A genotypes distribution between endometriosis patients and healthy women (P>0.05); Compared with the 6A/6A genotype, either the 5A/5A or the 5A/5A + 5A/6A genotype significantly modified the risk of developing endometriosis, the adjusted odds ratio were 2.51(95%CI=0.25~25)and 1.63(95%CI=0.92~2.98), respectively. 3) The combined effect of the MMP-1 and MMP-3 SNP showed that it increased 4-fold higher risk of developing endometriosis, as the 2G and 6A homozygotes were found in the subject at the same time, the adjusted odds ratio was 4.13(95%CI=1.55~10.99). 4) The frequency of the MMP-7 G allele among endometriosis patients (7.3%) was significantly higher than in the healthy controls (2.8%) (P<0.05); The frequencies of the A/A, A/G and G/G genotypes among endometriosis patients (86.0%, 13.3% and 0.7%, respectively) were significantly different from those in healthy controls (94.4%, 5.6% and 0, respectively) (P<0.05); Compared with the A/A genotype, the subjects with G allele significantly increased the risk of developing endometriosis, the odds ratios was 2.71 (95%CI=1.19~6.16). 5 ) The frequencies of the MMP-9 C and T allele among endometriosis patients and healthy controls were 88.8%, 11.2% and 91.9%, 8.1%, respectively; No significant difference in the MMP3 allele distribution was shown between the case and controls (P>0.05); The frequencies of the C/C, C/T and T/T genotypes among endometriosis patients (78.3%, 21% and 0.7%, respectively) were not significantly different from those in healthy controls (83.8%, 16.2% and 0, respectively) (P>0.05); Compared with the C/C genotype, the T allele did not significantly increase the risk of developing endometriosis, the adjusted odds ratio was 1.41(95%CI=0.79~2.52).
Conclusion: This study is the first to investigate the relation between MMPs promoter SNPs and the risk of EMs all over the world. Our result showed 1) There was the association of the MMP-1 promoter -1607 1G/2G with the risk of endometriosis, in other words, 2G allele could significantly increase susceptibility to endometriosis. 2) Although the MMP-3 promoter -1171 5A/6A could not be a layering marking to detect the risk of endometriosis, the 6A/6A and MMP-1 2G/2G genotype could be the conjunctive layering marking. 3) Our data suggest an association of the MMP-7 promoter -181 A/G with the risk of endometriosis, G allele could increase susceptibility to endometriosis. 4) It was not found to the association of the MMP-9 promoter -1562 C/T with the risk of endometriosis. 5) Some polymorphisms in MMPs could be the independent molecule marking to detect the risk of endometriosis.
PartIII Association of the mRNA and the protein expression of MMP-1 and MMP-7 with SNPs
Objective: To investigate the relation between polymorphisms at MMPs promoter region and the mRNA and protein expression.
Methods: The transcriptional activity and protein expression of the MMPs in eutopic endometrium for endometriosis patients, which took with the different genotypes of the MMP-1 and MMP-7, were analyzed by reverse transcription-polymerase chain raction (RT-PCR) and immunohistochemistry, respectively. Wilcoxon signed-rank test was used to measure the difference of mMRA and protein expression in eutopic endometrium with the different genotypes.
Results: 1) The relative expression of mMRA in eutopic endometrium for endometriosis patients with the MMP-1 1G/1G, 1G/2G and 2G/2G genotypes was 0.33±0.10, 0.43±0.16 and 0.54±0.24, respectively. The significant difference in the MMP-1 mMRA expression was shown among those (P=0.04). 2) There was significant difference in the relative expression of MMP-7 mMRA in eutopic endometrium for endometriosis patients with G allele (A/G+G/G) (0.37±0.26) and A/A genotype (0.37±0.26) (P=0.01). 3) The MMP-1 protein was mainly expressed in the stromal cells of eutopic endometrium, the expression of MMP-1 protein in eutopic endometrium for endometriosis patients with 2G/2G genotype was significantly higher than those with 1G/1G (P=0.047) and 1G/1G + 1G/2G genotypes (P=0.019). 4) The MMP-7 protein expressed primarily in endothelial cells of eutopic endometrium, compared with A/A genotype, the expression of MMP-7 protein in eutopic endometrium for endometriosis patients with A/G genotype was significantly high (P=0.016).
Conclusion: Our study is the first to confirm different transcriptive activity and protein expression for subjects with different genotypes, which result in the difference of eutopic endometrium for different subject, further cause different risk of EMs. 1) There was significant difference in the mMRA and protein expression of MMP-1 in eutopic endometrium for endometriosis patients with the different MMP-1 genotypes, in other words, the mMRA and protein expression of MMP-1 for ones with the 2G/2G genotypes was significantly higher than the others, which show the 2G allele could result in the increasing expression of MMP-1 protein in eutopic endometrium by enhancing gene transcriptional activity. 2) The mMRA and protein expression of MMP-7 in eutopic endometrium for ones with the different MMP-7 genotypes had significant difference, that was to say the subjects with G allele could significantly increase the mMRA and protein expression of MMP-7 in eutopic endometrium, which show the G allele could enhance gene transcriptional activity to result in the increasing expression of MMP-7 protein in eutopic endometrium.
In conclusion, our study confirms further that MMPs could play an important role in the development of EMs. In addition, we presume that the role of different MMPs is distinct in various stages of EMs development. The difference of subjects which is resulted by the genetic difference of MMP-1 has the association with the risk of EMs, and the abnormal expression of protein may have relation with the development of EMs; The abnormal expression of MMP-3 has a very important role in the development of EMs; As a protein of endothelial expression, MMP-7 may participate in the development of EMs, endometrial cells with high-expression MMP-7 easily take place ectopic implantation in the blood of menstruate countercurrented and increase the risk of EMs; It is not confirmed in our study that there are the association of MMP-9 with the risk of EMs, but in view of other study, we will further evaluate the role of MMP-9 in the development of EMs.
引文
1 谭先杰, 郎景和. 子宫内膜异位症的基础研究进展. 中华妇产科杂志, 1999, 34(4): 378
2 Bruner KL, Rier SE, Eisenberg E, et al. The potential role of environmental toxins in the pathophysiology of endometriosis. General Obstet Invest, 1999, 48(1): 45
3 Koks CA, Groothuis PG, Slaats P, et al. Matrix metalloproteinases and their tissue inhibitors in antegradely shed menstruum and peritoneal fluid, 2000, 73(3): 604~612
4 Morkve O, Leaerum OD. Flow cytometry measurement of p21, p53 protein expression and DNA content in paraffin embedded tissues from bronchial carcinoma. Cytometry, 1991, 12: 438~444
5 Witz CA, Monotoya-Rodriguez IA, Schenken RS. Whole explants of peritoneum and endometrium: A novel model of theearly endometriosis lesion. Fertil Steril, 1999, 71: 56~60
6 Spuijbroek MDEH, Dunselman GAJ, Menkeere PP, et al. Early endometriosis invades the extracellularmatrix. Fertil Steril, 1992, 58: 929~933
7 Hulboy DL, Rudolph LA, Matrisia LM. Matrix metalloproteinases as mediators of reproductive functionMolecular Human Reproduction, 1997, 3: 27~45
8 Rodgers WH, Matrisian LM, Giudice LC, et al. Patterns of matrix metalloproteinase expression in cycling endometrium imply differential functions and regulation by steroids. J Clin Invest, 1994, 94: 946~953
9 Wenzl RJ, Heinz H. Localization of matrix metalloproteinase-2 in uterine endometrium and ectopic implants. Gynecol Obstet Invest, 1998, 45: 253~257
10 Kokerin I, Eeckhout Yves, Nisolle M, et al. Expression of interstitial collagenase (matrix metalloproteinase-1) is related to the activity of human endometriotic lesions. Fertil Steril, 1997, 68: 246~251
11 Gottschalk C, Malberg K, Arndt M, et al. Matrix metalloproteinases and TACE play a role in the pathogenesis of endometriosis. Adv Exp Med Biol, 2000, 477: 483~48
12 Sillem M, Prifti S, Koch A, et al. Regulation of matrix metalloproteinases and their inhibitors in uterine endometrial cells of patients with and without endometriosis. Eur J Obstet Gynecol Reprod Biol, 2001, 95(2): 167~174
13 何月, 孔丽娜. MMP-3、TGF-β1 在子宫内膜异位症中的表达及其意义. 皖南医学院学报, 2006, 25: 105~107
14 翦薇, 何福仙. 肿瘤坏死因子α及孕酮对异位子宫内膜间质细胞分泌基质金属蛋白酶-3 的调节. 现代妇产科进展, 2004, 6: 410~412
15 Chung HW, Wen Y, Chun SH, et al. Matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-3 mRNA expression in ectopic and eutopic endometrium in women with endometriosis: a rationale for endometriotic invasiveness. Fertil Steril, 2001, 75(1): 152~159
16 邱晓红, 李荷莲. 基质金属蛋白酶 MMP-2 MMP-9 及其抑制因子TIMP-1 TIMP-2 在子宫内膜异位症中的表达及意义. 中国实用妇科与产科杂志, 2004, 20(3): 158~160
17 王红, 吴若松. 基质金属蛋白酶-2、-9 在子宫内膜异位症中的表达. 现代妇产科进展, 2002, 11(4): 261~262
18 安晓汾, 陈必良, 王德堂, 等. MMP-9 及 TIMP-1 在子宫内膜异位症中的表达及意义. 第四军医大学学报, 2003, 24(6): 553~556
19 陈必良, 安晓汾, 辛晓燕, 等. 基质金属蛋白酶 9 和 14 在子宫内膜异位症中的表达. 肿瘤防治研究, 2003, 30(4): 285~289
1 Sampson J. Peritoneal endometriosis due to menstrual dissemaination of endometrial tissue into the peritoneal cavity. Am J Obstet Gynecol, 1927, 14: 422~469
2 郎景和. 子宫内膜异位症研究的新里程. 中华妇产科杂志, 2005, 40(1): 3~4
3 Egeblad M., Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nat Rev cancer, 2002, 2: 161~174
4 Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nvcleated cells. Nucleic Acids Res, 1998, 16: 1215
5 Rutter JL, Mitchell TI, Buttice G, et al. A single nucleotide polymorphism in the matrix metalloproteinase-1 promoter creates an Ets binding site and augments transcription. Cancer Res, 1998, 58: 5321~5325
6 Ye S, Eriksson P, Hamsten A, et al. Progression of coronary atherosclerosis are associated with a common genetic variant of the human stromelysis-1 promoter which results in reduced gene expression. J Biol Chem, 1996, 271: 13055~1306
7 Jormsjo S, Whatling C, Walter DH, et al. Allele-specific regulation of matrix metalloproteinase-7 promoter activity is associated with coronary artery luminal dimensions among hypercholesterolemic patients. Arterioscler Thromb Vasc Biol, 2001, 21: 1834~1839
8 Zhang B, Ye S, Herrmann SM, et al. Functional polymorphism in the regulatory region of gelatinase B gene in relation to severity of coronary atherosclerosis. Circulation, 1999, 99: 1788~1794.
9 Brinckerhoff CE, Rutter JL, Benbow U. Interstitial collagenases as markers of tumor progression. Clin Cancer Res, 2000, 6: 4823~4830
10 Kokorine I, Eeckhout Yves, Nisolle M, et al. Expression of interstitial collagenase (matrix metalloproteinase-1) is related to the activity of human endometriotic lesions. Fertil Steril, 1997, 68: 246~251
11 Nishioka Y, Sagae S, Nishikawa A, et al. A relationship between Matrix metalloproteinase-1 (MMP-1) promoter polymorphism and cervical cancer progression. Cancer Lett, 2003, 200: 49~55
12 Rutter JL, Mitchell TI, Buttice G, et al. A single nucleotide polymorphism in the matrix metalloproteinase-1 promoter creates an Ets binding site and augments transcription. Cancer Res, 1998, 58: 5321~5325
13 Kanamori Y, Matsushima M, Minaguchi T, et al. Correlation between expression of the matrix metalloproteinase-1 gene in ovarian cancers and an insertion/deletion polymorphism in its promoter region. Cancer Res, 1999, 59: 4225~4227
14 Tower GB, Coon CI, Brinckerhoff CE. The 2G single nucleotide polymorphism (SNP) in the MMP-1 promoter contributes to high levels of MMP-1 transcription in MCF-7/ADR breast cancer cells. Breast Cancer Res Treat, 2003, 82(2): 75~82
15 Mizumoto H, Saito T, Ashihara K, et al. Expression of matrix metalloproteinases in ovarian endometriomas: immunohistochemical study and enzyme immunoassay. Life Sci, 2002, 71(3): 259~273
16 Wenzl R J, Heinz H. Localization of matrix metalloproteinase-2 in uterine endometrium and ectopic implants. Gynecol Obstet Invest, 1998, 45: 253~257
17 Koks C A, Groothuis P G, Slaats P, et al. Matrix metalloproteinases and their tissue inhibitors in antegradely shed menstruum and peritoneal fluid. Fertil Steril, 2000, 73(3): 604~612
18 Hinoda Y, Okayama N, Takano N, et al. Association of functional polymorphisms of matrix metalloproteinase MMP-1 and MMP-3 genes with colorectal cancer. Int J Cancer, 2002, 102(5): 526~529
19 Ghilardi G, Biondi ML, Caputo, et al. A single nucleotide polymorphism in the matrix metalloproteinase-3 promoter enhances breast cancer susceptibility. Clin Cancer Res, 2002, 8: 3820~3823
20 Smolarz B, Szyllo K, Romanowicz-Makowska H, et al. PCR analysis of matrix metalloproteinase 3 (MMP-3) gene promoter polymorphism in ovarian cancer. Pol J Pathol, 2003, 54: 233~238
21 Szyllo K, Smolarz B, Romanowicz-Makowska H, et al. The promoter polymorphism of the matrix metalloproteinase3 (MMP-3) gene in women with ovarian cancer. Exp Clin Cancer Res, 2002, 21(3): 357~361
22 Knox JD, Boreham DR, Walker JA, et al. Mapping of the metalloproteinase gene matrilysin (MMP-7) to human chromosome 11q21-q22. Cytogen Cell Genet, 1996, 72(2-3): 179~182
23 Mori M, Barnard GF, Mjmorik, et al. Overexpression of matrix metalloproteinase-7 mRNA in human colon carcinomas. Cancer, 1995, 75: 1516~1519
24 Powell WC, Knox JD, Navre M, et al. Expression of the metalloproteinase matrilysin in DU-145 cells increases their invasive potential in severe combined inmunodeficient mice. Cancer Res, 1993, 53: 417~422
25 Osteen KG, Bruner KL, Sharpe-Timms KL, et al. Steroid and growth factor regulation of matrix metalloproteinase expression and endometriosis. Semin Reprod Endocrinol, 1996, 14: 247~255
26 Ghilardi G, Biondi ML, Erario M, et al. Colorectal carcinoma susceptibility and metastases are associated with matrix metalloproteinase-7 promoter polymorphisms. Clin Chem, 2003, 49: 1940~1942
27 Kenichi Ohashi, Tetsuo Nemoto, Kyoichi Nakamura, et al. Increased Expression of Matrix Metalloproteinase7 and 9 and Membrane Type1-Matrix Metalloproteinase in Esophageal Squamous Cell Carcinomas.Cancer, 2000, 88(10): 2201~2209
28 Aglund K, Rauvala M, Puistola U, et al. Gelatinases A and B (MMP-2 and MMP-9) in endometrial cancer-MMP-9 correlates to the grade and the stage. Gynecol Oncol, 2004, 94: 699~704
29 Chung HW, Wen Y, Chun SH, et al. Matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-3 mRNA expression in ectopic and eutopicendometrium in women with endometriosis: a rationale for endometriotic invasiveness. Fertil Steril, 2001, 75: 152~159
30 于云英, 郭新华, 钱金花, 等. 基质金属蛋白酶 9 及其组织抑制剂TIMP-3 在子宫内膜异位症的表达, 现代妇产科进展, 2003, 12: 25~27
31 Ria R, Loverro G, Vacca A, et al. Angiogenesis extent and expression of matrix metalloproteinase-2 and -9 agree with progression of ovarian endometriomas. Eur J Clin Invest, 2002, 32: 199~206
32 Matsumura S, Oue N, Nakayama H, et al. A single nucleotide polymorphism in the MMP-9 promoter affects tumor progression and invasive phenotype of gastric cancer. J Cancer Res Clin Oncol, 2005, 131: 19~25
33 Zhang B, Dhillon S, Geary I, et al. Polymorphisms in matrix metalloproteinase-1, -3, -9, and -12 genes in relation to subarachnoid hemorrhage. Stroke, 2001, 32: 2198~2202
34 Kim JS, Park HY, Kwon JH, et al. The roles of stromelysin-1 and the gelatinase B gene polymorphism in stable angina. Yonsei Med J, 2002, 43: 473~481
1 Kennedy S. Is there a genetic basis to endometriosis? Semin Reprod Endocrinol, 1997, 15(3): 309~318
2 Simpson JL, Elias S, Malinak LR, et al. Heritable aspects of endometriosis I. Genetic studies. Am J Obstet Gynecol, 1980, 137: 327~331
3 Lamb K, Hoffmann RG, Nichols TR. Family trait analysis: a case-control study of 43 women with endometriosis and their best friends. Am J Obstet Gynecol, 1986, 154: 596~601
4 Moen MH, Magnus P. The familial risk of endometriosis. Acta Obstet. Gynecol. Scand, 1993, 72: 560~564
5 Malinak LR, Buttram VC Jr. Heritage aspects of endometriosis II Clinical characteristics of familial endometriosis.Am J Obstet Gynecol, 1980, 137(3):332~337
6 Moen MH. Endometriosis in monozygotic twins. Acta Obstet Gynecol Scand, 1994,.73: 59~62
7 Hadfield RM, Mardon HJ, Barlow DH, et al. Endometriosis in monozygotic twins. Fertil Steril, 1997, 68: 941~942
8 Marshall E. Snipping a way at genome patenting. Science, 1997, 227:1752~1753.
9 Lattuada D, Vigano P, Somigliana E, et al. Androgen receptor gene cytosine, adenine, and guanine trinucleotide repeats in patients with endometriosis. J Soc Gynecol Investig, 2004, 11(4): 237~240
10 Hsieh YY, Chang CC, Tsai FJ, et al. T allele for VEGF gene -460 polymorphism at the 5'-untranslated region: association with a higher susceptibility to endometriosis. J Reprod Med, 2004, 49(6):468~472
11 Nakago S, Hadfield RM, Zondervan KT, et al. Association between endometriosis and N-acetyl transferase 2 polymorphisms in a UK population. Mol Hum Reprod, 2001, 7(11): 1079~1083
12 Hadfield RM, Manek S, Nakago S, et al. Absence of a relationshipbetween endometriosis and the N314D polymorphism of galactose-1-phosphate uridyl transferase in a UK population. Mul Hum Reprod, 1999, 5(10):990~993
13 Kiyohara C, Nakanishi Y, Inutsuka S, et al. The relationship between CYP1A1 aryI hydrocarbon hydroxylase activity and lung cancer in a Japanese population. Pharmacogenetics, 1998, 8: 315~323
14 Kanamori Y, Matsushima M, Minaguchi T, et al. Correlation between expression of the matrix metalloproteinase-1 gene in ovarian cancers and an insertion/deletion polymorphism in its promoter region. Cancer Res, 1999, 59(17): 4225~4227
15 Lin TS, Huang HH, Fan YH, et al. Genetic polymorphism and gene expression of microsomal epoxide hydrolase in non-small cell lung cancer. Oncol Rep, 2007 Mar, 17(3): 565~572
16 Higashi T, Kyo S, Inoue M, et al. Novel functional single nucleotide polymorphisms in the latent transforming growth factor-beta binding protein-1L promoter: effect on latent transforming growth factor-beta binding protein-1L expression level and possible prognostic significance in ovarian cancer. J Mol Diagn, 2006, Jul, 8(3):342~350
17 Ying-De Wang, Pei-Yun Yan. Expression of matrix metalloproteinase-1 and tissue inhibitor of metalloproteinase-1 in ulcerative colitis. World J Gastroenterol, 2006, 12(37): 6050~6053
18 Yonemura Y, Fujimura T, Ninomiya I, et al. Prediction of Peritoneal Micrometastasis by Peritoneal Lavaged Cytology and Reverse Transcriptase-Polymerase Chain Reaction for Matrix Metalloproteinas -e-7 mRNA. Clin Cancer Res, 2001, 7(6): 1647~1653
19 Sampson J. Peritoneal endometriosis due to menstrual dissemaination of endometrial tissue into the peritoneal cavity. Am J Obstet Gynecol, 1927, 14: 422~469
20 Lu XE, Ning WX, Dong MY, et al. Vascular endothelial growth factor and matrix metalloproteinase-2 expedite formation of endometriosis in the early stage ICR mouse model. Fertil Steril, 2006, 86(4): 1175~1181
21 Nishioka Y, Sagae S, Nishikawa A, et al. A relationship between Matrix metalloproteinase-1 (MMP-1) promoter polymorphism and cervical cancer progression. Cancer Lett, 2003, 200: 49~55
22 Tower GB, Coon CI, Brinckerhoff CE. The 2G single nucleotide polymorphism (SNP) in the MMP-1 promoter contributes to high levels of MMP-1 transcription in MCF-7/ADR breast cancer cells. Breast Cancer Res Treat, 2003, 82(2): 75~82
23 Nishioka Y, Sagae S, Nishikawa A, et al. A relationship between Matrix metalloproteinase-1 (MMP-1) promoter polymorphism and cervical cancer progression. Cancer Lett, 2003, 200(1): 49~55
24 Hirata H, Naito K, Yoshihiro S, et al. A single nucleotide polymorphism in the matrix metalloproteinase-1 promoter is associated with conventional renal cell carcinoma. Int J Cancer, 2003, 106(3): 372~374
25 Hinoda Y, Okayama N, Takano N, et al. Association of functional polymorphisms of matrix metalloproteinase (MMP)-1 and MMP-3 genes with colorectal cancer. Int J Cancer, 2002, 102(5): 526~529
26 Zhu Y, Spitz MR, Lei L, et al. A single nucleotide polymorphism in the matrix metalloproteinase-1 promoter enhances lung cancer susceptibility. Cancer Res, 2001, 61(21): 7825~7829
27 Mori M, Barnard GF, Mjmorik, et al. Overexpression of matrix metalloproteinase-7 mRNA in human colon carcinomas. Cancer, 1995, 75: 1516~1519
28 Powell WC, Knox JD, Navre M, et al. Expression of the metalloproteinase matrilysin in DU-145 cells increases their invasive potential in severe combined inmunodeficient mice. Cancer Res, 1993, 53: 417~422
29 郭源, 万远廉, 魏群, 等. 基质金属蛋白酶-7 基因在胃癌中的表达.中华普通外科杂志, 2000, 15(2): 82~84
30 Adachi Y, Yamamoto H, Itoh F, et al. Contribution of matrilysin(MMP-7) to the metastatic pathway of human colorectal cancer. Gut, 1999, 45(2): 252~258
31 Lynch CC, McDonnell S.The role of matrilysin (MMP-7) in leukaemia cell invasion. Clin Exp Metastasis, 2000, 18(5): 401~406
32 Jormsjo S, Whatling C, Walter DH, et al. Allele-specific regulation of matrix metalloproteinase-7 promoter activity is associated with coronary artery luminal dimensions among hypercholesterolemic patients. Arterioscler. Thromb. Vasc. Biol., 2001, 21: 1834~1839
33 Giorgio Ghilardi, Maria Luisa Biondi, Maddalena Erario, et al. Colorectal Carcinoma Susceptibility and Metastases Are Associated with Matrix Metalloproteinase-7 Promoter Polymorphisms. Clinical Chemistry, 2003, 49: 1940~1942
1 Gottschalk C, Malberg K, Arndt M, et al. Matrix metalloproteinases and TACE play a role in the pathogenesis of endometriosis. Adv Exp Med Biol, 2000, 477: 483~486
2 Brandstetter H, Grams F, Glitz D, et al. The 1.8-A crystal ctructure of a matrix metalloproteinase 8-barbiturate inhibitor complex reveals a previously unobserved mechanism for collagenase substrate recognition. J Biol Chem, 2001, 276(20): 17405~17412
3 Fini ME, Girard MT. Expression of collagenolytic/gelatinolytic metalloproteinases by normal cornea. Invest Ophthalmol Vis Sci, 1990, 31(9): 1779~1788
4 Murphy G, Cockett MI, Ward RV, et al. Matrix metalloproteinase degradation of elastin, type IV collagen and proteoglycan. A quantitative comparison of the activities of 95 kDa and 72 kDa gelatinases, stromelysins-1 and -2 and punctuated metalloproteinase (PUMP). Biochem. J, 1991, 277(Pt 1): 277~279
5 Damjanovski S, Amano T, Li Q, et al. Overexpression of matrix metalloproteinases leads to lethality in transgenic Xenopus laevis: implications for tissue-dependent functions of matrix metallopro- teinases during late embryonic development. Dev Dyn, 2001, 221(1): 37~47
6 Hozumi A, Nishimura Y, Nishiuma T, et al. Induction of MMP-9 in normal human bronchial epithelial cells by TNF-alpha via NF-kappa B-mediated pathway. Am J Physiol Lung Cell Mol Physiol, 2001, 281(6): L1444~1452
7 Mengshol JA, Vincenti MP, Brinckerhoff CE. IL-1 induces collagenase-3 (MMP-13) promoter activity in stably transfected chondrocytic cells: requirement for Runx-2 and activation by p38 MAP and JNK pathways. Nucleic Acids Res, 2001, 29(21): 4361~4372
8 Alper O, Bergmann-Leitner ES, Bennett TA, et al. Epidermal growth factor receptor signaling and the invasive phenotype of ovarian carcinoma cells. JNatl Cancer Inst, 2001, 93(18): 1375~1384
9 Alexander JP, Acott TS. Involvement of protein kinase C in TNFalpha regulation of trabecular matrix metalloproteinases and TIMPs. Invest Ophthalmol Vis Sci, 2001, 42(12): 2831~2838
10 Yang JQ, Zhao W, Duan H, et al. v-Ha-RaS oncogene upregulates the
92-kDa type IV collagenase (MMP-9) gene by increasing cellular superoxide production and activating NF-kappaB. Free Radic Biol Med, 2001, 31(4): 520~529
11 Yoon A, Hurta RA. Insulin like growth factor-1 selectively regulates the expression of matrix metalloproteinase-2 in malignant H-ras transformed cells. Mol Cell Biochem, 2001, 223(1-2): 1~6
12 Wick W, Plattern M, Weller M. Glioma cell invasion: regulation of metalloproteinase activity by TGF-beta. J Neurooncol, 2001, 53(2): 177~185
13 Frankenberger M, Hauck RW, Frankenberger B, et al. All trans-retinoic acid selectively down-regulates matrix metalloproteinase-9 (MMP-9) and up-regulates tissue inhibitor of metalloproteinase-1 (TIMP-1) in human bronchoalveolar lavage cells. Mol Med. 2001, 7(4): 263~270
14 Galboiz Y, Shapiro S, Lahat N, et al. Matrix metalloproteinases and their tissue inhibitors as markers of disease subtype and response to interferon-beta therapy in relapsing and secondary-progressive multiple sclersis patients. Ann Neurol, 2001, 50(4): 443~451
15 Luo XH, Liao EY. Progesterone differentially regulates the membrane-type matrix metalloproteinase-1 (MT1-MMP) compartment of proMMP-2 activation in MG-63 cells. Horm Metab Res, 2001, 33(7): 383~388
16 Benbow U, Brinckerhoff CE. The AP-1 site and MMP gene regulation: what is all the fuss about? Matrix Biol, 1997, 15(8-9): 519~526
17 Rutter JL, Mitchell TI, Buttice G, et al. A single nucleotide polymorphism in the matrix metalloproteinase-1 promoter creates an Ets binding site and augments transcription. Cancer Res, 1998, 58(23): 5321~5325
18 Lafleur MA, Hollenberg MD, Atkinson SJ, et al. Activation of pro-(matrixmetalloproteinase-2) (pro-MMP-2) by thrombin is membrane-type -MMP- dependent in human umbilical vein endothelial cells and generates a distinct 63 kDa active species. Biochem J, 2001, 357(Pt 1): 107~115
19 Sate H, Seiki M. Membrane-type matrix metalloproteinases (MT-MMPs) in tumour metastasis. J Biochem, 1996, 119(2): 209~215
20 Butler GS, Butler MJ, Atkinson SJ, et al. The TIMP-2 membrane type 1 metalloproteinase ‘receptor’ regulates the concentration and efficient activation of progelatinase A. A kinetic study. J Biol Chem, 1998, 273(2): 871~880
21 Knauper V, Will H, Lopez-Otin C, et al. Cellular mechanisms for human procollagenase-3 (MMP-13) activation. Evidence that MT1-MMP (MMP-14) and gelatinase A (MMP-2) are able to generate active enzyme. J Biol Chem, 1996, 271(29): 17124~17131
22 Gomez DE, Alonso DF, Yoshiji H, et al. Tissue inhibitors of metalloproteinases: structure, regulation and biological functions. Eur J Cell Biol, 1997, 74(2): 111~122
23 Ishiguro N, Ito T, Oguchi T, et al. Relationships of matrix metallo- proteinases and their inhibitors to cartilage proteoglycan and collagen turnover and inflammation as revealed by analyses of synovial fluids from patients with rheumatoid arthritis. Arthritis Rheum, 2001, 44(11): 2503~2511
24 Ogata Y, Miura K, Ohkita A, et al. Imbalance between matrix metalloproteinase 9 and tissue inhibitor of metalloproteinases 1 expression by tumor cells implicated in liver metastasis from colorectal carcinoma. Kurume Med J, 2001, 48(3): 211~218
25 Hoashi T, Kadono T, Kikuchi K, et al. Differential growth regulation in human melanoma cell lines by TIMP-1 and TIMP-2. Biochem Biophys Res Commun, 2001, 288(2): 371~379
26 Zeng Z, Sun Y, Shu W, et al. Tissue inhibitor of metalloproteinase-3 is a basement membrane-associated protein that is significantly decreased in human colorectal cancer. Dis Colon Rectum, 2001, 44(9): 1290~1296metalloproteinase-2) (pro-MMP-2) by thrombin is membrane-type -MMP- dependent in human umbilical vein endothelial cells and generates a distinct 63 kDa active species. Biochem J, 2001, 357(Pt 1): 107~115
19 Sate H, Seiki M. Membrane-type matrix metalloproteinases (MT-MMPs) in tumour metastasis. J Biochem, 1996, 119(2): 209~215
20 Butler GS, Butler MJ, Atkinson SJ, et al. The TIMP-2 membrane type 1 metalloproteinase ‘receptor’ regulates the concentration and efficient activation of progelatinase A. A kinetic study. J Biol Chem, 1998, 273(2): 871~880
21 Knauper V, Will H, Lopez-Otin C, et al. Cellular mechanisms for human procollagenase-3 (MMP-13) activation. Evidence that MT1-MMP (MMP-14) and gelatinase A (MMP-2) are able to generate active enzyme. J Biol Chem, 1996, 271(29): 17124~17131
22 Gomez DE, Alonso DF, Yoshiji H, et al. Tissue inhibitors of metalloproteinases: structure, regulation and biological functions. Eur J Cell Biol, 1997, 74(2): 111~122
23 Ishiguro N, Ito T, Oguchi T, et al. Relationships of matrix metallo- proteinases and their inhibitors to cartilage proteoglycan and collagen turnover and inflammation as revealed by analyses of synovial fluids from patients with rheumatoid arthritis. Arthritis Rheum, 2001, 44(11): 2503~2511
24 Ogata Y, Miura K, Ohkita A, et al. Imbalance between matrix metalloproteinase 9 and tissue inhibitor of metalloproteinases 1 expression by tumor cells implicated in liver metastasis from colorectal carcinoma. Kurume Med J, 2001, 48(3): 211~218
25 Hoashi T, Kadono T, Kikuchi K, et al. Differential growth regulation in human melanoma cell lines by TIMP-1 and TIMP-2. Biochem Biophys Res Commun, 2001, 288(2): 371~379
26 Zeng Z, Sun Y, Shu W, et al. Tissue inhibitor of metalloproteinase-3 is a basement membrane-associated protein that is significantly decreased in human colorectal cancer. Dis Colon Rectum, 2001, 44(9): 1290~1296Reprod, 1977, 3(9): 735~741
36 Osteen KG. The endocrinology of decidualization In: Bazer F, ed. The Endocrinology of Pregnancy. Totowa, NJ: Humana Press, 1998: 541~663
37 Kamat BR, Isaacson PG. The immunocytochemical distribution of leukocytic subpopulations in human endometrium. Am J Pathol, 1987, 127(1): 66~73
38 Bonatz G, Hansmann ML, Buchholz F, et al. Macrophage- and lymphocyte-subtypes in the endometrium during different phases of the ovarian cycle. Int J Gynaecol Obstet, 1992, 37(1): 29~36
39 Loke YW, King A. Human Implantation: Cell Biology and Immunology. New York: Cambridge University Press. 1996
40 Bruner KL, Rodgers WH, Gold LI, et al. Transforming growth factor beta mediates the progesterone suppression of an epithelial metalloproteinase by adjacent stroma in the human endometrium. Proc Natl Acad Sci USA, 1995, 92(16): 7362~7366
41 Vincent AJ, Salamonsen LA. The role of matrix metalloproteinases and leukocytes in abnormal uterine bleeding associated with progestin only contraceptives. Hum Reprod, 2000, 15(suppl 3): 135~143
42 Bruner-Tran KL, Eisenberg E, Yeaman GR, et al. Steroid and cytokine regulation of matrix metalloproteinase expression in endometriosis and the establishment of experimental endometriosis in nude mice. J Clin Endocrinol Metab, 2002, 87(10): 4782~4791
43 Schroen DJ, Brinckerhoff CE. Nuclear hormone receptors inhibit matrix metalloproteinase (MMP) gene expression through diverse mechanisms. Gene Expr, 1996, 6(4): 197~207
44 Kushner PJ, Agard DA, Greene GL, et al. Estrogen receptor pathways to AP-1. J Steroid Biochem Mol Biol, 2000, 74: 311~317
45 Teyssier C, Belguise K, Galtier F, et al. Characterization of the physical interaction between estrogen receptor alpha and JUN proteins. J Biol Chem, 2001, 276(39): 36361~36369
46 Benbow U, Brinckerhoff CE. The AP-1 site and MMP gene regulation:what is all the fuss about? Matrix Biol, 1997, 15(8-9): 519~526
47 Osteen KG, Rodgers WH, Gaire M, et al. Stromal-epithelial interaction mediates steroidal regulation of metalloproteinase expression in human endometrium. Proc Natl Acad Sci U S A, 1994, 91(21): 10129~10133
48 Schatz F, Papp C, Toth-Pal E, et al. Ovarian steroid-modulated stromelysin-1 expression in human endometrial stromal and decidual cells. J Clin Endocrinol Metab, 1994, 78(6): 1467~1472
49 Rudolph-Owen LA, Slayden OD, Matrisian LM, et al. Matrix metalloproteinase expression in Macaca mulatta endometrium: evidence for zone-specific regulatory tissue gradients. Biol Reprod, 1998, 59(6): 1349~1359
50 Curry TE Jr, Osteen KG. Cyclic changes in the matrix metalloproteinase system in the ovary and uterus. Biol Reprod, 2001, 64(5): 1285~1296
51 Bamberger AM, Bamberger CM, Gellersen B, et al. Modulation of AP-1 activity by the human progesterone receptor in endometrial adenocarcinoma cells. Proc Natl Acad Sci USA, 1996, 93(12): 6169~6174
52 Salmi A, Ammala M, Rutanen EM. Proto-oncogenes c-jun and c-fos are down-regulated in human endometrium during pregnancy: relationship to oestrogen receptor status. Mol Hum Reprod, 1996, 2(12): 979~984
53 Kirkland JL, Murthy L, Stancel GM. Progesterone inhibits the estrogen-induced expression of c-fos messenger ribonucleic acid in the uterus. Endocrinology, 1992, 130(6): 3223~3230
54 Osteen KG, Bruner-Tran KL, Ong D, et al. Paracrine mediators of endometrial matrix metalloproteinase expression: potential targets for progestin-based treatment of endometriosis. Ann N Y Acad Sci, 2002, 955: 139~146; discussion 157~158, 396~406
55 Osteen KG, Keller NR, Feltus FA, et al. Paracrine regulation of matrix metalloproteinase expression in the normal human endometrium. Gynecol Obstet Invest, 1999, 48(suppl 1): 2~13
56 Matrisian LM. Matrix metalloproteinase gene expression. Ann N Y Acad Sci, 1994, 732: 42~50
57 Kokerin I, Nisolle M, Donnez J, et al. Expression of interstitial collagenase (matrix metalloproteinase-1) is related to the activity of human endometriotic lesions. Fertil Steril, 1997, 68(2): 246~251
58 Gottschalk C, Malberg K, Arndt M, et al. Matrix metalloproteinases and TACE play a role in the pathogenesis of endometriosis. Adv Exp Med Biol, 2000, 477: 483~486
59 Wenzl RJ, Heinzl H. Localization of matrix metalloproteinase-2 in uterine endometrium and ectopic implants. Gynecol Obstet Invest, 1998, 45(4): 253~257
60 Chung HW, Wen Y, Chun SH, et al. Matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-3 mRNA expression in ectopic and eutopic endometrium in women with endometriosis: a rationale for endometriotic invasiveness. Fertil Steril, 2001, 75(1): 152~159
61 Sillem M, Prifti S, Koch A, et al. Regulation of matrix metalloproteinases and their inhibitors in uterine endometrial cells of patients with and without endometriosis. Eur J Obstet Gynecol Reprod Biol, 2001, 95(2): 167~174
62 邱晓红, 李荷莲. 基质金属蛋白酶 MMP-2 MMP-9 及其抑制因子TIMP-1 TIMP-2 在子宫内膜异位症中的表达及意义. 中国实用妇科与产科杂志, 2004, 20(3): 158~160
63 Steward WP. Marimastat (BB2516): current status of development. Cancer Chemother Pharmacol, 1999, 43(Suppl): S56~60
64 Rothenberg ML, Nelson AR, Hande KR. New drugs on the Horizon: Matrix Metalloproteinase Inhibitors. Oncologist, 1998, 3(4): 271~274
1 Kennedy S. Is there a genetic basic to endometriosis? Senin Reprod, 1997, 15(3): 309~311
2 Hsieh Y, Chanq CC, Tsai CH, et al. Estrogen receptor alpha dinucleotide repeat and cytochrome P450c17alpha gene polymorphisms are associated with susceptibility to endometriosis. Fertil Steril, 2005, 83(3):567~572
3 Wang Z, Yoshida S, Negoro K, et al. Polymorphisms in the estrogen receptor beta gene but not estrogen receptor alpha gene affect the risk of developing endometriosis in a Japanese population. Fertil Steril, 2004, 81: 1650~1656
4 宋绿茵, 何凤仪, 方小玲, 等。雌激素受体基因多态性与子宫内膜异位症的相关性研究. 中华妇产科杂志, 2005, 40(1): 47~48
5 黄海玲, 韦叶生, 方晓燕, 等. 雌激素受体 β 基因多态性与子宫内膜异位症的相关性研究. 中华妇产科杂志, 2005, 40(9): 644~645
6 Lattuada D, Somigliana E, Vigano P, et al. Genetics of endometriosis: a role for the progesterone receptor gene polymorphism PROGINS? Clin Endocrinol (Oxf), 2004, 61(2): 190~194
7 Treloar SA, Zhao ZZ, Montqomery GW, et al. Association between polymorphisms in the progesterone receptor gene and endometriosis. Mol Hum Reprod, 2005, 11(9): 641~647
8 Van Kaam KJ, Romano A, Groothuis PG, et al. Progesterone receptor polymorphism +331G/A is associated with a decreased risk of deep infiltrating endometriosis. Hum Reprod, 2006, 18
9 康山, 王瑛, 李琰, 等. 基质金属蛋白酶基因启动子区基因多态性与子宫内膜异位症遗传易感性的相关性研究. 中华妇产科杂志, 2005, 40(9): 601~604
10 Ferrari MM, Biondi ML, Viqano P, et al. Analysis of two polymorphisms in the promoter region of matrix metalloproteinase 1 and 3 genes in women with endometriosis. Acta Obstet Gynecol Scand, 2006, 85(2):212~217
11 Shan K, Lian-Fu Z, Yan L, et al. Polymorphisms in the promoter regions ofthe matrix metalloproteinases-7, -9 and the risk of endometriosis and adenomyosis in China. Mol Hum Reprod, 2006, 12(1): 35~39
12 彭冬先, 何援利, 丘立文, 等. 子宫内膜异位症与细胞色素 P450 1A1 基因 A4889G 突变的相关性. 中华医学遗传学杂志, 2003, 20(4): 284~286
13 Asqhar T, Yoshida S, et al. Lack of association between endometriosis and the CYP17 MspA1 polymorphism in UK and Japanese populations. Gynecol Endocrinol, 2005, 20(2): 59~63
14 Hsieh YY, Chanq CC, et al. Estrogen receptor alpha dinucleotide repeat and cytochrome P450c17alpha gene polymorphisms are associated with susceptibility to endometriosis. Fertil Steril, 2005, 83(3): 567~572
15 彭东先, 何援利, 丘立文, 等. 谷胱甘肽-S-转移酶 M1 基因缺失与子宫内膜异位症易感性的关系. 第一军医大学学报, 2003, 23(5): 458~459
16 Baxter SW, Thornas E J, Campbell IG. GSTM1 null polymorphism and susceptibility to endometriosis and ovarian cancer. Carcinogenesis, 2001, 22 (1): 63~65
17 Morizane M, Yoshida S, Nakago S, et al. No association of endometriosis with glutathione S-transferase M1 and T1 null mutations in a Japanese population. J Soc Gynecol Investig, 2004, 11(2): 118~121
18 Lin HJ, Han CY. Slow acetylor mutations in the human polymorphic N-acetyltransferase gene in 786 Asians, Blacks, Hispanics, and Whites: Application to metabolic epidemiology.Am J Hum Genet, 1993, 52(4): 827~834
19 Bischoff FZ, Marquez-DO. Association of NAT2 genetid polymorphism resulting in decreased capacity to detoxify aromatic amines in women with endometriosis. Gynecol Invest, 5(S): 111A
20 Nakago S. Association between endometriosis and N-acetyltransferase 2 polymorphisms in a UK population Molecular Human Reproduction, 2001, 7(11): 1079~1083
21 Baranova H, Canis M. Possible involvement of arylamine N-acetyltransferase 2, glutathione S-transferase M1 and T1 genes in the development of endometriosis. Mol Hum Repord, 1999, 5(7): 636~641
22 Cramer, D.W., Hornstein, MD. Endometriosis associated with the N314D mutation of GALT. Mol Hum Reprod, 1996, 2: 149~152
23 Hadfield RM, Manek S, Nakago S, et al. Absence of a relationship between endometriosis and the N314D polymorphism of galactose-1-phosphate uridyl transferase in a UK population. Mul Hum Reprod, 1999, 5(10): 990~993
24 Wieser F, Hefler L, Tempfer C, et al. Polymorphism of the interleukin-1 beta gene and endometriosis. J Soc Gynecol Investig, 2003, 10(3): 172~175
25 Hsieh YY, Chang CC, Tsai FJ, et al. Polymorphisms for interleukin-1 beta (IL-1 beta)-511 promoter, IL-1 beta exon 5, and IL-1 receptor antagonist: nonassociation with endometriosis. J Assist Reprod Genet, 2001, 18(9): 506~511
26 D’Amora P, Sato H, et al. Polymorphisms in exons 1B and 1C of the type I interleukin-1 receptor gene in patients with endometriosis. Am J Reprod Immunol, 2006, 56(3): 178~184
27 Wieser F, Fabjani G, Tempfer C, et al. Analysis of an interleukin-6 gene promoter polymorphism in women with endometriosis by pyrosequencing. J Soc Gynecol Investig, 2003, 10(1): 32~36
28 Bhanoori M, Babu KA, et al. The interleukin-6 -174G/C promoter polymorphism is not associated with endometriosis in South Indian women. J Soc Gynecol Investing. 2005, 12(5): 365~369
29 Kitawaki J, Kiyomizu M. Synergistic effect of interleukin-6 promoter (IL6 -634C/G) and intercellular adhesion molecule-1 (ICAM-1 469K/E) gene polymorphisms on the risk of endometriosis in Japanese women. Am J Reprod Immunol, 2006, 56(4):267~274
30 Hsieh YY, Chang CC, Tsai FJ, et al. Association of an A allele for interleukin-10 -627 gene promoter polymorphism with higher susceptibility to endometriosis. J Reprod Med, 2003, 48(9): 735~738
31 Kitawaki J, Obayashi H, Ohta M, et al. Genetic contribution of the interleukin-10 promoter polymorphism in endometriosis susceptibility. Am J Reprod Immunol, 2002, 47(1): 12~18
32 Hsieh YY, Chang CC, Tsai FJ, et al. T allele for VEGF gene-460 polymorphism at the 5'-untranslated region: association with a higher susceptibility to endometriosis. J Reprod Med, 2004, 49(6):468~472
33 Bhanoori M, Arvind Babu K. The vascular endothelial growth factor (VEGF) +405G>C 5'-untranslated region polymorphism and increased risk of endometriosis in South Indian women: a case control study. Hum Reprod. 2005, 20(7): 1844~1849
34 Teramoto M, Kitawaki J, Koshiba H, et al. Genetic contribution of tumor necrosis factor (TNF)-alpha gene promoter (-1031, -863 and -857) and TNF receptor 2 gene polymorphisms in endometriosis susceptibility. Am J Reprod Immunol, 2004, 51(5): 352~357
35 Hsieh YY, Chang CC, et al. Interleukin-2 receptor beta (IL-2R beta)-627*C homozygote but not IL-12R beta 1 codon 378 or IL-18 105 polymorphism is associated with higher susceptibility to endometriosis. Fertil Steril, 2005, 84(2):510-512
36 罗敏, 何援利. 广东妇女子宫内膜异位症与肿瘤坏死因子基因多态性的相关性研究. 南方医科大学学报, 2006, 26(8): 1163~1165
37 Vigano P, Infantino M, Lattuada D. Intercellular adhesion molecule-1 (ICAM-1) gene polymorphisms in endometriosis. Mol Hum Reprod, 2003, 9(1): 47~52
38 Yamashita M , Yoshida S. Association study of endometriosis and intercellular adhesion molecule-1 (ICAM-1) gene polymorphisms in a Japanese population. J Soc Gynecol Investig, 2005, 12(4): 267~271
39 宗利丽, 潘德京, 陈为明, 等. HLA-DQA1、-DRB1 等位基因与子宫内膜异位症和子宫腺肌病的比较性研究. 中华医学遗传学杂志, 2002, 19(1):49~51
40 王新, 刘春宇, 林秋华, 等. 子宫内膜异位症与人类白细胞抗原 DRB1等位基因多态性的关系. 中华妇产科杂志, 2002, 37(6): 346~348
41 Whang DH, Kim SH. No association between HLA-DRB1 alleles and susceptibility to advanced stage endometriosis in a Korean population. Hum Reprod, 2006, 21(1):129~133
42 Chang CC, Hsieh YY, Tsai FJ, et al. The proline form of p53 codon 72 polymorphism is associated with endometriosis. Fertil Steril, 2002, 77(1): 43~45
43 Lattuada D, Vigano P, Somigliana E, et al. Analysis of the codon 72 polymorphism of the TP53 gene in patients with endometriosis. Mol Hum Reprod, 2004, 10(9): 651~654
44 Hsieh YY, Lin CS. P53 codon 11, 72, and 248 gene polymorphisms in endometriosis. Int J Biol Sci, 2006, 2(4):188~193
2 Bruner KL, Rier SE, Eisenberg E, et al. The potential role of environmental toxins in the pathophysiology of endometriosis. General Obstet Invest, 1999, 48(1): 45
3 Koks CA, Groothuis PG, Slaats P, et al. Matrix metalloproteinases and their tissue inhibitors in antegradely shed menstruum and peritoneal fluid, 2000, 73(3): 604~612
4 Morkve O, Leaerum OD. Flow cytometry measurement of p21, p53 protein expression and DNA content in paraffin embedded tissues from bronchial carcinoma. Cytometry, 1991, 12: 438~444
5 Witz CA, Monotoya-Rodriguez IA, Schenken RS. Whole explants of peritoneum and endometrium: A novel model of theearly endometriosis lesion. Fertil Steril, 1999, 71: 56~60
6 Spuijbroek MDEH, Dunselman GAJ, Menkeere PP, et al. Early endometriosis invades the extracellularmatrix. Fertil Steril, 1992, 58: 929~933
7 Hulboy DL, Rudolph LA, Matrisia LM. Matrix metalloproteinases as mediators of reproductive functionMolecular Human Reproduction, 1997, 3: 27~45
8 Rodgers WH, Matrisian LM, Giudice LC, et al. Patterns of matrix metalloproteinase expression in cycling endometrium imply differential functions and regulation by steroids. J Clin Invest, 1994, 94: 946~953
9 Wenzl RJ, Heinz H. Localization of matrix metalloproteinase-2 in uterine endometrium and ectopic implants. Gynecol Obstet Invest, 1998, 45: 253~257
10 Kokerin I, Eeckhout Yves, Nisolle M, et al. Expression of interstitial collagenase (matrix metalloproteinase-1) is related to the activity of human endometriotic lesions. Fertil Steril, 1997, 68: 246~251
11 Gottschalk C, Malberg K, Arndt M, et al. Matrix metalloproteinases and TACE play a role in the pathogenesis of endometriosis. Adv Exp Med Biol, 2000, 477: 483~48
12 Sillem M, Prifti S, Koch A, et al. Regulation of matrix metalloproteinases and their inhibitors in uterine endometrial cells of patients with and without endometriosis. Eur J Obstet Gynecol Reprod Biol, 2001, 95(2): 167~174
13 何月, 孔丽娜. MMP-3、TGF-β1 在子宫内膜异位症中的表达及其意义. 皖南医学院学报, 2006, 25: 105~107
14 翦薇, 何福仙. 肿瘤坏死因子α及孕酮对异位子宫内膜间质细胞分泌基质金属蛋白酶-3 的调节. 现代妇产科进展, 2004, 6: 410~412
15 Chung HW, Wen Y, Chun SH, et al. Matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-3 mRNA expression in ectopic and eutopic endometrium in women with endometriosis: a rationale for endometriotic invasiveness. Fertil Steril, 2001, 75(1): 152~159
16 邱晓红, 李荷莲. 基质金属蛋白酶 MMP-2 MMP-9 及其抑制因子TIMP-1 TIMP-2 在子宫内膜异位症中的表达及意义. 中国实用妇科与产科杂志, 2004, 20(3): 158~160
17 王红, 吴若松. 基质金属蛋白酶-2、-9 在子宫内膜异位症中的表达. 现代妇产科进展, 2002, 11(4): 261~262
18 安晓汾, 陈必良, 王德堂, 等. MMP-9 及 TIMP-1 在子宫内膜异位症中的表达及意义. 第四军医大学学报, 2003, 24(6): 553~556
19 陈必良, 安晓汾, 辛晓燕, 等. 基质金属蛋白酶 9 和 14 在子宫内膜异位症中的表达. 肿瘤防治研究, 2003, 30(4): 285~289
1 Sampson J. Peritoneal endometriosis due to menstrual dissemaination of endometrial tissue into the peritoneal cavity. Am J Obstet Gynecol, 1927, 14: 422~469
2 郎景和. 子宫内膜异位症研究的新里程. 中华妇产科杂志, 2005, 40(1): 3~4
3 Egeblad M., Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nat Rev cancer, 2002, 2: 161~174
4 Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nvcleated cells. Nucleic Acids Res, 1998, 16: 1215
5 Rutter JL, Mitchell TI, Buttice G, et al. A single nucleotide polymorphism in the matrix metalloproteinase-1 promoter creates an Ets binding site and augments transcription. Cancer Res, 1998, 58: 5321~5325
6 Ye S, Eriksson P, Hamsten A, et al. Progression of coronary atherosclerosis are associated with a common genetic variant of the human stromelysis-1 promoter which results in reduced gene expression. J Biol Chem, 1996, 271: 13055~1306
7 Jormsjo S, Whatling C, Walter DH, et al. Allele-specific regulation of matrix metalloproteinase-7 promoter activity is associated with coronary artery luminal dimensions among hypercholesterolemic patients. Arterioscler Thromb Vasc Biol, 2001, 21: 1834~1839
8 Zhang B, Ye S, Herrmann SM, et al. Functional polymorphism in the regulatory region of gelatinase B gene in relation to severity of coronary atherosclerosis. Circulation, 1999, 99: 1788~1794.
9 Brinckerhoff CE, Rutter JL, Benbow U. Interstitial collagenases as markers of tumor progression. Clin Cancer Res, 2000, 6: 4823~4830
10 Kokorine I, Eeckhout Yves, Nisolle M, et al. Expression of interstitial collagenase (matrix metalloproteinase-1) is related to the activity of human endometriotic lesions. Fertil Steril, 1997, 68: 246~251
11 Nishioka Y, Sagae S, Nishikawa A, et al. A relationship between Matrix metalloproteinase-1 (MMP-1) promoter polymorphism and cervical cancer progression. Cancer Lett, 2003, 200: 49~55
12 Rutter JL, Mitchell TI, Buttice G, et al. A single nucleotide polymorphism in the matrix metalloproteinase-1 promoter creates an Ets binding site and augments transcription. Cancer Res, 1998, 58: 5321~5325
13 Kanamori Y, Matsushima M, Minaguchi T, et al. Correlation between expression of the matrix metalloproteinase-1 gene in ovarian cancers and an insertion/deletion polymorphism in its promoter region. Cancer Res, 1999, 59: 4225~4227
14 Tower GB, Coon CI, Brinckerhoff CE. The 2G single nucleotide polymorphism (SNP) in the MMP-1 promoter contributes to high levels of MMP-1 transcription in MCF-7/ADR breast cancer cells. Breast Cancer Res Treat, 2003, 82(2): 75~82
15 Mizumoto H, Saito T, Ashihara K, et al. Expression of matrix metalloproteinases in ovarian endometriomas: immunohistochemical study and enzyme immunoassay. Life Sci, 2002, 71(3): 259~273
16 Wenzl R J, Heinz H. Localization of matrix metalloproteinase-2 in uterine endometrium and ectopic implants. Gynecol Obstet Invest, 1998, 45: 253~257
17 Koks C A, Groothuis P G, Slaats P, et al. Matrix metalloproteinases and their tissue inhibitors in antegradely shed menstruum and peritoneal fluid. Fertil Steril, 2000, 73(3): 604~612
18 Hinoda Y, Okayama N, Takano N, et al. Association of functional polymorphisms of matrix metalloproteinase MMP-1 and MMP-3 genes with colorectal cancer. Int J Cancer, 2002, 102(5): 526~529
19 Ghilardi G, Biondi ML, Caputo, et al. A single nucleotide polymorphism in the matrix metalloproteinase-3 promoter enhances breast cancer susceptibility. Clin Cancer Res, 2002, 8: 3820~3823
20 Smolarz B, Szyllo K, Romanowicz-Makowska H, et al. PCR analysis of matrix metalloproteinase 3 (MMP-3) gene promoter polymorphism in ovarian cancer. Pol J Pathol, 2003, 54: 233~238
21 Szyllo K, Smolarz B, Romanowicz-Makowska H, et al. The promoter polymorphism of the matrix metalloproteinase3 (MMP-3) gene in women with ovarian cancer. Exp Clin Cancer Res, 2002, 21(3): 357~361
22 Knox JD, Boreham DR, Walker JA, et al. Mapping of the metalloproteinase gene matrilysin (MMP-7) to human chromosome 11q21-q22. Cytogen Cell Genet, 1996, 72(2-3): 179~182
23 Mori M, Barnard GF, Mjmorik, et al. Overexpression of matrix metalloproteinase-7 mRNA in human colon carcinomas. Cancer, 1995, 75: 1516~1519
24 Powell WC, Knox JD, Navre M, et al. Expression of the metalloproteinase matrilysin in DU-145 cells increases their invasive potential in severe combined inmunodeficient mice. Cancer Res, 1993, 53: 417~422
25 Osteen KG, Bruner KL, Sharpe-Timms KL, et al. Steroid and growth factor regulation of matrix metalloproteinase expression and endometriosis. Semin Reprod Endocrinol, 1996, 14: 247~255
26 Ghilardi G, Biondi ML, Erario M, et al. Colorectal carcinoma susceptibility and metastases are associated with matrix metalloproteinase-7 promoter polymorphisms. Clin Chem, 2003, 49: 1940~1942
27 Kenichi Ohashi, Tetsuo Nemoto, Kyoichi Nakamura, et al. Increased Expression of Matrix Metalloproteinase7 and 9 and Membrane Type1-Matrix Metalloproteinase in Esophageal Squamous Cell Carcinomas.Cancer, 2000, 88(10): 2201~2209
28 Aglund K, Rauvala M, Puistola U, et al. Gelatinases A and B (MMP-2 and MMP-9) in endometrial cancer-MMP-9 correlates to the grade and the stage. Gynecol Oncol, 2004, 94: 699~704
29 Chung HW, Wen Y, Chun SH, et al. Matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-3 mRNA expression in ectopic and eutopicendometrium in women with endometriosis: a rationale for endometriotic invasiveness. Fertil Steril, 2001, 75: 152~159
30 于云英, 郭新华, 钱金花, 等. 基质金属蛋白酶 9 及其组织抑制剂TIMP-3 在子宫内膜异位症的表达, 现代妇产科进展, 2003, 12: 25~27
31 Ria R, Loverro G, Vacca A, et al. Angiogenesis extent and expression of matrix metalloproteinase-2 and -9 agree with progression of ovarian endometriomas. Eur J Clin Invest, 2002, 32: 199~206
32 Matsumura S, Oue N, Nakayama H, et al. A single nucleotide polymorphism in the MMP-9 promoter affects tumor progression and invasive phenotype of gastric cancer. J Cancer Res Clin Oncol, 2005, 131: 19~25
33 Zhang B, Dhillon S, Geary I, et al. Polymorphisms in matrix metalloproteinase-1, -3, -9, and -12 genes in relation to subarachnoid hemorrhage. Stroke, 2001, 32: 2198~2202
34 Kim JS, Park HY, Kwon JH, et al. The roles of stromelysin-1 and the gelatinase B gene polymorphism in stable angina. Yonsei Med J, 2002, 43: 473~481
1 Kennedy S. Is there a genetic basis to endometriosis? Semin Reprod Endocrinol, 1997, 15(3): 309~318
2 Simpson JL, Elias S, Malinak LR, et al. Heritable aspects of endometriosis I. Genetic studies. Am J Obstet Gynecol, 1980, 137: 327~331
3 Lamb K, Hoffmann RG, Nichols TR. Family trait analysis: a case-control study of 43 women with endometriosis and their best friends. Am J Obstet Gynecol, 1986, 154: 596~601
4 Moen MH, Magnus P. The familial risk of endometriosis. Acta Obstet. Gynecol. Scand, 1993, 72: 560~564
5 Malinak LR, Buttram VC Jr. Heritage aspects of endometriosis II Clinical characteristics of familial endometriosis.Am J Obstet Gynecol, 1980, 137(3):332~337
6 Moen MH. Endometriosis in monozygotic twins. Acta Obstet Gynecol Scand, 1994,.73: 59~62
7 Hadfield RM, Mardon HJ, Barlow DH, et al. Endometriosis in monozygotic twins. Fertil Steril, 1997, 68: 941~942
8 Marshall E. Snipping a way at genome patenting. Science, 1997, 227:1752~1753.
9 Lattuada D, Vigano P, Somigliana E, et al. Androgen receptor gene cytosine, adenine, and guanine trinucleotide repeats in patients with endometriosis. J Soc Gynecol Investig, 2004, 11(4): 237~240
10 Hsieh YY, Chang CC, Tsai FJ, et al. T allele for VEGF gene -460 polymorphism at the 5'-untranslated region: association with a higher susceptibility to endometriosis. J Reprod Med, 2004, 49(6):468~472
11 Nakago S, Hadfield RM, Zondervan KT, et al. Association between endometriosis and N-acetyl transferase 2 polymorphisms in a UK population. Mol Hum Reprod, 2001, 7(11): 1079~1083
12 Hadfield RM, Manek S, Nakago S, et al. Absence of a relationshipbetween endometriosis and the N314D polymorphism of galactose-1-phosphate uridyl transferase in a UK population. Mul Hum Reprod, 1999, 5(10):990~993
13 Kiyohara C, Nakanishi Y, Inutsuka S, et al. The relationship between CYP1A1 aryI hydrocarbon hydroxylase activity and lung cancer in a Japanese population. Pharmacogenetics, 1998, 8: 315~323
14 Kanamori Y, Matsushima M, Minaguchi T, et al. Correlation between expression of the matrix metalloproteinase-1 gene in ovarian cancers and an insertion/deletion polymorphism in its promoter region. Cancer Res, 1999, 59(17): 4225~4227
15 Lin TS, Huang HH, Fan YH, et al. Genetic polymorphism and gene expression of microsomal epoxide hydrolase in non-small cell lung cancer. Oncol Rep, 2007 Mar, 17(3): 565~572
16 Higashi T, Kyo S, Inoue M, et al. Novel functional single nucleotide polymorphisms in the latent transforming growth factor-beta binding protein-1L promoter: effect on latent transforming growth factor-beta binding protein-1L expression level and possible prognostic significance in ovarian cancer. J Mol Diagn, 2006, Jul, 8(3):342~350
17 Ying-De Wang, Pei-Yun Yan. Expression of matrix metalloproteinase-1 and tissue inhibitor of metalloproteinase-1 in ulcerative colitis. World J Gastroenterol, 2006, 12(37): 6050~6053
18 Yonemura Y, Fujimura T, Ninomiya I, et al. Prediction of Peritoneal Micrometastasis by Peritoneal Lavaged Cytology and Reverse Transcriptase-Polymerase Chain Reaction for Matrix Metalloproteinas -e-7 mRNA. Clin Cancer Res, 2001, 7(6): 1647~1653
19 Sampson J. Peritoneal endometriosis due to menstrual dissemaination of endometrial tissue into the peritoneal cavity. Am J Obstet Gynecol, 1927, 14: 422~469
20 Lu XE, Ning WX, Dong MY, et al. Vascular endothelial growth factor and matrix metalloproteinase-2 expedite formation of endometriosis in the early stage ICR mouse model. Fertil Steril, 2006, 86(4): 1175~1181
21 Nishioka Y, Sagae S, Nishikawa A, et al. A relationship between Matrix metalloproteinase-1 (MMP-1) promoter polymorphism and cervical cancer progression. Cancer Lett, 2003, 200: 49~55
22 Tower GB, Coon CI, Brinckerhoff CE. The 2G single nucleotide polymorphism (SNP) in the MMP-1 promoter contributes to high levels of MMP-1 transcription in MCF-7/ADR breast cancer cells. Breast Cancer Res Treat, 2003, 82(2): 75~82
23 Nishioka Y, Sagae S, Nishikawa A, et al. A relationship between Matrix metalloproteinase-1 (MMP-1) promoter polymorphism and cervical cancer progression. Cancer Lett, 2003, 200(1): 49~55
24 Hirata H, Naito K, Yoshihiro S, et al. A single nucleotide polymorphism in the matrix metalloproteinase-1 promoter is associated with conventional renal cell carcinoma. Int J Cancer, 2003, 106(3): 372~374
25 Hinoda Y, Okayama N, Takano N, et al. Association of functional polymorphisms of matrix metalloproteinase (MMP)-1 and MMP-3 genes with colorectal cancer. Int J Cancer, 2002, 102(5): 526~529
26 Zhu Y, Spitz MR, Lei L, et al. A single nucleotide polymorphism in the matrix metalloproteinase-1 promoter enhances lung cancer susceptibility. Cancer Res, 2001, 61(21): 7825~7829
27 Mori M, Barnard GF, Mjmorik, et al. Overexpression of matrix metalloproteinase-7 mRNA in human colon carcinomas. Cancer, 1995, 75: 1516~1519
28 Powell WC, Knox JD, Navre M, et al. Expression of the metalloproteinase matrilysin in DU-145 cells increases their invasive potential in severe combined inmunodeficient mice. Cancer Res, 1993, 53: 417~422
29 郭源, 万远廉, 魏群, 等. 基质金属蛋白酶-7 基因在胃癌中的表达.中华普通外科杂志, 2000, 15(2): 82~84
30 Adachi Y, Yamamoto H, Itoh F, et al. Contribution of matrilysin(MMP-7) to the metastatic pathway of human colorectal cancer. Gut, 1999, 45(2): 252~258
31 Lynch CC, McDonnell S.The role of matrilysin (MMP-7) in leukaemia cell invasion. Clin Exp Metastasis, 2000, 18(5): 401~406
32 Jormsjo S, Whatling C, Walter DH, et al. Allele-specific regulation of matrix metalloproteinase-7 promoter activity is associated with coronary artery luminal dimensions among hypercholesterolemic patients. Arterioscler. Thromb. Vasc. Biol., 2001, 21: 1834~1839
33 Giorgio Ghilardi, Maria Luisa Biondi, Maddalena Erario, et al. Colorectal Carcinoma Susceptibility and Metastases Are Associated with Matrix Metalloproteinase-7 Promoter Polymorphisms. Clinical Chemistry, 2003, 49: 1940~1942
1 Gottschalk C, Malberg K, Arndt M, et al. Matrix metalloproteinases and TACE play a role in the pathogenesis of endometriosis. Adv Exp Med Biol, 2000, 477: 483~486
2 Brandstetter H, Grams F, Glitz D, et al. The 1.8-A crystal ctructure of a matrix metalloproteinase 8-barbiturate inhibitor complex reveals a previously unobserved mechanism for collagenase substrate recognition. J Biol Chem, 2001, 276(20): 17405~17412
3 Fini ME, Girard MT. Expression of collagenolytic/gelatinolytic metalloproteinases by normal cornea. Invest Ophthalmol Vis Sci, 1990, 31(9): 1779~1788
4 Murphy G, Cockett MI, Ward RV, et al. Matrix metalloproteinase degradation of elastin, type IV collagen and proteoglycan. A quantitative comparison of the activities of 95 kDa and 72 kDa gelatinases, stromelysins-1 and -2 and punctuated metalloproteinase (PUMP). Biochem. J, 1991, 277(Pt 1): 277~279
5 Damjanovski S, Amano T, Li Q, et al. Overexpression of matrix metalloproteinases leads to lethality in transgenic Xenopus laevis: implications for tissue-dependent functions of matrix metallopro- teinases during late embryonic development. Dev Dyn, 2001, 221(1): 37~47
6 Hozumi A, Nishimura Y, Nishiuma T, et al. Induction of MMP-9 in normal human bronchial epithelial cells by TNF-alpha via NF-kappa B-mediated pathway. Am J Physiol Lung Cell Mol Physiol, 2001, 281(6): L1444~1452
7 Mengshol JA, Vincenti MP, Brinckerhoff CE. IL-1 induces collagenase-3 (MMP-13) promoter activity in stably transfected chondrocytic cells: requirement for Runx-2 and activation by p38 MAP and JNK pathways. Nucleic Acids Res, 2001, 29(21): 4361~4372
8 Alper O, Bergmann-Leitner ES, Bennett TA, et al. Epidermal growth factor receptor signaling and the invasive phenotype of ovarian carcinoma cells. JNatl Cancer Inst, 2001, 93(18): 1375~1384
9 Alexander JP, Acott TS. Involvement of protein kinase C in TNFalpha regulation of trabecular matrix metalloproteinases and TIMPs. Invest Ophthalmol Vis Sci, 2001, 42(12): 2831~2838
10 Yang JQ, Zhao W, Duan H, et al. v-Ha-RaS oncogene upregulates the
92-kDa type IV collagenase (MMP-9) gene by increasing cellular superoxide production and activating NF-kappaB. Free Radic Biol Med, 2001, 31(4): 520~529
11 Yoon A, Hurta RA. Insulin like growth factor-1 selectively regulates the expression of matrix metalloproteinase-2 in malignant H-ras transformed cells. Mol Cell Biochem, 2001, 223(1-2): 1~6
12 Wick W, Plattern M, Weller M. Glioma cell invasion: regulation of metalloproteinase activity by TGF-beta. J Neurooncol, 2001, 53(2): 177~185
13 Frankenberger M, Hauck RW, Frankenberger B, et al. All trans-retinoic acid selectively down-regulates matrix metalloproteinase-9 (MMP-9) and up-regulates tissue inhibitor of metalloproteinase-1 (TIMP-1) in human bronchoalveolar lavage cells. Mol Med. 2001, 7(4): 263~270
14 Galboiz Y, Shapiro S, Lahat N, et al. Matrix metalloproteinases and their tissue inhibitors as markers of disease subtype and response to interferon-beta therapy in relapsing and secondary-progressive multiple sclersis patients. Ann Neurol, 2001, 50(4): 443~451
15 Luo XH, Liao EY. Progesterone differentially regulates the membrane-type matrix metalloproteinase-1 (MT1-MMP) compartment of proMMP-2 activation in MG-63 cells. Horm Metab Res, 2001, 33(7): 383~388
16 Benbow U, Brinckerhoff CE. The AP-1 site and MMP gene regulation: what is all the fuss about? Matrix Biol, 1997, 15(8-9): 519~526
17 Rutter JL, Mitchell TI, Buttice G, et al. A single nucleotide polymorphism in the matrix metalloproteinase-1 promoter creates an Ets binding site and augments transcription. Cancer Res, 1998, 58(23): 5321~5325
18 Lafleur MA, Hollenberg MD, Atkinson SJ, et al. Activation of pro-(matrixmetalloproteinase-2) (pro-MMP-2) by thrombin is membrane-type -MMP- dependent in human umbilical vein endothelial cells and generates a distinct 63 kDa active species. Biochem J, 2001, 357(Pt 1): 107~115
19 Sate H, Seiki M. Membrane-type matrix metalloproteinases (MT-MMPs) in tumour metastasis. J Biochem, 1996, 119(2): 209~215
20 Butler GS, Butler MJ, Atkinson SJ, et al. The TIMP-2 membrane type 1 metalloproteinase ‘receptor’ regulates the concentration and efficient activation of progelatinase A. A kinetic study. J Biol Chem, 1998, 273(2): 871~880
21 Knauper V, Will H, Lopez-Otin C, et al. Cellular mechanisms for human procollagenase-3 (MMP-13) activation. Evidence that MT1-MMP (MMP-14) and gelatinase A (MMP-2) are able to generate active enzyme. J Biol Chem, 1996, 271(29): 17124~17131
22 Gomez DE, Alonso DF, Yoshiji H, et al. Tissue inhibitors of metalloproteinases: structure, regulation and biological functions. Eur J Cell Biol, 1997, 74(2): 111~122
23 Ishiguro N, Ito T, Oguchi T, et al. Relationships of matrix metallo- proteinases and their inhibitors to cartilage proteoglycan and collagen turnover and inflammation as revealed by analyses of synovial fluids from patients with rheumatoid arthritis. Arthritis Rheum, 2001, 44(11): 2503~2511
24 Ogata Y, Miura K, Ohkita A, et al. Imbalance between matrix metalloproteinase 9 and tissue inhibitor of metalloproteinases 1 expression by tumor cells implicated in liver metastasis from colorectal carcinoma. Kurume Med J, 2001, 48(3): 211~218
25 Hoashi T, Kadono T, Kikuchi K, et al. Differential growth regulation in human melanoma cell lines by TIMP-1 and TIMP-2. Biochem Biophys Res Commun, 2001, 288(2): 371~379
26 Zeng Z, Sun Y, Shu W, et al. Tissue inhibitor of metalloproteinase-3 is a basement membrane-associated protein that is significantly decreased in human colorectal cancer. Dis Colon Rectum, 2001, 44(9): 1290~1296metalloproteinase-2) (pro-MMP-2) by thrombin is membrane-type -MMP- dependent in human umbilical vein endothelial cells and generates a distinct 63 kDa active species. Biochem J, 2001, 357(Pt 1): 107~115
19 Sate H, Seiki M. Membrane-type matrix metalloproteinases (MT-MMPs) in tumour metastasis. J Biochem, 1996, 119(2): 209~215
20 Butler GS, Butler MJ, Atkinson SJ, et al. The TIMP-2 membrane type 1 metalloproteinase ‘receptor’ regulates the concentration and efficient activation of progelatinase A. A kinetic study. J Biol Chem, 1998, 273(2): 871~880
21 Knauper V, Will H, Lopez-Otin C, et al. Cellular mechanisms for human procollagenase-3 (MMP-13) activation. Evidence that MT1-MMP (MMP-14) and gelatinase A (MMP-2) are able to generate active enzyme. J Biol Chem, 1996, 271(29): 17124~17131
22 Gomez DE, Alonso DF, Yoshiji H, et al. Tissue inhibitors of metalloproteinases: structure, regulation and biological functions. Eur J Cell Biol, 1997, 74(2): 111~122
23 Ishiguro N, Ito T, Oguchi T, et al. Relationships of matrix metallo- proteinases and their inhibitors to cartilage proteoglycan and collagen turnover and inflammation as revealed by analyses of synovial fluids from patients with rheumatoid arthritis. Arthritis Rheum, 2001, 44(11): 2503~2511
24 Ogata Y, Miura K, Ohkita A, et al. Imbalance between matrix metalloproteinase 9 and tissue inhibitor of metalloproteinases 1 expression by tumor cells implicated in liver metastasis from colorectal carcinoma. Kurume Med J, 2001, 48(3): 211~218
25 Hoashi T, Kadono T, Kikuchi K, et al. Differential growth regulation in human melanoma cell lines by TIMP-1 and TIMP-2. Biochem Biophys Res Commun, 2001, 288(2): 371~379
26 Zeng Z, Sun Y, Shu W, et al. Tissue inhibitor of metalloproteinase-3 is a basement membrane-associated protein that is significantly decreased in human colorectal cancer. Dis Colon Rectum, 2001, 44(9): 1290~1296Reprod, 1977, 3(9): 735~741
36 Osteen KG. The endocrinology of decidualization In: Bazer F, ed. The Endocrinology of Pregnancy. Totowa, NJ: Humana Press, 1998: 541~663
37 Kamat BR, Isaacson PG. The immunocytochemical distribution of leukocytic subpopulations in human endometrium. Am J Pathol, 1987, 127(1): 66~73
38 Bonatz G, Hansmann ML, Buchholz F, et al. Macrophage- and lymphocyte-subtypes in the endometrium during different phases of the ovarian cycle. Int J Gynaecol Obstet, 1992, 37(1): 29~36
39 Loke YW, King A. Human Implantation: Cell Biology and Immunology. New York: Cambridge University Press. 1996
40 Bruner KL, Rodgers WH, Gold LI, et al. Transforming growth factor beta mediates the progesterone suppression of an epithelial metalloproteinase by adjacent stroma in the human endometrium. Proc Natl Acad Sci USA, 1995, 92(16): 7362~7366
41 Vincent AJ, Salamonsen LA. The role of matrix metalloproteinases and leukocytes in abnormal uterine bleeding associated with progestin only contraceptives. Hum Reprod, 2000, 15(suppl 3): 135~143
42 Bruner-Tran KL, Eisenberg E, Yeaman GR, et al. Steroid and cytokine regulation of matrix metalloproteinase expression in endometriosis and the establishment of experimental endometriosis in nude mice. J Clin Endocrinol Metab, 2002, 87(10): 4782~4791
43 Schroen DJ, Brinckerhoff CE. Nuclear hormone receptors inhibit matrix metalloproteinase (MMP) gene expression through diverse mechanisms. Gene Expr, 1996, 6(4): 197~207
44 Kushner PJ, Agard DA, Greene GL, et al. Estrogen receptor pathways to AP-1. J Steroid Biochem Mol Biol, 2000, 74: 311~317
45 Teyssier C, Belguise K, Galtier F, et al. Characterization of the physical interaction between estrogen receptor alpha and JUN proteins. J Biol Chem, 2001, 276(39): 36361~36369
46 Benbow U, Brinckerhoff CE. The AP-1 site and MMP gene regulation:what is all the fuss about? Matrix Biol, 1997, 15(8-9): 519~526
47 Osteen KG, Rodgers WH, Gaire M, et al. Stromal-epithelial interaction mediates steroidal regulation of metalloproteinase expression in human endometrium. Proc Natl Acad Sci U S A, 1994, 91(21): 10129~10133
48 Schatz F, Papp C, Toth-Pal E, et al. Ovarian steroid-modulated stromelysin-1 expression in human endometrial stromal and decidual cells. J Clin Endocrinol Metab, 1994, 78(6): 1467~1472
49 Rudolph-Owen LA, Slayden OD, Matrisian LM, et al. Matrix metalloproteinase expression in Macaca mulatta endometrium: evidence for zone-specific regulatory tissue gradients. Biol Reprod, 1998, 59(6): 1349~1359
50 Curry TE Jr, Osteen KG. Cyclic changes in the matrix metalloproteinase system in the ovary and uterus. Biol Reprod, 2001, 64(5): 1285~1296
51 Bamberger AM, Bamberger CM, Gellersen B, et al. Modulation of AP-1 activity by the human progesterone receptor in endometrial adenocarcinoma cells. Proc Natl Acad Sci USA, 1996, 93(12): 6169~6174
52 Salmi A, Ammala M, Rutanen EM. Proto-oncogenes c-jun and c-fos are down-regulated in human endometrium during pregnancy: relationship to oestrogen receptor status. Mol Hum Reprod, 1996, 2(12): 979~984
53 Kirkland JL, Murthy L, Stancel GM. Progesterone inhibits the estrogen-induced expression of c-fos messenger ribonucleic acid in the uterus. Endocrinology, 1992, 130(6): 3223~3230
54 Osteen KG, Bruner-Tran KL, Ong D, et al. Paracrine mediators of endometrial matrix metalloproteinase expression: potential targets for progestin-based treatment of endometriosis. Ann N Y Acad Sci, 2002, 955: 139~146; discussion 157~158, 396~406
55 Osteen KG, Keller NR, Feltus FA, et al. Paracrine regulation of matrix metalloproteinase expression in the normal human endometrium. Gynecol Obstet Invest, 1999, 48(suppl 1): 2~13
56 Matrisian LM. Matrix metalloproteinase gene expression. Ann N Y Acad Sci, 1994, 732: 42~50
57 Kokerin I, Nisolle M, Donnez J, et al. Expression of interstitial collagenase (matrix metalloproteinase-1) is related to the activity of human endometriotic lesions. Fertil Steril, 1997, 68(2): 246~251
58 Gottschalk C, Malberg K, Arndt M, et al. Matrix metalloproteinases and TACE play a role in the pathogenesis of endometriosis. Adv Exp Med Biol, 2000, 477: 483~486
59 Wenzl RJ, Heinzl H. Localization of matrix metalloproteinase-2 in uterine endometrium and ectopic implants. Gynecol Obstet Invest, 1998, 45(4): 253~257
60 Chung HW, Wen Y, Chun SH, et al. Matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-3 mRNA expression in ectopic and eutopic endometrium in women with endometriosis: a rationale for endometriotic invasiveness. Fertil Steril, 2001, 75(1): 152~159
61 Sillem M, Prifti S, Koch A, et al. Regulation of matrix metalloproteinases and their inhibitors in uterine endometrial cells of patients with and without endometriosis. Eur J Obstet Gynecol Reprod Biol, 2001, 95(2): 167~174
62 邱晓红, 李荷莲. 基质金属蛋白酶 MMP-2 MMP-9 及其抑制因子TIMP-1 TIMP-2 在子宫内膜异位症中的表达及意义. 中国实用妇科与产科杂志, 2004, 20(3): 158~160
63 Steward WP. Marimastat (BB2516): current status of development. Cancer Chemother Pharmacol, 1999, 43(Suppl): S56~60
64 Rothenberg ML, Nelson AR, Hande KR. New drugs on the Horizon: Matrix Metalloproteinase Inhibitors. Oncologist, 1998, 3(4): 271~274
1 Kennedy S. Is there a genetic basic to endometriosis? Senin Reprod, 1997, 15(3): 309~311
2 Hsieh Y, Chanq CC, Tsai CH, et al. Estrogen receptor alpha dinucleotide repeat and cytochrome P450c17alpha gene polymorphisms are associated with susceptibility to endometriosis. Fertil Steril, 2005, 83(3):567~572
3 Wang Z, Yoshida S, Negoro K, et al. Polymorphisms in the estrogen receptor beta gene but not estrogen receptor alpha gene affect the risk of developing endometriosis in a Japanese population. Fertil Steril, 2004, 81: 1650~1656
4 宋绿茵, 何凤仪, 方小玲, 等。雌激素受体基因多态性与子宫内膜异位症的相关性研究. 中华妇产科杂志, 2005, 40(1): 47~48
5 黄海玲, 韦叶生, 方晓燕, 等. 雌激素受体 β 基因多态性与子宫内膜异位症的相关性研究. 中华妇产科杂志, 2005, 40(9): 644~645
6 Lattuada D, Somigliana E, Vigano P, et al. Genetics of endometriosis: a role for the progesterone receptor gene polymorphism PROGINS? Clin Endocrinol (Oxf), 2004, 61(2): 190~194
7 Treloar SA, Zhao ZZ, Montqomery GW, et al. Association between polymorphisms in the progesterone receptor gene and endometriosis. Mol Hum Reprod, 2005, 11(9): 641~647
8 Van Kaam KJ, Romano A, Groothuis PG, et al. Progesterone receptor polymorphism +331G/A is associated with a decreased risk of deep infiltrating endometriosis. Hum Reprod, 2006, 18
9 康山, 王瑛, 李琰, 等. 基质金属蛋白酶基因启动子区基因多态性与子宫内膜异位症遗传易感性的相关性研究. 中华妇产科杂志, 2005, 40(9): 601~604
10 Ferrari MM, Biondi ML, Viqano P, et al. Analysis of two polymorphisms in the promoter region of matrix metalloproteinase 1 and 3 genes in women with endometriosis. Acta Obstet Gynecol Scand, 2006, 85(2):212~217
11 Shan K, Lian-Fu Z, Yan L, et al. Polymorphisms in the promoter regions ofthe matrix metalloproteinases-7, -9 and the risk of endometriosis and adenomyosis in China. Mol Hum Reprod, 2006, 12(1): 35~39
12 彭冬先, 何援利, 丘立文, 等. 子宫内膜异位症与细胞色素 P450 1A1 基因 A4889G 突变的相关性. 中华医学遗传学杂志, 2003, 20(4): 284~286
13 Asqhar T, Yoshida S, et al. Lack of association between endometriosis and the CYP17 MspA1 polymorphism in UK and Japanese populations. Gynecol Endocrinol, 2005, 20(2): 59~63
14 Hsieh YY, Chanq CC, et al. Estrogen receptor alpha dinucleotide repeat and cytochrome P450c17alpha gene polymorphisms are associated with susceptibility to endometriosis. Fertil Steril, 2005, 83(3): 567~572
15 彭东先, 何援利, 丘立文, 等. 谷胱甘肽-S-转移酶 M1 基因缺失与子宫内膜异位症易感性的关系. 第一军医大学学报, 2003, 23(5): 458~459
16 Baxter SW, Thornas E J, Campbell IG. GSTM1 null polymorphism and susceptibility to endometriosis and ovarian cancer. Carcinogenesis, 2001, 22 (1): 63~65
17 Morizane M, Yoshida S, Nakago S, et al. No association of endometriosis with glutathione S-transferase M1 and T1 null mutations in a Japanese population. J Soc Gynecol Investig, 2004, 11(2): 118~121
18 Lin HJ, Han CY. Slow acetylor mutations in the human polymorphic N-acetyltransferase gene in 786 Asians, Blacks, Hispanics, and Whites: Application to metabolic epidemiology.Am J Hum Genet, 1993, 52(4): 827~834
19 Bischoff FZ, Marquez-DO. Association of NAT2 genetid polymorphism resulting in decreased capacity to detoxify aromatic amines in women with endometriosis. Gynecol Invest, 5(S): 111A
20 Nakago S. Association between endometriosis and N-acetyltransferase 2 polymorphisms in a UK population Molecular Human Reproduction, 2001, 7(11): 1079~1083
21 Baranova H, Canis M. Possible involvement of arylamine N-acetyltransferase 2, glutathione S-transferase M1 and T1 genes in the development of endometriosis. Mol Hum Repord, 1999, 5(7): 636~641
22 Cramer, D.W., Hornstein, MD. Endometriosis associated with the N314D mutation of GALT. Mol Hum Reprod, 1996, 2: 149~152
23 Hadfield RM, Manek S, Nakago S, et al. Absence of a relationship between endometriosis and the N314D polymorphism of galactose-1-phosphate uridyl transferase in a UK population. Mul Hum Reprod, 1999, 5(10): 990~993
24 Wieser F, Hefler L, Tempfer C, et al. Polymorphism of the interleukin-1 beta gene and endometriosis. J Soc Gynecol Investig, 2003, 10(3): 172~175
25 Hsieh YY, Chang CC, Tsai FJ, et al. Polymorphisms for interleukin-1 beta (IL-1 beta)-511 promoter, IL-1 beta exon 5, and IL-1 receptor antagonist: nonassociation with endometriosis. J Assist Reprod Genet, 2001, 18(9): 506~511
26 D’Amora P, Sato H, et al. Polymorphisms in exons 1B and 1C of the type I interleukin-1 receptor gene in patients with endometriosis. Am J Reprod Immunol, 2006, 56(3): 178~184
27 Wieser F, Fabjani G, Tempfer C, et al. Analysis of an interleukin-6 gene promoter polymorphism in women with endometriosis by pyrosequencing. J Soc Gynecol Investig, 2003, 10(1): 32~36
28 Bhanoori M, Babu KA, et al. The interleukin-6 -174G/C promoter polymorphism is not associated with endometriosis in South Indian women. J Soc Gynecol Investing. 2005, 12(5): 365~369
29 Kitawaki J, Kiyomizu M. Synergistic effect of interleukin-6 promoter (IL6 -634C/G) and intercellular adhesion molecule-1 (ICAM-1 469K/E) gene polymorphisms on the risk of endometriosis in Japanese women. Am J Reprod Immunol, 2006, 56(4):267~274
30 Hsieh YY, Chang CC, Tsai FJ, et al. Association of an A allele for interleukin-10 -627 gene promoter polymorphism with higher susceptibility to endometriosis. J Reprod Med, 2003, 48(9): 735~738
31 Kitawaki J, Obayashi H, Ohta M, et al. Genetic contribution of the interleukin-10 promoter polymorphism in endometriosis susceptibility. Am J Reprod Immunol, 2002, 47(1): 12~18
32 Hsieh YY, Chang CC, Tsai FJ, et al. T allele for VEGF gene-460 polymorphism at the 5'-untranslated region: association with a higher susceptibility to endometriosis. J Reprod Med, 2004, 49(6):468~472
33 Bhanoori M, Arvind Babu K. The vascular endothelial growth factor (VEGF) +405G>C 5'-untranslated region polymorphism and increased risk of endometriosis in South Indian women: a case control study. Hum Reprod. 2005, 20(7): 1844~1849
34 Teramoto M, Kitawaki J, Koshiba H, et al. Genetic contribution of tumor necrosis factor (TNF)-alpha gene promoter (-1031, -863 and -857) and TNF receptor 2 gene polymorphisms in endometriosis susceptibility. Am J Reprod Immunol, 2004, 51(5): 352~357
35 Hsieh YY, Chang CC, et al. Interleukin-2 receptor beta (IL-2R beta)-627*C homozygote but not IL-12R beta 1 codon 378 or IL-18 105 polymorphism is associated with higher susceptibility to endometriosis. Fertil Steril, 2005, 84(2):510-512
36 罗敏, 何援利. 广东妇女子宫内膜异位症与肿瘤坏死因子基因多态性的相关性研究. 南方医科大学学报, 2006, 26(8): 1163~1165
37 Vigano P, Infantino M, Lattuada D. Intercellular adhesion molecule-1 (ICAM-1) gene polymorphisms in endometriosis. Mol Hum Reprod, 2003, 9(1): 47~52
38 Yamashita M , Yoshida S. Association study of endometriosis and intercellular adhesion molecule-1 (ICAM-1) gene polymorphisms in a Japanese population. J Soc Gynecol Investig, 2005, 12(4): 267~271
39 宗利丽, 潘德京, 陈为明, 等. HLA-DQA1、-DRB1 等位基因与子宫内膜异位症和子宫腺肌病的比较性研究. 中华医学遗传学杂志, 2002, 19(1):49~51
40 王新, 刘春宇, 林秋华, 等. 子宫内膜异位症与人类白细胞抗原 DRB1等位基因多态性的关系. 中华妇产科杂志, 2002, 37(6): 346~348
41 Whang DH, Kim SH. No association between HLA-DRB1 alleles and susceptibility to advanced stage endometriosis in a Korean population. Hum Reprod, 2006, 21(1):129~133
42 Chang CC, Hsieh YY, Tsai FJ, et al. The proline form of p53 codon 72 polymorphism is associated with endometriosis. Fertil Steril, 2002, 77(1): 43~45
43 Lattuada D, Vigano P, Somigliana E, et al. Analysis of the codon 72 polymorphism of the TP53 gene in patients with endometriosis. Mol Hum Reprod, 2004, 10(9): 651~654
44 Hsieh YY, Lin CS. P53 codon 11, 72, and 248 gene polymorphisms in endometriosis. Int J Biol Sci, 2006, 2(4):188~193