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RECK、KISS-1和MMP-2在子宫内膜异位症组织中的表达

The Expression and Significance of RECK、 KISS-1 and MMP-2 in the in Endometriosis

作者: 专业:妇产科学 导师:边爱平 年度:2010 学位:硕士  院校: 郑州大学

Keywords

Endometriosis, Anti-metastasis gene, RECK, KISS-1, MMP-2

        子宫内膜异位症(endometriosis EMT)是育龄期妇女常见的一种疾病,以痛经、慢性盆腔疼痛和不孕为主要临床表现,具有侵袭性和易复发等类似恶性肿瘤的临床行为,本病的发病机制尚未完全阐明。关于异位子宫内膜的来源,目前主要有种植学说(经血逆流、淋巴及静脉播撒)、体腔上皮化生学说、诱导学说等。目前经血倒流内膜种植学说已为人们所公认,但无法解释盆腔外的如胃肠道、泌尿道等部位的子宫内膜异位症发病原因。子宫内膜异位症虽为良性疾病,但具有类似恶性肿瘤远处转移和种植生长能力,如无限制生长、新血管生成和凋亡细胞数量减少等。最显著的特征是具有细胞侵蚀能力,能局部或远处转移,浸润并损伤其他组织,且受肿瘤转移抑制基因的调控。近几年研究显示肿瘤转移抑制基因KISS-1 (Kisspeptins)和RECK (reversion inducing cysteine rich protein with Kazal motifs)即回复引导半胱氨酸丰富蛋白Kazal基元在多种恶性肿瘤的发病中发挥重要作用。RECK是近年来发现的肿瘤转移抑制基因,在多种正常人体组织中表达,肿瘤组织中呈低表达。KISS-1多肽能明显抑制肿瘤细胞的化学趋向性和侵袭性,并限制肿瘤细胞的迁移蠕动功能,表达于正常心脏、肝脏、肺、骨骼肌、肾组织和胰腺,而且在胎盘和脑观察到了有较高的表达。KISS-1基因对人类肿瘤转移有抑制作用,调节癌细胞的生长信号,调节肿瘤的生物行为方面有潜在的作用。基质金属蛋白酶-2(matrix metallo proteinase-2, MMP-2)是基质金属蛋白酶(matrix metalloproteinase, MMPs)家族的成员之一,又称Ⅳ型胶原酶或明胶酶,能够降解基底膜中的Ⅳ型胶原、明胶、弹性蛋白、并能特异性地降解Ⅳ型胶原—基底膜的骨架,造成基底膜的断裂、缺失、血管破坏、损伤淋巴管基底膜的完整性,肿瘤细胞侵入小血管、淋巴管从而发生转移,在肿瘤的发生、浸润和新血管形成中起着重要的作用。有文献证明RECK、KISS-1与基质金属蛋白酶MMP-2存在相关性,另有报道RECK基因及MMP的相互调节对于肿瘤新生血管形成起着重要作用,但是RECK在子宫内膜异位症中的研究国内外尚无报道。因此,研究RECK、KISS-1和MMP-2在EMT组织中的表达,对进一步认识子宫内膜异位症的发病机制有重要意义。目的通过对RECK、KISS-1和MMP-2在子宫内膜异位症组织中表达的研究,并对三种因子进行相关性分析,探讨三者在子宫内膜异位症发生发发展中的关系,为临床治疗和预防子宫内膜异位症的发生提供新的思路和理论依据。材料和方法收集2008年7月至2009年4月因子宫内膜异位症(术后病理证实为子宫内膜异位症)在郑州大学第三附属医院住院行手术治疗的病人30例为研究对象,分别取其异位内膜组织(A组,包括卵巢子宫内膜异位症18例,盆腔子宫内膜异位症10例和腹壁子宫内膜异位症2例),同时取其在位内膜组织(B组)进行研究,其中在位组内膜中增生期16例,分泌期14例(按病理结果进行分期)。正常对照组:同期因子宫畸形住院手术病人30例,取其正常子宫内膜组织(C组,术后病理证实为正常子宫内膜组织)。其中增生期18例,分泌期12例(按病理结果进行分期)。标本的临床特征:所有患者年龄23-42岁,体重45-65千克。月经周期规律,月经期28-33天,无其他内外科疾病,术前6个月均未使用过激素类药物。两组在年龄、体重和月经周期上的差异无统计学意义,所有标本术后均经病理证实。采用链霉素抗生物蛋白-过氧化物酶染色法(SP法)免疫组织化学技术检测三组组织中RECK、KISS-1和MMP-2的表达。采用上海山富科学仪器有限公司的Biosens Digatal Imaging Systerm对三种因子表达进行灰度值分析。采用SPSS13.0对数据进行分析,计量资料三组间比较采用单因素方差分析,组间进一步两两比较用LSD法,计量资料两组间比较采用t检验,指标间相关性采用Pearson相关分析,检验水准均为a=0.05。结果1 RECK在EMT异位内膜组织及在位子宫内膜组中的表达均低于对照组,差异均有统计学意义(P<0.05);RECK在EMT在位子宫内膜组和对照组子宫内膜组织中均有增生期和分泌期表达差异无统计学意义(P>0.05)。2 KISS-1在EMT异位内膜组织及在位子宫内膜组中的表达均低于对照组,差异均有统计学意义(P<0.05); KISS-1在EMT在位子宫内膜组和对照组中均有增生期和分泌期表达差异无统计学意义(P>0.05)。3 MMP-2在EMT异位内膜组织及在位子宫内膜组中表达均高于对照组,差异有统计学意义(P<0.05); MMP-2在EMT在位子宫内膜组和对照组中均有增生期和分泌期表达差异无统计学意义(P>0.05)。4 EMT患者异位内膜组织和在位内膜组织中RECK和MMP-2表达呈负相关,差异有统计学意义(P<0.05); KISS-1和MMP-2的表达呈负相关,差异有统计学意义(P<0.05); RECK和KISS-1的表达无相关性,差异无统计学意义(P>0.05)。结论1 RECK和KISS-1在EMT患者异位内膜组织和在位内膜组织中的表达均较正常对照组表达降低,MMP-2在EMT患者异位内膜组织和在位内膜组织中的表达较正常对照组表达升高,提示三者可能在EMT的发生发展过程中起一定的作用。2 RECK、KISS-1和MMP-2在EMT患者异位内膜组织和在位内膜组织表达的一致性,提示在EMT发生前其在位内膜可能已经发生变化,在位内膜的变化可能在EMT的发生中发挥重要作用。3 RECK与MMP-2在EMT患者子宫内膜组织中的表达呈负相关性,KISS-1与MMP-2在EMT患者子宫内膜组织中的表达呈负相关,提示三者在EMT血管形成方面可能发挥协同作用,在EMT的发生中共同发挥作用。
    Endometriosis is a common and popular gynecologic disease in women of the reproductive age. The main clinical symptoms are dysmenorrhea,chronic pain of pelvic cavity and infertility. It has the high invasion and recurrence. Its pattern of growth is similar to malignant disease. Recently the incidence of endometriosis has been distinctly increased. EMT seriously impacts the quality of life of reproductive women and their families,The exact mechanism of EMT is unknown.About the resource of the endometriosis have many theories such as:implantology theory (contraflow of menstrual bleeding,lymph and vein sprinkle),celothel epithelial metaplasia theory,induction theory and so on. Now the contraflow of menstrual bleeding implantology theory has been generally accepted. But above mechanisms unaccountability the other endometriosis morbidity cause such as the exterior cavitas pelvis gastrointestinal tract,urinary tract and so on. Endometriosis although a innocence disease,is similar to malignant disease distant place aversion and energy for growth, such as absoluteness growth, neovascularity and the quantity decrease of apoptosis cell and so on.The most conspicuous characteristic is have cell erosiveness, can part and distant place aversion,and infiltrate and damage other tissue,also to suffer the control of tumor metastasis.Recently a lot of studies have shown that anti-metastasis gene RECK and KISS-1 have an important contribution in many malignant tumor. RECK is a new anti-metastasis gene for the past few years discovered. RECK in many kinds of tissue of the health human body is express,in the tumor tissue is low express.KISS-1 polypeptide can obviously abaissement the chemistry tropism and infestation for the tumour cell, and its confine the function of the immigration and movements for the tumour cell. KISS-1 were expressed in the normal heart,liver,lung,musculi skeleti,nephridian tissue,and abdominal salivary gland,in the placenta and brain were high expressed.KISS-1 gene in mankind tumor metastasis have depressant effect,and to regulate accretion signal of the cancer cell.KISS-1 have potential effective to regulate the biology behavior. Many evidences had demonstrated that KISS-1 is lower express in EMT and play an important effect in the EMT development.Another report that RECK KISS-1 and MMP-2 have associativity. Some reference reported that the drop of the expression and activity of RECK play an important role in pathogenesis of EMT. So to investigate the expression of RECK KISS-1 and MMP-2 in endometriosis will have a very important meaning for the pathogeny of the EMT.ResearchThe purpose is to explore the relationship of RECK,KISS-1 and MMP-2 in EMT and to supply an new consideration for treatment and preservation of EMT.Materials and MethodsInpatients with endometriosis (n=30) accepted operation and the specimen collect at gynecological department of the Third affiliated Hospital of ZhengZhou University from july in 2008 to april in 2009,in which there were 16 cases in proliferate phase and 14 cases in secretary phase.Their endometrium tissues were assigned into two groups,the eutopic endometrium group and the ectopic endometrium group. The controls were the normal endometrium tissues of inpatients (n= 30) with uterine malformation for operations at the same time.The normal endomertium were investigated as the normal endomertium group. All the patients were collected at random. Their difference in age、weight and menstrual cycle has not statistically significant. All patients had no physical and surgical disease and had not accepted the hormone therapy six months before operations. The study used the Biosens Digital System to exam the average gray value of production of RECK KISS-1 and MMP-2.SPSS 16.0 was performed to analysis the study date. All the date was express as x±s. Means among several groups was compared by One-Way ANOVA and Means of every group was compared by LSD-T Test. Means between two groups was compared by t test. Correlations between groups were analysised by Pearson. Statistical significance was defined asα=0.05. Results1 The expression of RECK in eutopic and ectopic endometrium group was significantly lower than that in normal endometrium group (P<0.05). No significant difference was found in the expression of RECK between the proliferative phase and the secretory phase in eutopic Group and normal endometrium Group (P>0.05).2 The expression of KISS-1 in eutopic and ectopic endometrium group was significantly lower than that in normal endometrium group (P<0.05). The expression of KISS-1 was significantly lower in the proliferative phase than the secretory phase in normal endometrium Group (P<0.05). However, no significant difference was found in the expression of KISS-1 between the proliferative phase and the secretory phase in eutopic Group (P>0.05).3 The expression of MMP-2 in eutopic and ectopic endometrium group was significantly higher than that in normal endometrium group (P< 0.05). The expression of MMP-2 was significantly lower in the proliferative phase than the secretory phase in normal endometrium Group (P<0.05). However,no significant difference was found in the expression of MMP-2 between the proliferative phase and the secretory phase in eutopic Group of EMT (P>0.05).4 In entopic and entopic endometrial, the expression of RECK and MMP-2. was minus correlation(P< 0.05),the expression of KISS-1 and MMP-2.was minus correlation(P<0.05),the expression of RECK and KISS-1 was not correlation(P> 0.05).Conclusions1 The lower expression of RECK and KISS-1 and the higher expression of MMP-2 in endometriosis might play an important role in the genesis of endometriosis.2 The changes of RECK KISS-1 and MMP-2 in eutopic endometrum are associated with them in ectopic.It suggest that the apoptosis characteristic of eutopic endometrum of endometriosis might have changed. 3 The high correlation of RECK KISS-1 and MMP-2suggested that they may co participate in the generating of endometriosis.
        

RECK、KISS-1和MMP-2在子宫内膜异位症组织中的表达

摘要4-8
Abstract8-11
论文部分14-44
    引言14-16
    材料与方法16-21
    结果21-28
    讨论28-36
    结论36-37
    附图37-39
    参考文献39-44
综述部分 子宫内膜异位症相关肿瘤转移抑制基因研究进展44-55
    参考文献51-55
个人简历、在校期间发表的学术论文与科研成果55-56
致谢56
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