Survivin在早孕小鼠子宫内膜的表达及功能研究
摘要
背景:
胚胎着床是人类和哺乳动物生殖过程中的重要环节,也是决定妊娠成功与否的关键,然而其机制尚未完全明了。这个过程受滋养层细胞的介导,滋养层细胞是一群特化的细胞,起源于滋养外胚层,它包围着囊胚腔以及内细胞团[1]。在小鼠,胚泡孵化10～15 h后滋养层发育成侵入表型,侵入子宫内膜,这一过程包括胚泡与子宫内膜上皮的识别、黏附和侵入子宫内膜等环节。在“着床窗”开放期,胚泡的成功植入取决于处于容受状态的子宫内膜和具有侵入性胚泡的同步发育,这一过程受极其复杂而精细的多因素的调节。
有人将胚胎视为“良性瘤”,研究表明,胚胎着床时胚胎滋养层侵入子宫内膜的过程和肿瘤细胞的浸润转移等方面的生物学行为极为相似[2],不少在肿瘤中发挥作用的原癌基因和抑癌基因在胚胎着床过程中也发挥了作用。Survivin是凋亡蛋白抑制因子(inhibitor of apoptosis protein,IAP)家族的一个新成员,是迄今为止克隆出的最小的IAP。Survivin基因定位于人染色体17q25.3,全长14.7kb,编码142个氨基酸,分子量为16.5kD的蛋白。Survivin在人与鼠的胚胎组织和大多数人类的恶性肿瘤组织中表达[3]。而Survivin基因敲除可导致妊娠4～5天后小鼠胚胎的死亡[4],认为Survivin是一种胚胎发育过程中必不可少的肿瘤抑制因子,因此我们推测,在胚胎植入的过程中,Survivin在诱导子宫内膜腔上皮细胞,蜕膜细胞及滋养层细胞的凋亡、促细胞增殖和血管形成过程中发挥重要的作用。然而Survivin在小鼠妊娠早期子宫内膜中的表达情况国内外尚无文献报道,是一个值得研究的课题。
目的:研究凋亡抑制基因Survivin在小鼠子宫内膜表达的规律性变化及其对胚胎植入的影响,初步探讨它在小鼠生殖中的作用。
方法:
1.收集未孕和早孕2、3、4、5、6、7天小鼠子宫内膜,共7组,每组20只小鼠。(1)运用实时荧光定量聚合酶链反应(FQ-PCR)技术测定Survivin mRNA的表达规律;(2)免疫组织化学SP法检测小鼠子宫内膜中Survivin蛋白的表达情况。
2.于孕4天晨8时小鼠子宫角注射Survivin抗体,于孕8天观察着床胚胎数。
结果:
1.FQ-PCR:早孕小鼠子宫内膜和非孕小鼠子宫内膜均有Survivin mRNA表达,妊娠的子宫内膜组织Survivin的表达高于未妊娠的子宫内膜组织,且随着妊娠天数的增加呈现逐渐增加的趋势,到妊娠第六天达到最高。
2.免疫组织化学:Survivin蛋白在子宫内膜广泛表达,特别是腔上皮、腺上皮细胞胞膜和胞浆,以及血管内皮细胞和基质细胞的细胞核内表达也较丰富,Survivin蛋白的表达规律与mRNA结果基本一致。
3.于孕4天晨8时子宫角注射Survivin抗体,观察结果显示注射Survivin抗体组着床胚胎数明显减少,差异显著(p<0.05)。
结论
Survivin在妊娠第6天高表达,表明它可能对抑制蜕膜细胞的凋亡,协调子宫内膜的蜕膜化和滋养层细胞的侵入起一定的作用。用Survivin抗体子宫角注射,发现着床胚胎数明显减少,推测Survivin在胚胎着床中可能扮演重要的角色。
Backgroud:
Blastocyst implantation is an important step in reproduction of humans and mammals, it is crucial for successful pregnancy, however, its mechanism has not been well cleared. This process can be mediated through trophoblastic cell which originated in trophectoderm; the blastocyst cavity surrounded it and the inner cell mass [1]. Trophoblast cells develop into invasive phenotype and invade endometrial after 10-15 h with mice blastocyst hatching, this process includes the blastocyst discriminate, adhere and invade endometrial epithelium and so on. At“nidation window phase”, the success blastocyst implantation depends on circumstance of endometrial receptivity and synchronous development of invasive blastocyst, which is accurately regulated by the extremely complex multi-factor.
Embryos were called as a "benign tumor" by some people, that is because there are many similarities in the process and the biological mechanism between embryonic trophoblast invading into endometrial and invasion and metastasis of tumor cells, [2] A great many people pay more attention to the function and mechanism of proto-oncogenes and anti-oncogenes during blastocyst implantation. Survivin, inhibitor of apoptosis proteins (IAP) family of a new member, is by far the smallest cloned IAP and locate in human chromosome 17 q25.3 with a total length of 14.7 kb, encoding 142 amino acids and 16.5 kD protein.
Survivin is existed in mouse embryonic tissue and the majority of human malignant tumor tissues[3]. Survivin gene knock-out can lead to the death of mouse embryos of d4-5[4]. In short, Survivin is an essential tumor suppressor factor in the process of embryonic development. Therefore, we supposed that Survivin plays an important role in the process of inducing apoptosis of endometrial epithelial cells, decidual cells and trophoblast cell and promoting cell proliferation and forming blood vessel during embryo implantation. However, at home and abroad, Survivin expression in early pregnancy mice endometrial has no reported in the literature of related research topic.
Objective: To investigate the expression of Survivin in mouse endometrium and its function during Blastocyst implantation
Methods:
1. Mouse endometrium in un-pregnant and pregnant mice on days 2, 3, 4, 5, 6, 7 of pregnancy were used to study. There are 7 groups, each group has 10 mice. Real-time fluorescent quantitative PCR (FQ-PCR) and immunohistoc- hemical techniques were applied to detect Survivin mRNA and protein expressions, respectively.
2. Survivin antibody was injected into the horns of uterus in pregnant mice on day 4 of pregnancy and the number of implantation sites was recorded on day 8 of pregnancy.
Results :
1. The higher expressions of Survivin mRNA /β-actin mRNA were observed in pregnant mice compared with that in un-pregnant mice, with a steady increasing from day 2 to 7 of pregnancy and reaching the maximal level on day 6 of pregnancy.
2. Immunohistochemical analysis showed that the expression of Survivin protein was same with the one of mRNA. Survivin protein extensive expressed in mouse endometrium, especially in the luminal epithelium and glandular epithelial cell membrane and the cytoplasm, as well as vascular endothelial cells and the nucleus of stromal cells.
3. At 8:00 in the morning the polyclonal antibodies of Survivin were injected into uterine horn of pregnant mice on days 4 of pregnancy and the number of implantation sites was recorded on day 8, the results showed that the number of Survivin antibody injection group significantly decreased, comparing with saline injection (p <0.05).
Conclusion: Expression of survivin in mouse endometrium during early pregnancy indicates that survivin might inhibit apoptosis of decidual cells, coordinating further decidualization of endometrium and invasion of trophoblastic cells. The result of Survivin antibody injection in uteri horn showed that the number of implantation was significantly decreased. These results suggested that Survivin might participate in the process of blastocyst implantation in mice.
胚胎着床是人类和哺乳动物生殖过程中的重要环节,也是决定妊娠成功与否的关键,然而其机制尚未完全明了。这个过程受滋养层细胞的介导,滋养层细胞是一群特化的细胞,起源于滋养外胚层,它包围着囊胚腔以及内细胞团[1]。在小鼠,胚泡孵化10～15 h后滋养层发育成侵入表型,侵入子宫内膜,这一过程包括胚泡与子宫内膜上皮的识别、黏附和侵入子宫内膜等环节。在“着床窗”开放期,胚泡的成功植入取决于处于容受状态的子宫内膜和具有侵入性胚泡的同步发育,这一过程受极其复杂而精细的多因素的调节。
有人将胚胎视为“良性瘤”,研究表明,胚胎着床时胚胎滋养层侵入子宫内膜的过程和肿瘤细胞的浸润转移等方面的生物学行为极为相似[2],不少在肿瘤中发挥作用的原癌基因和抑癌基因在胚胎着床过程中也发挥了作用。Survivin是凋亡蛋白抑制因子(inhibitor of apoptosis protein,IAP)家族的一个新成员,是迄今为止克隆出的最小的IAP。Survivin基因定位于人染色体17q25.3,全长14.7kb,编码142个氨基酸,分子量为16.5kD的蛋白。Survivin在人与鼠的胚胎组织和大多数人类的恶性肿瘤组织中表达[3]。而Survivin基因敲除可导致妊娠4～5天后小鼠胚胎的死亡[4],认为Survivin是一种胚胎发育过程中必不可少的肿瘤抑制因子,因此我们推测,在胚胎植入的过程中,Survivin在诱导子宫内膜腔上皮细胞,蜕膜细胞及滋养层细胞的凋亡、促细胞增殖和血管形成过程中发挥重要的作用。然而Survivin在小鼠妊娠早期子宫内膜中的表达情况国内外尚无文献报道,是一个值得研究的课题。
目的:研究凋亡抑制基因Survivin在小鼠子宫内膜表达的规律性变化及其对胚胎植入的影响,初步探讨它在小鼠生殖中的作用。
方法:
1.收集未孕和早孕2、3、4、5、6、7天小鼠子宫内膜,共7组,每组20只小鼠。(1)运用实时荧光定量聚合酶链反应(FQ-PCR)技术测定Survivin mRNA的表达规律;(2)免疫组织化学SP法检测小鼠子宫内膜中Survivin蛋白的表达情况。
2.于孕4天晨8时小鼠子宫角注射Survivin抗体,于孕8天观察着床胚胎数。
结果:
1.FQ-PCR:早孕小鼠子宫内膜和非孕小鼠子宫内膜均有Survivin mRNA表达,妊娠的子宫内膜组织Survivin的表达高于未妊娠的子宫内膜组织,且随着妊娠天数的增加呈现逐渐增加的趋势,到妊娠第六天达到最高。
2.免疫组织化学:Survivin蛋白在子宫内膜广泛表达,特别是腔上皮、腺上皮细胞胞膜和胞浆,以及血管内皮细胞和基质细胞的细胞核内表达也较丰富,Survivin蛋白的表达规律与mRNA结果基本一致。
3.于孕4天晨8时子宫角注射Survivin抗体,观察结果显示注射Survivin抗体组着床胚胎数明显减少,差异显著(p<0.05)。
结论
Survivin在妊娠第6天高表达,表明它可能对抑制蜕膜细胞的凋亡,协调子宫内膜的蜕膜化和滋养层细胞的侵入起一定的作用。用Survivin抗体子宫角注射,发现着床胚胎数明显减少,推测Survivin在胚胎着床中可能扮演重要的角色。
Backgroud:
Blastocyst implantation is an important step in reproduction of humans and mammals, it is crucial for successful pregnancy, however, its mechanism has not been well cleared. This process can be mediated through trophoblastic cell which originated in trophectoderm; the blastocyst cavity surrounded it and the inner cell mass [1]. Trophoblast cells develop into invasive phenotype and invade endometrial after 10-15 h with mice blastocyst hatching, this process includes the blastocyst discriminate, adhere and invade endometrial epithelium and so on. At“nidation window phase”, the success blastocyst implantation depends on circumstance of endometrial receptivity and synchronous development of invasive blastocyst, which is accurately regulated by the extremely complex multi-factor.
Embryos were called as a "benign tumor" by some people, that is because there are many similarities in the process and the biological mechanism between embryonic trophoblast invading into endometrial and invasion and metastasis of tumor cells, [2] A great many people pay more attention to the function and mechanism of proto-oncogenes and anti-oncogenes during blastocyst implantation. Survivin, inhibitor of apoptosis proteins (IAP) family of a new member, is by far the smallest cloned IAP and locate in human chromosome 17 q25.3 with a total length of 14.7 kb, encoding 142 amino acids and 16.5 kD protein.
Survivin is existed in mouse embryonic tissue and the majority of human malignant tumor tissues[3]. Survivin gene knock-out can lead to the death of mouse embryos of d4-5[4]. In short, Survivin is an essential tumor suppressor factor in the process of embryonic development. Therefore, we supposed that Survivin plays an important role in the process of inducing apoptosis of endometrial epithelial cells, decidual cells and trophoblast cell and promoting cell proliferation and forming blood vessel during embryo implantation. However, at home and abroad, Survivin expression in early pregnancy mice endometrial has no reported in the literature of related research topic.
Objective: To investigate the expression of Survivin in mouse endometrium and its function during Blastocyst implantation
Methods:
1. Mouse endometrium in un-pregnant and pregnant mice on days 2, 3, 4, 5, 6, 7 of pregnancy were used to study. There are 7 groups, each group has 10 mice. Real-time fluorescent quantitative PCR (FQ-PCR) and immunohistoc- hemical techniques were applied to detect Survivin mRNA and protein expressions, respectively.
2. Survivin antibody was injected into the horns of uterus in pregnant mice on day 4 of pregnancy and the number of implantation sites was recorded on day 8 of pregnancy.
Results :
1. The higher expressions of Survivin mRNA /β-actin mRNA were observed in pregnant mice compared with that in un-pregnant mice, with a steady increasing from day 2 to 7 of pregnancy and reaching the maximal level on day 6 of pregnancy.
2. Immunohistochemical analysis showed that the expression of Survivin protein was same with the one of mRNA. Survivin protein extensive expressed in mouse endometrium, especially in the luminal epithelium and glandular epithelial cell membrane and the cytoplasm, as well as vascular endothelial cells and the nucleus of stromal cells.
3. At 8:00 in the morning the polyclonal antibodies of Survivin were injected into uterine horn of pregnant mice on days 4 of pregnancy and the number of implantation sites was recorded on day 8, the results showed that the number of Survivin antibody injection group significantly decreased, comparing with saline injection (p <0.05).
Conclusion: Expression of survivin in mouse endometrium during early pregnancy indicates that survivin might inhibit apoptosis of decidual cells, coordinating further decidualization of endometrium and invasion of trophoblastic cells. The result of Survivin antibody injection in uteri horn showed that the number of implantation was significantly decreased. These results suggested that Survivin might participate in the process of blastocyst implantation in mice.
引文
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