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IKCa1与内膜容受性和胚胎植入的干系

来历:天津医药 作者:陈洪燕,孙星宇,李亚玲
宣布于:2020-06-01 共8474字

  摘    要: 目标 检测中电导钙激活性钾离子通道(IKCa1)在围着床期子宫内膜的抒发及其在胚胎着床进程中的感化。方式 别离取排泄和增生早、中、初期子宫内膜构造各5例。操纵q PCR和免疫组化手艺检测各期IKCa1 m RNA和卵白的抒发。体外培育人子宫内膜癌Ishikawa细胞,差别浓度(0、10、20、30?mol/L)IKCa1停滞剂TRAM-34干涉干与后,q PCR检测细胞IKCa1抒发,CCK-8法检测细胞增殖才能,Transwell尝试检测细胞体外胚胎黏附才能,Western blot检测细胞上皮-间质转化(EMT)相干卵白E盒连系卵白1(Zeb1)和上皮型钙黏卵白(E-cadherin)抒发。成果 IKCa1在人子宫内膜中呈时序性抒发,排泄期抒发程度较增生期光鲜较着增高,以排泄中期最高。TRAM-34按捺IKCa1抒发后,Ishikawa细胞增殖和胚胎黏附才能削弱;EMT标记卵白E-cadherin抒发光鲜较着上调,Zeb1抒发光鲜较着下调(P<0.05)。论断 IKCa1能够到场围着床期子宫内膜容受性的成立,并经由进程影响子宫内膜细胞增殖和EMT调控胚胎着床。

  关头词: 刹时电导钙激活钾通道; 子宫内膜; 胚胎植入; 上皮-间质转化; 钙黏着糖卵白类; E盒连系锌指卵白1;

  Abstract: Objective To detect the expression of intermediate-conductance-Ca2+-activated K+channels(IKCa1) in endometrium during peri-implantation and explore the role of IKCa1 in embryo implantation.Methods tissue samples of early, middle and late secretory stages and early, middle and late proliferative stages were taken respectively in 5 cases. Immunohistochemistry and quantitative PCR(qPCR) were used to detect the expression of IKCa1 mRNA and protein in endometrial tissues of different stages. Ishikawa cells were cultured in vitro and treated with different concentrations(0, 10, 20 and 30 ?mol/L) of IKCa1 blocker TRAM-34. The expression of IKCa1 was detected by qPCR, cell proliferation was detected by CCK8, the cell adhesion was detected by Transwell and the expressions of EMT related proteins, E-box binding protein 1(Zeb1) and E-cadherin were detected by Western blot assay.Results The expression of IKCa1 was time-dependent in human endometrium. The expression level of IKCa1 was significantly higher in secretory phase than that in proliferative phase, especially in middle secretory phase. The expression of IKCa1 was inhibited by TRAM-34 in Ishikawa cells. The cell proliferation and embryo adhesion decreased, the expression of EMT marker protein Ecadherin was significantly up-regulated, and the expression of Zeb1 protein was significantly down regulated(P<0.05).Conclusion regulate embryo implantation by influencing endometrial cell proliferation and EMT.

  Keyword: intermediate-conductance calcium-activated potassium channels; endometrium; embryo implantation; epithelial-mesenchymal transition; cadherins; zinc finger E-box-binding homeobox 1;
 

IKCa1与内膜容受性和胚胎植入的干系
 

  胚胎的胜利着床取决于胚胎的侵入才能和子宫内膜的容受性。胚胎植入时须要敏捷重塑子宫内膜上皮樊篱和规复其免疫功效,而子宫内膜上皮细胞的上皮-间质转化(EMT)对子宫内膜上皮细胞的容受性起着首要感化[1]。血管天生和血管重塑也为内膜容受性的成立供给物资根本[2]。胚胎着床是一个母胎彼此辨认、彼此融会的庞杂进程。围着床期母胎免疫调理的任一关头变态都能够致使着床失利。中电导钙激活性钾离子通道(IKCa1)属钙激活钾通道(KCa)卵白家属成员,由IKCa1基因编码。研讨证明IKCa1在子宫内膜上皮及其癌细胞株中抒发,可增进EMT[3],并增进细胞增殖、迁徙和侵袭[4,5,6];亦可调理Th1/Th2细胞功效,到场血管天生[7,8,9]。由此猜测IKCa1能够经由进程增进胚胎侵入,引诱子宫内膜EMT和血管天生,加快子宫内膜重塑和成立容受性,调理母胎免疫耐受等到场调理胚胎植入。为切磋IKCa1在胚胎着床进程中的感化,本研讨接纳免疫组化手艺检测IKCa1和EMT标记卵白在围着床期子宫内膜的抒发,并操纵IKCa1通道停滞剂TRAM-34降落子宫内膜细胞IKCa1抒发及活性,切磋IKCa1与内膜容受性和胚胎植入的干系。

  1 、材料与方式

  1.1、材料

  1.1.1、构造标本

  搜集2018年1月—12月在东北医科大学从属病院生殖中间接管体外受精-胚胎移植(IVF-ET)助孕前1周期行子宫内膜活检的患者,别离取排泄和增生早、中、初期子宫内膜构造各5例。归入规范:春秋<38岁,月经周期纪律且有排卵,根本性激素程度一般,周期25~35 d,近3个月无激素类药物操纵史及宫腔操纵史,宫腔形状一般。解除规范:有子宫黏膜下肌瘤、子宫畸形、内膜瘜肉、宫腔粘连者,宫腔形状非常、染色体非常者,性传布疾病者。一切标本一局部经10%中性福尔马林牢固,白腊包埋后用于免疫组化染色,一局部冻存于液氨内用于后续研讨。本研讨经病院伦理委员会会商经由进程,一切患者均签订知情赞成书。

  1.1.2、细胞系

  人子宫内膜癌Ishikawa细胞株和人绒毛膜癌JAR细胞购自东北医科大学从属病院医学尝试中间,苏醒后单层培育于含10%胎牛血清的DMEM培育液中,置于37℃、5%CO2培育箱中培育。

  1.1.3、首要试剂

  SP-9000免疫组化染色试剂盒购自北京中杉金桥生物手艺无限公司,DAB染色试剂盒、4%多聚甲醛溶液、兔抗E-cadherin多克隆抗体购自武汉博士德生物工程无限公司,TRAM-34、DMSO购自美国Sigma公司,胎牛血清、DMEM培育液、Transwell小室购自美国Corning公司,结晶紫、SDS-PAGE凝胶试剂盒、PVDF膜、ECL发光液、BCA卵白浓度检测试剂盒购自上海碧云天生物手艺无限公司,兔抗GAPDH多克隆抗体购自武汉三鹰生物手艺无限公司,兔抗IKCa1、E盒连系卵白1(Zeb1)多克隆抗体购自美国SAB公司,SYBR Green荧光定量PCR(q PCR)检测试剂盒购自康为世纪生物科技无限公司,辣根过氧化物酶(HRP)标记山羊抗兔Ig G二抗购自安徽合肥兰杰柯科技无限公司,引物拜托上海生工生物工程手艺办事无限公司分解。

  1.2、方式

  1.2.1、qPCR检测子宫内膜构造和Ishikawa细胞IKCa1m RNA抒发

  增生期和排泄期子宫内膜构造和Ishikawa细胞,根据TRIzol一步法提取总RNA,用Oligo(d T)18停止逆转录。IKCa1引物序列:下流5'-GTGCGTGCAGGATTTAGGG-3',下流5'-TGCTAAGCAGCTCAGTCAGGG-3';内参照GAPDH引物序列:下流5'-ATGCTGGCGCTGAGTACGTC-3',下流5'-GGTCATGAGTCCTTCCACGATA-3'。PCR总反映体系:c DNA 1?L,上、下流引物各1?L,2×Ultra SYBR Mix 10?L,dd H2O补充至20?L。PCR扩增反映前提:95℃预变性10 min;94℃变性10 s,65℃退火20 s,72℃延长15 s,轮回40次;72℃终末延长10 min。以2-ΔCt方式阐发IKCa1 m RNA的绝对抒发量。

  1.2.2、免疫组化检测子宫内膜构造IKCa1卵白抒发

  白腊切片经脱蜡、水化后,置于柠檬酸盐缓冲液中加热至95~100℃12 min停止抗原修复。经PBS洗濯3 min×3次,3%过氧化氢孵育10 min,洗濯,5%山羊血清封锁20 min。插手IKCa1一抗(1∶100)4℃孵育留宿,洗濯,生物素连系山羊抗兔Ig G聚合物室温30 min,HRP标记的链霉亲和素溶液室温30 min。DAB显色剂显色1~2 min,自来水冲刷,苏木素复染2 min,盐酸乙醇分解2 s。经脱水、通明、封片后,于显微镜下察看染色成果并摄影。染色强度分级:0分(无染色),1分(弱染色),2分(中度染色),3分(激烈染色)。阳性细胞百分率:0分(0~5%)、1分(6%~25%)、2分(26%~50%)和3分(51%~100%)。免疫组化评分即二者乘积,总分≥3分为阳性,<3分为阳性[10]。

  1.2.3、细胞培育与分组

  对数发展期Ishikawa细胞接种于含10%胎牛血清的DMEM中,置于37℃、5%CO2培育箱中惯例培育。接纳DMSO配制10 mmol/L TRAM-34储蓄液,待细胞贴壁后,尝试组插手差别浓度TRAM-34,使其终浓度别离为0(仅插手等量DMSO)、10、20、30?mol/L,各组细胞持续培育48 h后别离搜集细胞停止后续尝试。

  1.2.4、CCK-8法检测子宫内膜细胞增殖

  取对数发展期Ishikawa细胞制备成细胞悬液,接种到96孔板中,每孔增添200?L细胞悬液,各组设3个反复样本。37℃,5%CO2培育48 h后每孔插手10?L CCK-8试剂,用酶标仪检测其在450nm处的光密度(OD)值。

  1.2.5、体外摹拟胚胎植入尝试(Transwell法)

  取对数发展期Ishikawa细胞用含10%胎牛血清的DMEM制成细胞悬液,每孔1×105个接种培育于24孔板,待细胞贴壁后插手差别浓度的TRAM-34。安排Transwell小室,JAR细胞接种前予无血清DMEM处置细胞24 h,每孔1×104个JAR细胞接种培育于小室上室,置CO2培育箱(5%CO2、37℃)中培育48 h。掏出小室,将小室内正面的细胞断根,保留外正面的细胞。4%多聚甲醛牢固细胞30 min。甩干,结晶紫孵育30 min,自来水冲刷5 min,室温下天然枯燥。在颠倒相差显微镜(OLYMPUS,日本)下察看并摄影。随机读取5个视线并计数穿膜细胞数。

  1.2.6、Western blot检测子宫内膜细胞EMT标记卵白抒发变更

  Ishikawa细胞裂解后12 000×g离心15 min,搜集上清,以BCA法测卵白浓度。配制10%分手胶和5%稀释胶,卵白样品煮沸10 min预变性,上样,以稀释胶80 V 40 min,分手胶120 V 70 min停止恒压电泳,250 m A恒流转膜,PVDF膜置于5%脱脂牛奶室温2 h;TBST洗膜,一抗E-cadherin(1∶500)、Zeb1(1∶500)和GAPDH(1∶8 000)4℃留宿,二抗(1∶10 000)室温孵育2 h。洗膜后增添ECL发光液,置于Bio-Rad凝胶成像体系显影后阐发目标卵白的绝对抒发量。SPSS 19.0 Graphpad 6.0

  1.3、统计学方式

  一切数据接纳SPSS 19.0和Graphpad 6.0停止统计学阐发,合适正态散布的计量材料以均数±规范差(±s)表现,2组均数间比拟接纳自力样本t查验,多组均数间比拟用单身分方差阐发,组间多重比拟接纳LSD-t法。P<0.05为差别有统计学意思。

  2 、成果

  2.1、 IKCa1在一般月经周期子宫内膜的抒发情况

  q PCR成果显现,IKCa1 m RNA在人子宫内膜月经周期各期均有抒发,增生各期抒发处于低程度,差别无统计学意思(F=0.563,P>0.05)。IKCa1 m RNA在排泄期子宫内膜的抒发,以排泄中期(即围着床期)最为光鲜较着(F=27.750,P<0.01),见图1。免疫组化染色成果显现,IKCa1在子宫内膜增生各期呈低抒发或不抒发,在排泄期呈高抒发,排泄中期抒发最强,首要抒发于腺上皮和腔上皮细胞胞浆,见图2。

  图1 一般月经各周期子宫内膜IKCa1 m RNA抒发程度
图1 一般月经各周期子宫内膜IKCa1 m RNA抒发程度

  Fig.1 The expressions of IKCa1 m RNA in endometrium of normal menstrual cycle

  2.2、 差别浓度TRAM-34对Ishikawa细胞增殖的影响

  q PCR成果显现,与0?mol/L组比拟,10、20、30?mol/L TRAM-34处置组IKCa1 m RNA抒发程度随药物浓度增添较着降落(F=26.230,P<0.01),见图3。CCK-8成果显现,随TRAM-34浓度的增添,Ishikawa细胞增殖才能较着降落(F=275.100,P<0.01);此中以30?mol/L组降落最为光鲜较着,见图4。

  2.3 、差别浓度TRAM-34对Ishikawa细胞体外胚胎植入才能的影响

  Transwell成果显现TRAM-34干涉干与子宫内膜Ishikawa细胞48 h,其对体外胚胎的黏附才能光鲜较着降落,穿过小室基底膜的JAR细胞数光鲜较着削减,差别有统计学意思(F=40.520,P<0.01),见图5、6。

  图2 一般月经各周期子宫内膜IKCa1卵白抒发(免疫组化染色,×200)
图2 一般月经各周期子宫内膜IKCa1卵白抒发(免疫组化染色,×200)

  Fig.2 The IKCa1 expressions in endometrium of normal menstrual cycle(Immunohistochemical staining,×200)

  图3 差别浓度TRAM-34处置后IKCa1 mRNA在子宫内膜细胞的抒发
图3 差别浓度TRAM-34处置后IKCa1 mRNA在子宫内膜细胞的抒发

  Fig.3 Expressions of IKCa1 mRNA in endometrial carcinomaIshikawa cells treatment with TRAM-34

  图4 差别浓度TRAM-34处置后Ishikawa细胞增殖才能变更
图4 差别浓度TRAM-34处置后Ishikawa细胞增殖才能变更

  Fig.4 Changes of Ishikawa cell proliferation ability after treatment withdifferent concentrations of TRAM-34

  图5 差别浓度TRAM-34处置后Ishikawa细胞对体外胚胎的黏附才能变更(Transwell尝试,×200)
图5 差别浓度TRAM-34处置后Ishikawa细胞对体外胚胎的黏附才能变更(Transwell尝试,×200)

  Fig.5 Changes of Ishikawa cell adhersion ability to embryos in vitro after treatment with different concentrations of TRAM-34(Transwell assay,×200)

  图6 差别浓度TRAM-34处置后Ishikawa细胞侵袭数目比拟
图6 差别浓度TRAM-34处置后Ishikawa细胞侵袭数目比拟

  Fig.6 Comparison of the number of Ishikawa cells invaded by differentconcentrations of TRAM-34

  2.4 、差别浓度TRAM-34对子宫内膜细胞EMT相干卵白抒发的影响

  与0?mol/L组比拟,30?mol/L组细胞E-cadherin卵白抒发较着上调(t=29.275,P<0.01),Zeb1卵白抒发较着下调(t=15.487,P<0.01),见图7。

  3、 会商

  胚胎着床是怀胎的关头关头,是具备着床才能的胚胎与子宫成立慎密接洽的进程[11]。围着床期子宫内膜处于容受状况,许可胚胎黏附并侵入子宫内膜,子宫内膜基质细胞普遍增殖和分解,产生蜕膜化构成低级蜕膜区,从而实现胚胎着床[12]。胚胎着床不只须要发育成熟的囊胚,容受态的子宫内膜也是必不可少的,只要子宫内膜处于容受态时才会产生囊胚黏附[13]。在赞助生殖进程中胚胎移植胜利率低的首要缘由之一是胚胎移植时子宫内膜处于非容受态[14]。胚胎的一般着床对后续怀胎保持和临蓐均起首要感化,非常的胚胎着床可致流产、早产等[15]。

  图7 TRAM-34处置后Ishikawa细胞EMT相干卵白抒发变更
图7 TRAM-34处置后Ishikawa细胞EMT相干卵白抒发变更

  Fig.7 Expression of EMT-related proteins in Ishikawa cells after treatment with TRAM-34

  KCa包含大电导KCa通道[BK(Ca)]、IKCa1和小电导KCa通道(SK3),均在子宫内膜细胞中抒发,BK(Ca)经由进程介导子宫内膜感触感染性因子的抒发来影响胚胎着床,SK3抒发削减与怀胎失利相干,IKCa1则到场细胞增殖的调控[16,17]。IKCa1可增进血管内皮细胞增殖和血管天生[18],血管天生即成立血窦与血管收集体系,在胎盘构成之前,其为胚泡供给养分和保送氧,以保障胚胎保存和胜利怀胎[19,20,21]。是以笔者猜测,IKCa1通道能够也与胚胎着床有必然干系。本研讨发明,子宫内膜排泄中期IKCa1抒发较着下降,此期正处于围着床期,提醒IKCa1能够到场子宫内膜着床窗的开放,有能够作为子宫内膜容受性的潜伏份子标记物,促使子宫内膜达到容受态从而有益于胚胎黏附和植入。

  胚胎着床时,胚胎外滋润层的细胞穿透子宫内膜上皮细胞并侵袭入子宫内膜间质细胞,此时子宫内膜上皮细胞迁徙和转化的生物学行动和肿瘤细胞的侵袭和转移具备极大的类似性[22]。今朝常操纵人子宫内膜癌细胞与人绒毛膜癌细胞摹拟体外胚胎着床进程[23]。有研讨发明EMT也到场了胚胎植入的调理,其引发植入部位的子宫内膜上皮细胞的活动和迁徙,从而在胚胎达到之前使子宫内膜取得容受态[8]。本研讨鉴戒其尝试方式,成果发明,TRAM-34降落子宫内膜癌Ishikawa细胞IKCa1抒发后,细胞的增殖才能降落,EMT进程遭到按捺,对体外胚胎黏附才能降落,提醒IKCa1通道能够经由进程EMT到场了胚胎植入的调理,阐扬增进胚胎着床的感化。

  综上所述,IKCa1在子宫内膜的抒发呈周期性,在围着床期高抒发,有能够作为子宫内膜容受性的潜伏标记物。是以,体外受精-胚胎移植前检测子宫内膜IKCa1的抒发量,以评价子宫内膜的容受性,有助于进步胚胎移植胜利率。

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作者单元:东北医科大学从属病院药学部 东北医科大学从属病院生殖中间 东北医科大学从属病院综合推销部
原文来由:陈洪燕,孙星宇,李亚玲,何金三,刘玲.IKCa1在围着床期子宫内膜的抒发及其感化[J].天津医药,2021,49(05):460-464.
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