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Article(id=1208073006438523048, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1208073005197009056, articleNumber=null, orderNo=null, doi=10.11855/j.issn.0577-7402.2022.05.0451, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1628265600000, receivedDateStr=2021-08-07, revisedDate=null, revisedDateStr=null, acceptedDate=1631635200000, acceptedDateStr=2021-09-15, onlineDate=1765956649646, onlineDateStr=2025-12-17, pubDate=1653667200000, pubDateStr=2022-05-28, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1765956649646, onlineIssueDateStr=2025-12-17, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1765956649646, creator=13701087609, updateTime=1765956649646, updator=13701087609, issue=Issue{id=1208073005197009056, tenantId=1146029695717560320, journalId=1189873630562394117, year='2022', volume='47', issue='5', pageStart='427', pageEnd='532', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1765956649350, creator=13701087609, updateTime=1765956710955, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1208073263641633510, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1208073005197009056, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1208073263641633511, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1208073005197009056, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=451, endPage=457, ext={EN=ArticleExt(id=1208073007680037036, articleId=1208073006438523048, tenantId=1146029695717560320, journalId=1189873630562394117, language=EN, title=Mechanism and effect of nodakenin regulating EMT on the invasion and migration of cervical cancer cells, columnId=1190310110212751762, journalTitle=Medical Journal of Chinese People’s Liberation Army, columnName=Basic Research, runingTitle=null, highlight=null, articleAbstract=

Objective To explore the mechanism of nodakenin (NDK) affecting the invasion and migration of cervical cancer cells by regulating epithelial-mesenchymal transformation (EMT), and analyze its effect on microRNA (miR)-324-3P/WNT3a axis. Methods Human cervical cancer HeLa cells in logarithmic growth phase were divided into four groups: blank group(cultivated in a 37 ℃, 5% CO2-saturated humidity incubator), NDK group (20 mmol/L NDK was added to culture), miR-324-3P inhibitor group (hsa-miR-324-3p inhibitor transfection), and miR-324-3P inhibitor+NDK group (after transfection of miR-324-3P inhibitor, 20 mmol/L NDK was added to culture) all were treated for 48 h. Transwell test was used to detect the invasion ability of cells in each group. Cell scratch test was performed to detect cell migration ability of each group. qRT-PCR to detect the mRNA level of miR-324-3P and WNT3a in each group of cells. Western blotting was carried out to detect the expression of EMT-related marker proteins E-cadherin, vimentin, Neural cadherin (N-cadherin), WNT3a, and β-catenin protein in each group of cells. Dual luciferase reporter gene was used to detect the targeting relationship between miR-324-3P and WNT3a gene. Results Compared with the blank group, the number of transmembrane HeLa cells increased in miR-324-3P inhibitor group, the scratch healing rate increased, the mRNA expression level of miR-324-3P decreased, and of WNT3a increased; the relative expression of E-cadherin protein decreased, while the relative expressions of vimentin, N-cadherin, WNT3a and β-catenin increased (P<0.05). While for NDK group and miR-324-3P inhibitor+NDK group, the number of transmembrane HeLa cells decreased, the scar healing rate was also decreased, the mRNA expression level of miR-324-3P increased, the expression level of WNT3a mRNA decreased, the relative expression of E-cadherin protein increased, and the relative expression of vimentin, N-cadherin, WNT3a and β-catenin protein decreased (P<0.05); All the indexes mentioned above were lower in NDK group than those in miR-324-3P inhibitor+NDK group.The dual luciferase reporter gene results showed that miR-324-3P mimic could reduce WNT3a WT luciferase activity (P<0.05), but did not affect WNT3a mut luciferase activity (P>0.05). Conclusion NDK can inhibit the invasion and migration of cervical cancer cells by regulating EMT, and the mechanism of such action may be related to the regulation of miR-324-3P/WNT3a axis.

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目的 探讨紫花前胡苷(NDK)通过调控上皮-间质转化(EMT)影响宫颈癌细胞侵袭迁移的可能机制，并分析其对miR-324-3P/WNT3a轴的影响。方法 取对数生长期人宫颈癌HeLa细胞，分为4组：空白组(于37 ℃、5%CO2、饱和湿度培养箱中培养)、miR-324-3P inhibitor组(转染hsa-miR-324-3p inhibitor)、NDK组(加入20 mmol/L浓度的NDK培养)、miR-324-3P inhibitor+NDK组(转染miR-324-3P inhibitor后加入20 mmol/L浓度的NDK培养)，均处理48 h。采用Transwell实验检测各组细胞侵袭能力；细胞划痕实验检测各组细胞的迁移能力；qRT-PCR检测各组细胞中miR-324-3P、WNT3a mRNA表达水平；Western blotting检测各组EMT相关标志蛋白E-钙黏素(E-cadherin)、波形蛋白、神经型钙黏蛋白(N-cadherin)、WNT3a、β-catenin蛋白表达水平；双荧光素酶报告基因检测miR-324-3P与WNT3a基因的靶向关系。结果 与空白组比较，miR-324-3P inhibitor组HeLa细胞的穿膜细胞数增多，划痕愈合率增高，miR-324-3P mRNA表达水平下降，WNT3a mRNA表达水平升高，E-cadherin蛋白相对表达量降低，波形蛋白、N-cadherin、WNT3a和β-catenin蛋白相对表达量升高(P<0.05)；而NDK组、miR-324-3P inhibitor+NDK组HeLa细胞的穿膜细胞数减少，划痕愈合率降低，miR-324-3P mRNA表达水平升高，WNT3a mRNA表达水平降低，E-cadherin蛋白相对表达量升高，波形蛋白、N-cadherin、WNT3a和β-catenin蛋白相对表达量降低(P<0.05)；且NDK组上述各指标均低于miR-324-3P inhibitor+NDK组。双荧光素酶报告基因检测结果显示，miR-324-3P mimic可降低WNT3a WT荧光素酶活性(P<0.05)，但不影响WNT3a mut荧光素酶活性(P>0.05)。结论 NDK可通过调控EMT抑制宫颈癌细胞的侵袭及迁移，其作用机制可能与调节miR-324-3P/WNT3a轴有关。

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任璐，副主任医师，主要从事妇科肿瘤方面的研究

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任璐，副主任医师，主要从事妇科肿瘤方面的研究

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任璐，副主任医师，主要从事妇科肿瘤方面的研究

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language=CN, orderNo=4, keyword=细胞迁移), Keyword(id=1208073012616733056, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073006438523048, language=CN, orderNo=5, keyword=上皮-间质转化), Keyword(id=1208073012717396361, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073006438523048, language=CN, orderNo=6, keyword=miR-324-3P/WNT3a轴)], refs=[Reference(id=1208073014516752893, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073006438523048, doi=null, pmid=null, pmcid=null, year=2019, volume=71, issue=4, pageStart=313, pageEnd=320, url=null, language=null, rfNumber=[1], rfOrder=0, authorNames=Pimple SA, Mishra GA, journalName=Minerva Ginecol, refType=null, unstructuredReference=Pimple SA, Mishra GA. 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A. 结晶紫染色(×100)；B. 各组穿膜细胞数比较(n=3)；与空白组比较，(1)P<0.05；与NDK组比较，(2)P<0.05，与miR-324-3P inhibitor组比较，(3)P<0.05

, figureFileSmall=O8bdghttYjJGq71rC3ONFA==, figureFileBig=BMtpx9jfCWxu1t63GbKa1w==, tableContent=null), ArticleFig(id=1208073013153604006, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073006438523048, language=EN, label=Fig.2, caption=Effect of NDK on migration ability of HeLa cells in each group, figureFileSmall=XnDPLcMeUtnQtmuQkRNxtw==, figureFileBig=kNx00vYlquEfGbpv0vjR6A==, tableContent=null), ArticleFig(id=1208073013254267308, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073006438523048, language=CN, label=图2, caption=NDK对HeLa各组细胞迁移能力的影响

A. 划痕实验(×100)；B. 各组细胞的划痕愈合率比较(n=3)；与空白组比较，(1)P<0.05；与NDK组比较，(2)P<0.05；与miR-324-3P inhibitor组比较，(3)P<0.05

, figureFileSmall=XnDPLcMeUtnQtmuQkRNxtw==, figureFileBig=kNx00vYlquEfGbpv0vjR6A==, tableContent=null), ArticleFig(id=1208073013346542006, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073006438523048, language=EN, label=Fig. 3, caption=Comparison of the expression of miR-324-3P and WNT3a mRNA in each group of cells, figureFileSmall=JMPKL9mhS6aTI2ceb/yEnA==, figureFileBig=QObnwsKWvBMf8IsWS61+iA==, tableContent=null), ArticleFig(id=1208073013438816701, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073006438523048, language=CN, label=图3, caption=各组细胞miR-324-3P、WNT3a mRNA表达情况比较

与空白组比较，(1)P<0.05；与NDK组比较，(2)P<0.05；与miR-324-3P inhibitor组比较，(3)P<0.05

, figureFileSmall=JMPKL9mhS6aTI2ceb/yEnA==, figureFileBig=QObnwsKWvBMf8IsWS61+iA==, tableContent=null), ArticleFig(id=1208073013505925569, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073006438523048, language=EN, label=Fig.4, caption=Expressions of E-cadherin, vimentin, N-cadherin, WNT3a and β-catenin protein of cells in each group (n=3), figureFileSmall=L3/F9+zCCwDasfmqdiPdTA==, figureFileBig=drh6WX2xg95CqYjUI7w9kg==, tableContent=null), ArticleFig(id=1208073013619171787, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073006438523048, language=CN, label=图4, caption=各组细胞E-cadherin、波形蛋白、N-cadherin、WNT3a和β-catenin蛋白表达情况(n=3)

与空白组比较，(1)P<0.05；与miR-324-3P inhibitor组比较，(2)P<0.05；与miR-324-3P inhibitor+NDK组比较，(3)P<0.05

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与miR-324-3P mimic比较，(1)P<0.05

, figureFileSmall=1dL9qbkfPqB1USWpfP2YZw==, figureFileBig=oOYKaXy4MGZXR9VUL1YpSQ==, tableContent=null), ArticleFig(id=1208073014122488294, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073006438523048, language=EN, label=Tab.1, caption=

Primer sequence of RT-PCR

, figureFileSmall=null, figureFileBig=null, tableContent=
基因序列
miR-324-3P正义：5'-ACTGCCCCAGGTGCTGCTGG-3'
反义：5'-GCGAGCACAGAATTAATACGAC-3'
WNT3a正义：5'-ACCATGTTCGGGACCTATTCCA-3'
反义：5'-GCCTGTAGCATCTCGCTTCCA-3'
U6正义：5'-CTCGCTTCGGGCAGCACA-3'
反义：5'-AACGCTCTCACGAATTTGCGT-3'
β-actin正义：5'-TGCTATGTTGCCCTAGACTTCG-3'
反义：5'-GTTGGCATAGAGGTCTTTACGG-3'
), ArticleFig(id=1208073014210568683, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073006438523048, language=CN, label=表1, caption=

RT-PCR引物序列

, figureFileSmall=null, figureFileBig=null, tableContent=
基因序列
miR-324-3P正义：5'-ACTGCCCCAGGTGCTGCTGG-3'
反义：5'-GCGAGCACAGAATTAATACGAC-3'
WNT3a正义：5'-ACCATGTTCGGGACCTATTCCA-3'
反义：5'-GCCTGTAGCATCTCGCTTCCA-3'
U6正义：5'-CTCGCTTCGGGCAGCACA-3'
反义：5'-AACGCTCTCACGAATTTGCGT-3'
β-actin正义：5'-TGCTATGTTGCCCTAGACTTCG-3'
反义：5'-GTTGGCATAGAGGTCTTTACGG-3'
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紫花前胡苷调控EMT对宫颈癌细胞侵袭迁移的影响及其作用机制
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任璐 , 曹芹雪 , 杨少琴
解放军医学杂志 | 基础研究 2022,47(5): 451-457
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解放军医学杂志 | 基础研究 2022, 47(5): 451-457
紫花前胡苷调控EMT对宫颈癌细胞侵袭迁移的影响及其作用机制
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任璐, 曹芹雪, 杨少琴
作者信息
  • 河南大学淮河医院妇产科，河南开封 475000

    • 任璐，副主任医师，主要从事妇科肿瘤方面的研究

Mechanism and effect of nodakenin regulating EMT on the invasion and migration of cervical cancer cells
Lu Ren, Qin-Xue Cao, Shao-Qin Yang
Affiliations
  • Department of Obstetrics and Gynecology, Huaihe Hospital of Henan University, Kaifeng, Henan 475000, China
出版时间: 2022-05-28 doi: 10.11855/j.issn.0577-7402.2022.05.0451
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摘要
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目的 探讨紫花前胡苷(NDK)通过调控上皮-间质转化(EMT)影响宫颈癌细胞侵袭迁移的可能机制，并分析其对miR-324-3P/WNT3a轴的影响。方法 取对数生长期人宫颈癌HeLa细胞，分为4组：空白组(于37 ℃、5%CO2、饱和湿度培养箱中培养)、miR-324-3P inhibitor组(转染hsa-miR-324-3p inhibitor)、NDK组(加入20 mmol/L浓度的NDK培养)、miR-324-3P inhibitor+NDK组(转染miR-324-3P inhibitor后加入20 mmol/L浓度的NDK培养)，均处理48 h。采用Transwell实验检测各组细胞侵袭能力；细胞划痕实验检测各组细胞的迁移能力；qRT-PCR检测各组细胞中miR-324-3P、WNT3a mRNA表达水平；Western blotting检测各组EMT相关标志蛋白E-钙黏素(E-cadherin)、波形蛋白、神经型钙黏蛋白(N-cadherin)、WNT3a、β-catenin蛋白表达水平；双荧光素酶报告基因检测miR-324-3P与WNT3a基因的靶向关系。结果 与空白组比较，miR-324-3P inhibitor组HeLa细胞的穿膜细胞数增多，划痕愈合率增高，miR-324-3P mRNA表达水平下降，WNT3a mRNA表达水平升高，E-cadherin蛋白相对表达量降低，波形蛋白、N-cadherin、WNT3a和β-catenin蛋白相对表达量升高(P<0.05)；而NDK组、miR-324-3P inhibitor+NDK组HeLa细胞的穿膜细胞数减少，划痕愈合率降低，miR-324-3P mRNA表达水平升高，WNT3a mRNA表达水平降低，E-cadherin蛋白相对表达量升高，波形蛋白、N-cadherin、WNT3a和β-catenin蛋白相对表达量降低(P<0.05)；且NDK组上述各指标均低于miR-324-3P inhibitor+NDK组。双荧光素酶报告基因检测结果显示，miR-324-3P mimic可降低WNT3a WT荧光素酶活性(P<0.05)，但不影响WNT3a mut荧光素酶活性(P>0.05)。结论 NDK可通过调控EMT抑制宫颈癌细胞的侵袭及迁移，其作用机制可能与调节miR-324-3P/WNT3a轴有关。

紫花前胡苷  /  宫颈癌  /  细胞侵袭  /  细胞迁移  /  上皮-间质转化  /  miR-324-3P/WNT3a轴

Objective To explore the mechanism of nodakenin (NDK) affecting the invasion and migration of cervical cancer cells by regulating epithelial-mesenchymal transformation (EMT), and analyze its effect on microRNA (miR)-324-3P/WNT3a axis. Methods Human cervical cancer HeLa cells in logarithmic growth phase were divided into four groups: blank group(cultivated in a 37 ℃, 5% CO2-saturated humidity incubator), NDK group (20 mmol/L NDK was added to culture), miR-324-3P inhibitor group (hsa-miR-324-3p inhibitor transfection), and miR-324-3P inhibitor+NDK group (after transfection of miR-324-3P inhibitor, 20 mmol/L NDK was added to culture) all were treated for 48 h. Transwell test was used to detect the invasion ability of cells in each group. Cell scratch test was performed to detect cell migration ability of each group. qRT-PCR to detect the mRNA level of miR-324-3P and WNT3a in each group of cells. Western blotting was carried out to detect the expression of EMT-related marker proteins E-cadherin, vimentin, Neural cadherin (N-cadherin), WNT3a, and β-catenin protein in each group of cells. Dual luciferase reporter gene was used to detect the targeting relationship between miR-324-3P and WNT3a gene. Results Compared with the blank group, the number of transmembrane HeLa cells increased in miR-324-3P inhibitor group, the scratch healing rate increased, the mRNA expression level of miR-324-3P decreased, and of WNT3a increased; the relative expression of E-cadherin protein decreased, while the relative expressions of vimentin, N-cadherin, WNT3a and β-catenin increased (P<0.05). While for NDK group and miR-324-3P inhibitor+NDK group, the number of transmembrane HeLa cells decreased, the scar healing rate was also decreased, the mRNA expression level of miR-324-3P increased, the expression level of WNT3a mRNA decreased, the relative expression of E-cadherin protein increased, and the relative expression of vimentin, N-cadherin, WNT3a and β-catenin protein decreased (P<0.05); All the indexes mentioned above were lower in NDK group than those in miR-324-3P inhibitor+NDK group.The dual luciferase reporter gene results showed that miR-324-3P mimic could reduce WNT3a WT luciferase activity (P<0.05), but did not affect WNT3a mut luciferase activity (P>0.05). Conclusion NDK can inhibit the invasion and migration of cervical cancer cells by regulating EMT, and the mechanism of such action may be related to the regulation of miR-324-3P/WNT3a axis.

precursor glycosides  /  cervical cancer  /  invasion  /  cell migration  /  epithelial-mesenchymal transition  /  miR-324-3P/WNT3a axis
任璐, 曹芹雪, 杨少琴. 紫花前胡苷调控EMT对宫颈癌细胞侵袭迁移的影响及其作用机制. 解放军医学杂志, 2022 , 47 (5) : 451 -457 . DOI: 10.11855/j.issn.0577-7402.2022.05.0451
Lu Ren, Qin-Xue Cao, Shao-Qin Yang. Mechanism and effect of nodakenin regulating EMT on the invasion and migration of cervical cancer cells[J]. Medical Journal of Chinese People’s Liberation Army, 2022 , 47 (5) : 451 -457 . DOI: 10.11855/j.issn.0577-7402.2022.05.0451
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宫颈癌为常见的妇科恶性肿瘤，与人乳头瘤病毒感染、肥胖、激素替代治疗及口服避孕药等因素有关，肿瘤发生侵袭转移是患者死亡的主要原因，但其分子机制尚不清楚[1-3]。近年来，关于微小核糖核酸(microRNA，miRNA)调节基因表达与恶性肿瘤侵袭迁移关系的研究已成为热点，miRNA存在多种靶基因，且通过调控不同靶基因发挥不同生物学功能，如miR-324-3P可通过靶向调控Wnt2b抑制鼻咽癌的发生发展[4]。WNT3a为经典Wnt信号通路的重要蛋白，在细胞分化成熟中发挥重要作用，并与恶性肿瘤的发生发展有关[5]。上皮-间质转化(epithelial-mesenchymal transition，EMT)可促进细胞的侵袭和迁移等，因而可能成为抑制肿瘤侵袭、迁移的靶点。紫花前胡苷(nodakenin，NDK)是紫花前胡的有效成分，具有抗氧化、抗炎、免疫调节等作用，付琼等[6]报道NDK具有抑制宫颈癌细胞增殖的作用，但相关研究较少，其作用机制尚未阐明。本研究探讨了NDK通过调控EMT对宫颈癌细胞侵袭迁移的影响及其可能机制，旨在为研发治疗宫颈癌的新药提供实验依据。
1 材料与方法
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1.1 细胞株、药物、主要试剂与仪器
人宫颈癌永生化HeLa细胞株(上海极威生物科技有限公司)，NDK(纯度>98%，分子式：C20H24O9，分子量为408.4，南京森贝伽生物科技有限公司)。miR-324-3P mimic、hsa-miR-324-3p inhibitor(南通百奥迈科生物技术有限公司)。Transwell小室(美国Corning公司)，鼠抗人E-钙黏蛋白(E-cadherin)、波形蛋白、N-钙黏蛋白(N-cadherin)、WNT3a、β-catenin、GAPDH一抗(Abcam公司)，辣根过氧化物酶标记的兔抗鼠IgG二抗(美国Bioworld Technology公司)。Instrument QuantStudioTM 3型实时荧光定量PCR仪(美国Thermo Scientific公司)，PowerPacUniversal通用电泳仪(美国Bio-Rad公司)。
1.2 细胞培养
使用含10%胎牛血清的RPMI 1640培养基培养HeLa细胞，置于37 ℃、5%CO2、饱和湿度培养箱中培养，0.25%胰酶消化传代。所有实验均选用对数生长期细胞。
1.3 细胞转染与分组
将HeLa细胞密度调整为5×104个/ml，每孔2.5 ml接种于6孔板中。采用脂质体lipofectamine 2000转染HeLa细胞，分为4组：空白组(于37 ℃、5%CO2、饱和湿度培养箱中培养)，NDK组(加入20 mmol/L NDK培养)，miR-324-3P inhibitor组(转染hsa-miR-324-3p inhibitor)，miR-324-3P inhibitor+NDK组(转染miR-324-3P inhibitor后加入20 mmol/L NDK培养)，均处理48 h。
1.4 Transwell实验检测细胞侵袭能力
各组细胞转染48 h后，消化、重悬，加至Transwell小室上室底部微孔膜上，置入含500 μl高糖完全培养基的24孔板内，使微孔膜下室面与24孔板培养基接触。培养12 h后取出，下室面细胞用95%乙醇固定10 min，并行结晶紫染色，计算穿膜细胞数。
1.5 细胞划痕实验检测细胞迁移能力
将细胞接种于6孔板，细胞完全融合后，用无菌Tip头在6孔板中间划痕，无血清培养基培养。在划痕后0、72 h镜下观察细胞划痕愈合情况并拍照，计算划痕愈合率。划痕愈合率(%)=(0 h划痕宽度－72 h划痕宽度)/0 h划痕宽度×100%。实验重复3次，取平均值。
1.6 qRT-PCR检测细胞miR-324-3P、WNT3a mRNA表达水平
取各组细胞，用Trizol提取细胞总RNA，反转录为cDNA。以cDNA为模板，按SYBR Premix EX TaqTMⅡ qRT-PCR配制反应体系，反应条件为：95 ℃ 5 s；95 ℃ 5 s、65 ℃ 34 s，40个循环。检测各孔循环阈值，用2–ΔΔCt法计算miR-324-3P、WNT3a mRNA相对表达量，分别以U6、β-actin作为内参照。miR-324-3P、WNT3a、U6和β-actin引物序列均由日本TaKaRa公司设计合成(表1)。
1.7 Western blotting检测细胞中E-cadherin、波形蛋白、N-cadherin、WNT3a和β-catenin蛋白的表达水平
各组细胞用RIPA裂解后提取总蛋白，BCA法检测各蛋白浓度，加上样缓冲液，沸水浴变性，上样行SDS-PAGE电泳，湿转PVDF膜，5%脱脂牛奶封闭2 h。用鼠抗人E-cadherin、波形蛋白、N-cadherin、WNT3a、β-catenin和GAPDH一抗(1:1000)孵育过夜，次日加二抗(1:2000)室温孵育2 h，ECL化学发光法曝光蛋白条带。蛋白相对表达量为目的蛋白条带灰度值/内参蛋白条带灰度值。
1.8 双荧光素酶报告基因检测miR-324-3P与WNT3a基因的靶向关系
用TargetScan7.1软件(http://www.targetscan.org)预测miR-324-3P与WNT3a的结合片段，采用PCR扩增插入荧光素酶报告载体PGL3，构建WNT3a野生型(WT)质粒。用基因突变技术对WNT3a序列上与miR-324-3P结合位点上的个别核苷酸进行突变，构建WNT3a突变型(mut)质粒。将miR-324-3P mimic与WNT3a WT或WNT3a mut共同转染HeLa细胞，24 h后检测荧光素酶活性，以海肾荧光素酶活性作为内参照，计算荧光素酶活性。
1.9 统计学处理
采用SPSS 24.0软件进行统计分析。计量资料以$\bar{x}±s$表示，多组间比较采用单因素方差分析，进一步两两比较采用LSD-t检验。P<0.05为差异有统计学意义。
2 结果
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2.1 NDK对HeLa细胞侵袭能力的影响
结晶紫染色结果显示，与空白组[(49.22±3.24)个/视野]比较，miR-324-3P inhibitor组[(87.12±4.12)个/视野]的穿膜细胞数明显增多，而NDK组[(11.48±2.46)个/视野]及miR-324-3P inhibitor+NDK组[(34.32±3.68)个/视野]的穿膜细胞数明显减少(P<0.05)；与NDK组比较，miR-324-3P inhibitor组及miR-324-3P inhibitor+NDK组的穿膜细胞数明显增多(P<0.05)；与miR-324-3P inhibitor比较，miR-324-3P inhibitor+NDK组的穿膜细胞数明显减少(P<0.05)(图1)。
2.2 NDK对HeLa细胞迁移能力的影响
与空白组(60.68%±6.85%)比较，miR-324-3P inhibitor组(74.95%±6.32%)的划痕愈合率明显增高，而NDK组(30.35%±3.14%)及miR-324-3P inhibitor+NDK组(48.36%±5.11%)的划痕愈合率则明显降低(P<0.05)；与NDK组比较，miR-324-3P inhibitor组及miR-324-3P inhibitor+NDK组的划痕愈合率明显增高(P<0.05)；与miR-324-3P inhibitor组比较，miR-324-3P inhibitor+NKD组的划痕愈合率明显降低(P<0.05)(图2)。
2.3 各组细胞miR-324-3P、WNT3a mRNA表达情况比较
与空白组比较，miR-324-3P inhibitor组的miR-324-3P mRNA表达水平明显降低、WNT3a mRNA表达水平明显升高，NDK组及miR-324-3P inhibitor+NDK组miR-324-3P及WNT3a mRNA表达水平明显降低(P<0.05)；与NDK组比较，miR-324-3P inhibitor组及miR-324-3P inhibitor+NDK组miR-324-3P mRNA表达水平明显降低，WNT3a mRNA表达水平明显升高(P<0.05)；与miR-324-3P inhibitor比较，miR-324-3P inhibitor+NDK组miR-324-3P mRNA表达水平明显升高，WNT3a mRNA表达水平明显降低(P<0.05)(图3)。
2.4 各组细胞E-cadherin、波形蛋白、N-cadherin、WNT3a和β-catenin蛋白表达情况比较
与空白组比较，miR-324-3P inhibitor组细胞中E-cadherin蛋白相对表达量明显降低，波形蛋白、N-cadherin、WNT3a和β-catenin蛋白相对表达量明显升高(P<0.05)，miR-324-3P inhibitor+NDK组和NDK组细胞中E-cadherin蛋白相对表达量明显升高，波形蛋白、N-cadherin、WNT3a和β-catenin蛋白相对表达量明显降低(P<0.05)；与miR-324-3P inhibitor组比较，miR-324-3P inhibitor+NDK组及NDK组细胞中E-cadherin蛋白相对表达量明显升高，波形蛋白、N-cadherin、WNT3a和β-catenin蛋白相对表达量明显降低(P<0.05)；与miR-324-3P inhibitor+NDK组比较，NDK组细胞中E-cadherin蛋白相对表达量明显升高，波形蛋白、N-cadherin、WNT3a和β-catenin蛋白相对表达量明显降低(P<0.05)(图4)。
2.5 miR-324-3P与WNT3a的靶向关系
TargetScan7.1软件预测结果显示，miR-324-3P和WNT3a存在连续结合位点(图5)。双荧光素酶报告基因检测结果显示，miR-324-3P mimic与WNT3a WT转染后荧光素酶活性明显低于mimic NC(0.43±0.05 vs. 0.99±0.08，P<0.05)，但miR-324-3P mimic与WNT3a mut转染后荧光素酶活性与mimic NC比较差异无统计学意义(0.98±0.09 vs. 0.97±0.08，P>0.05)(图6)。
3 讨论
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宫颈癌发生、发展及转归是个极其复杂的过程，涉及多阶段、多环节、多基因调控，其发病机制尚未阐明[7-8]。细胞侵袭迁移能力的变化，以及原癌基因过度激活和抑癌基因异常表达是癌症发生发展的基本病理特征[9-10]。现有的宫颈癌化疗方案受到肿瘤转移等问题的困扰，研究新的抗癌药物具有一定临床意义。植物源性天然产物在癌症药物制作中已有数千年历史，如紫杉醇即取自于红豆杉[11]。NDK是线型四氢呋喃型香豆素苷类化合物，柯昌康等[12]发现其具有诱导癌细胞凋亡的作用，故本研究尝试采用NDK来抑制宫颈癌的侵袭迁移，并分析其可能的作用机制，以期为宫颈癌治疗药物的研发提供候选小分子单体结构。
本研究结果显示，与空白组比较，NDK组穿膜细胞数减少、划痕愈合率明显降低，提示NDK可抑制宫颈癌HeLa细胞的侵袭迁移。转移作为恶性肿瘤最突出的生物学特征，是一个多基因、多步骤的动态变化过程，涉及肿瘤细胞黏附与侵袭等环节，其中EMT在肿瘤转移中发挥了重要作用[13]。EMT是指上皮性癌细胞失去上皮特征，获得间叶细胞特征的一过性过程。E-cadherin是钙黏蛋白家族成员之一，分布于上皮组织，是上皮细胞的主要标志物，其表达缺失或降低是EMT发生的重要标志[14]。据报道，E-cadherin功能异常在肿瘤侵袭和转移过程中起关键作用，与正常上皮组织比较，其在低分化肿瘤中的表达往往下调甚至丧失[15]。E-cadherin表达降低可导致细胞失去极性，细胞间黏附性减弱，是癌细胞侵袭转移的分子基础。上皮标志物(E-cadherin)表达下调，间质标志物(波形蛋白、N-cadherin)表达上调被认为是癌细胞获得EMT的标志。本研究结果显示，与空白组比较，NDK组细胞中E-cadherin蛋白相对表达量明显升高，波形蛋白、N-cadherin蛋白相对表达量明显降低，提示NDK可抑制HeLa细胞的EMT过程，从而抑制细胞的侵袭和转移。同时，与空白组比较，miR-324-3P inhibitor组穿膜细胞数和划痕愈合率明显升高，E-cadherin蛋白相对表达量明显降低，波形蛋白、N-cadherin蛋白相对表达量明显升高，而miR-324-3P inhibitor+NDK组的穿膜细胞数、划痕愈合率及EMT相关蛋白表达水平的变化与miR-324-3P inhibitor组相反，提示NDK对宫颈癌细胞侵袭迁移和EMT的抑制作用可能与miR-324-3P表达有关。
miR-324-3P被证实与多种恶性肿瘤相关，具有促癌、抑癌的双重作用[16]。Liu等[17]报道，miR-324-3P过表达可抑制卵巢癌的侵袭迁移能力。Xie等[18]发现，miR-324-3P表达水平升高可抑制非小细胞肺癌的细胞增殖和侵袭，可能是通过调控EMT相关蛋白表达而发挥作用的。本研究经PCR检测发现，miR-324-3P inhibitor组、miR-324-3P inhibitor+NDK组、NDK组HeLa细胞中miR-324-3P mRNA表达水平逐渐升高，WNT3a mRNA表达水平逐渐降低，提示NDK可能通过上调miR-324-3P、下调WNT3a发挥其抑制宫颈癌细胞侵袭迁移的作用。WNT3a是WNT蛋白家族成员之一，在启动WNT/β-catenin信号通路中发挥重要作用。WNT/β-catenin信号通路在癌症的发生发展及转移过程中起关键作用，WNT3a为典型Wnt配体，与包括癌症在内的多种疾病病理学有关，可增强或抑制癌细胞的侵袭转移[19]。Feng等[20]发现，WNT3a激活可促进宫颈癌的发生。β-catenin为WNT/β-catenin信号通路中的功能蛋白，与转录因子互相作用促进信号途径转导[21-22]。本研究Western blotting检测结果显示，miR-324-3P inhibitor组、空白组、miR-324-3P inhibitor+NDK组、NDK组细胞中WNT3a和β-catenin蛋白相对表达量逐渐降低，提示NDK可能通过抑制WNT/β-catenin信号通路发挥作用。双荧光素酶报告基因检测结果提示miR-324-3P可靶向调控WNT3a。上述研究结果表明，NDK可能通过过表达miR-324-3P抑制WNT/β-catenin信号通路，实现对宫颈癌细胞侵袭迁移和EMT的抑制作用。
综上所述，本研究发现，NDK可能通过调控miR-324-3P/WNT3a轴抑制宫颈癌细胞的侵袭迁移和EMT过程。但本研究仍存在不足之处：(1)未能观察NDK对宫颈癌细胞凋亡的影响；(2)药物调控细胞生物学行为的信号通路比较复杂，NDK抑制宫颈癌细胞增殖、侵袭和迁移等过程是否涉及其他通路尚未可知；(3)仅通过体外细胞实验初步分析了NDK作用的可能机制等。后续研究可进一步分析NDK对宫颈癌细胞生物学行为的影响，并在体内验证NDK对宫颈癌的治疗作用及作用途径，为NDK的研发提供科学依据。
基金
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  • 河南省2018年科技发展计划(182102311175)
文献
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2022年第47卷第5期
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doi: 10.11855/j.issn.0577-7402.2022.05.0451
  • 接收时间：2021-08-07
  • 首发时间：2025-12-17
  • 出版时间：2022-05-28
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  • 收稿日期：2021-08-07
  • 录用日期：2021-09-15
基金
Henan Province 2018 Science and Technology Development Plan Project(182102311175)
河南省2018年科技发展计划(182102311175)
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    河南大学淮河医院妇产科，河南开封 475000
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https://castjournals.cast.org.cn/joweb/jfjyxzz/CN/10.11855/j.issn.0577-7402.2022.05.0451
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2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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