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Article(id=1207416365829427524, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1207416365246419268, articleNumber=null, orderNo=null, doi=10.11855/j.issn.0577-7402.2022.09.0879, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1634140800000, receivedDateStr=2021-10-14, revisedDate=null, revisedDateStr=null, acceptedDate=1646236800000, acceptedDateStr=2022-03-03, onlineDate=1765800094325, onlineDateStr=2025-12-15, pubDate=1664294400000, pubDateStr=2022-09-28, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1765800094325, onlineIssueDateStr=2025-12-15, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1765800094325, creator=13701087609, updateTime=1765800094325, updator=13701087609, issue=Issue{id=1207416365246419268, tenantId=1146029695717560320, journalId=1189873630562394117, year='2022', volume='47', issue='9', pageStart='851', pageEnd='956', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1765800094186, creator=13701087609, updateTime=1765800167087, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1207416671069904914, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1207416365246419268, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1207416671069904915, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1207416365246419268, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=879, endPage=885, ext={EN=ArticleExt(id=1207416366055919942, articleId=1207416365829427524, tenantId=1146029695717560320, journalId=1189873630562394117, language=EN, title=Effects and mechanism of RPDPC on proliferation and apoptosis of cervical cancer HeLa cells, columnId=1190310110212751762, journalTitle=Medical Journal of Chinese People’s Liberation Army, columnName=Basic Research, runingTitle=null, highlight=null, articleAbstract=

Objective To investigate the effect of Rhopaladins' analogs RPDPC on cell biological properties of human cervical cancer HeLa cells and miR-21-5P/PTEN/PI3K signaling pathway. Methods CCK-8 assay was used to detect the effects of different concentrations of RPDPC on the cell viabilities of HeLa cells treated for different time. DMSO (control), 12.5 μmol/L,25.0 μmol/L and 50.0 μmol/L RPDPC were selected to treat HeLa cells for 48 h. Hoechst 33258 staining and Annexin-FITC/PI double staining were used to detect the effect of RPDPC on HeLa cell apoptosis; The expression levels of miR-21 and mRNA of E6,E7, PTEN, PI3K, Akt were detected by qRT-PCR; The expression levels of PTEN, p-PI3K, p-PI3K, p-Akt and Akt were detected by immunoblotting (WB). Results Compared with the control group, viabilities of HeLa cells decreased significantly treated by RPDPC in different concentration and time (P<0.05); The apoptosis rate of HeLa cells tended to increase with increasing concentration of RPDPC (P<0.05); qRT-PCR results showed that compared with the control group, the expression level of miR-21-5P and mRNA of E6, E7, PI3K, Akt decreased significantly (P<0.05), the expression levels of PTEN mRNA increased significantly(P<0.05). WB results showed that compared with the control group, the expression level of PTEN protein increased significantly(P<0.05); The expression levels of p-PI3K, PI3K, p-Akt and Akt proteins decreased significantly (P<0.05). Conclusions RPDPC could inhibit the proliferation and promote the apoptosis of cervical cancer cells. The mechanism may be the inhibition of expression of E6 and E7, and may be related to mir-21/PTEN/PI3K/Akt signaling pathway.

, correspAuthors=Li-Na Ke, authorNote=null, correspAuthorsNote=
*E-mail:
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目的 探讨海洋生物碱Rhopaladins的合成类似物RPDPC对人宫颈癌HeLa细胞的细胞生物学特征的影响及其可能机制。方法 采用CCK-8法检测HeLa细胞在RPDPC不同浓度、不同时间处理后的存活率；分别以DMSO(对照组)或12.5 μmol/L、25.0 μmol/L、50.0 μmol/L RPDPC处理48 h后，采用Hoechst 33258染色和Annexin-FITC/PI双染色法观察HeLa细胞凋亡率，qRT-PCR检测HeLa细胞癌基因E6、E7和PTEN、PI3K、Akt的mRNA及miR-21表达水平，Western blotting检测PTEN、p-PI3K、PI3K、p-Akt、Akt蛋白的表达水平。结果 与对照组比较，RPDPC处理后HeLa细胞存活率明显下降并呈浓度及时间依赖性(P<0.05)。与对照组比较，RPDPC处理后HeLa细胞凋亡率明显上升且呈浓度依赖性(P<0.05)。qRT-PCR检测结果显示，与对照组比较，RPDPC处理后HeLa细胞E6、E7、PI3K、Akt的mRNA及miR-21-5P表达水平均明显降低(P<0.05)，PTEN mRNA表达水平则明显增高(P<0.05)。Western blotting检测结果显示，与对照组比较，RPDPC处理后HeLa细胞PTEN蛋白表达水平明显增高(P<0.05)，而p-PI3K、PI3K、p-Akt、Akt蛋白表达水平均明显降低(P<0.05)。结论 RPDPC可抑制宫颈癌HeLa细胞增殖并促进其凋亡，其机制可能与抑制miR-21-5P/PTEN/PI3K/Akt信号通路进而降低癌基因E6和E7的表达有关。

, correspAuthors=柯丽娜, authorNote=null, correspAuthorsNote=
柯丽娜，E-mail：
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陈凤，硕士研究生，主要从事妇科肿瘤方向的研究

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陈凤，硕士研究生，主要从事妇科肿瘤方向的研究

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陈凤，硕士研究生，主要从事妇科肿瘤方向的研究

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A. RPDPC处理；B. 顺铂(阳性对照)处理48 h；C. RPDPC处理48 h

, figureFileSmall=MujQXfkYoDEMpz5172b/vg==, figureFileBig=5ub5D1hAoAqQvqiL+rBFSA==, tableContent=null), ArticleFig(id=1207416372720669238, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1207416365829427524, language=EN, label=Fig. 2, caption=Morphological observation of HeLa cells treated by RPDPC in each group (n=6, ×100), figureFileSmall=zFh+9r7QQTi/s66DNBXNrA==, figureFileBig=zK80BWKy7/qnQTPOM0bopw==, tableContent=null), ArticleFig(id=1207416372800361018, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1207416365829427524, language=CN, label=图2, caption=RPDPC处理48 h后HeLa细胞的Hoechst 33258染色结果(n=6, ×100)

A. 对照组(DMSO)；B. 12.5 μmol/L RPDPC组；C. 25.0 μmol/L RPDPC组；D. 50.0 μmol/L RPDPC组

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与对照组(DMSO)比较，(1)P<0.05；与12.5 μmol/L RPDPC组比较，(2)P<0.05；与25.0 μmol/L RPDPC组比较，(3)P<0.05

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与对照组(DMSO)比较，(1)P<0.05；与12.5 μmol/L RPDPC组比较，(2)P<0.05；与25 μmol/L RPDPC组比较，(3)P<0.05

, figureFileSmall=GybvVy7pXBkm/8sg6JqgwQ==, figureFileBig=qDehnwPa363KMo/OTM6TpQ==, tableContent=null), ArticleFig(id=1207416374356447821, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1207416365829427524, language=EN, label=Fig. 5, caption=Comparison of the expression levels of PTEN, p-PI3K, PI3K, p-Akt and Akt in HeLa cells of each group treated by RPDPC(n=6), figureFileSmall=6Sg0Gi073EW+wKR6WXRVQQ==, figureFileBig=eAMFGp9VfJBDYiQ8kWyB3g==, tableContent=null), ArticleFig(id=1207416374465499728, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1207416365829427524, language=CN, label=图5, caption=RPDPC处理后各组HeLa细胞中PTEN、p-PI3K、PI3K、p-Akt、Akt相对蛋白表达水平比较(n=6)

与对照组(DMSO)比较，(1)P<0.05；与12.5 μmol/L RPDPC组比较，(2)P<0.05；与25 μmol/L RPDPC组比较，(3)P<0.05

, figureFileSmall=6Sg0Gi073EW+wKR6WXRVQQ==, figureFileBig=eAMFGp9VfJBDYiQ8kWyB3g==, tableContent=null), ArticleFig(id=1207416374549385812, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1207416365829427524, language=EN, label=Fig. 6, caption=The synthesis strategy for RPDP A–C as targets, figureFileSmall=/TZNtl+4hAh+Vs6Arve73g==, figureFileBig=W5WqcHhgyJ0cKSOtt0TzZA==, tableContent=null), ArticleFig(id=1207416374662632025, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1207416365829427524, language=CN, label=图6, caption=选择RPDP A－C作为目标分子的合成策略, figureFileSmall=/TZNtl+4hAh+Vs6Arve73g==, figureFileBig=W5WqcHhgyJ0cKSOtt0TzZA==, tableContent=null), ArticleFig(id=1207416374725546588, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1207416365829427524, language=EN, label=Tab. 1, caption=

Primer sequences for qRT-PCR

, figureFileSmall=null, figureFileBig=null, tableContent=
基因序列大小(bp)
E6正义：5'-TTGCTTTTCGGGATTTATGC-3'20
反义：5'-CAGGACACAGTGGCTTTTGA-3'26
E7正义：5'-GAACCGGACAGAGCCCATTA-3'24
反义：5'-AGAACAGATGGGGCACACAAT-3'27
PTEN正义：5'-GACCAGAGACAAAAAGGGAGTA-3'22
反义：5'-ACAAACTGAGGATTGCAAGTTC-3'22
PI3K正义：5'-GAGATTGCAAGCAGTGATAGTG-3'22
反义：5'-TAATTTTGGCAGTGATTGTGG-G-3'22
Akt正义：5'-TGACCATGAACGAGTTTGAGTA-322
反义：5'-GAGGATCTTCATGGCGTAGTAG-3'22
miR-215'-CCGCGTAGCTTATCAGACTGATGTTGA-3'27
U65'-GTGCTCGCTTCGGCAGCACATAT-3'23
), ArticleFig(id=1207416374826209888, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1207416365829427524, language=CN, label=表1, caption=

qRT-PCR引物序列

, figureFileSmall=null, figureFileBig=null, tableContent=
基因序列大小(bp)
E6正义：5'-TTGCTTTTCGGGATTTATGC-3'20
反义：5'-CAGGACACAGTGGCTTTTGA-3'26
E7正义：5'-GAACCGGACAGAGCCCATTA-3'24
反义：5'-AGAACAGATGGGGCACACAAT-3'27
PTEN正义：5'-GACCAGAGACAAAAAGGGAGTA-3'22
反义：5'-ACAAACTGAGGATTGCAAGTTC-3'22
PI3K正义：5'-GAGATTGCAAGCAGTGATAGTG-3'22
反义：5'-TAATTTTGGCAGTGATTGTGG-G-3'22
Akt正义：5'-TGACCATGAACGAGTTTGAGTA-322
反义：5'-GAGGATCTTCATGGCGTAGTAG-3'22
miR-215'-CCGCGTAGCTTATCAGACTGATGTTGA-3'27
U65'-GTGCTCGCTTCGGCAGCACATAT-3'23
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RPDPC对宫颈癌HeLa细胞增殖与凋亡的影响及其机制
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陈凤 1, 2 , 曾小华 3 , 张斌强 3 , 李斌 2 , 王彦娇 2 , 陈琴华 3 , 柯丽娜 2, *
解放军医学杂志 | 基础研究 2022,47(9): 879-885
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解放军医学杂志 | 基础研究 2022, 47(9): 879-885
RPDPC对宫颈癌HeLa细胞增殖与凋亡的影响及其机制
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陈凤1, 2, 曾小华3, 张斌强3, 李斌2, 王彦娇2, 陈琴华3, 柯丽娜2, *
作者信息
  • 1锦州医科大学国药东风总医院研究生培养基地，湖北十堰 442008
  • 2湖北医药学院国药东风总医院妇产科，湖北十堰 442008
  • 3武当特色中药研究湖北省重点实验室(湖北医药学院)，湖北十堰 442008

    • 陈凤，硕士研究生，主要从事妇科肿瘤方向的研究

通讯作者:

柯丽娜，E-mail：
Effects and mechanism of RPDPC on proliferation and apoptosis of cervical cancer HeLa cells
Feng Chen1, 2, Xiao-Hua Zeng3, Bin-Qiang Zhang3, Bin Li2, Yan-Jiao Wang2, Qin-Hua Chen3, Li-Na Ke2, *
Affiliations
  • 1Graduate Educational Base of Sinopharm Dongfeng General Hospital, Jinzhou Medical University, Shiyan, HuBei 442008, China
  • 2Department of Obstetrics and Gynecology, Sinopharm Dongfeng General Hospital, Hubei University of Medicine, Shiyan, HuBei 442008, China
  • 3Hubei Key Laboratory of Wudang Special Chinese Medicine Research (Hubei University of Medicine), Shiyan, HuBei 442008, China
出版时间: 2022-09-28 doi: 10.11855/j.issn.0577-7402.2022.09.0879
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摘要
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目的 探讨海洋生物碱Rhopaladins的合成类似物RPDPC对人宫颈癌HeLa细胞的细胞生物学特征的影响及其可能机制。方法 采用CCK-8法检测HeLa细胞在RPDPC不同浓度、不同时间处理后的存活率；分别以DMSO(对照组)或12.5 μmol/L、25.0 μmol/L、50.0 μmol/L RPDPC处理48 h后，采用Hoechst 33258染色和Annexin-FITC/PI双染色法观察HeLa细胞凋亡率，qRT-PCR检测HeLa细胞癌基因E6、E7和PTEN、PI3K、Akt的mRNA及miR-21表达水平，Western blotting检测PTEN、p-PI3K、PI3K、p-Akt、Akt蛋白的表达水平。结果 与对照组比较，RPDPC处理后HeLa细胞存活率明显下降并呈浓度及时间依赖性(P<0.05)。与对照组比较，RPDPC处理后HeLa细胞凋亡率明显上升且呈浓度依赖性(P<0.05)。qRT-PCR检测结果显示，与对照组比较，RPDPC处理后HeLa细胞E6、E7、PI3K、Akt的mRNA及miR-21-5P表达水平均明显降低(P<0.05)，PTEN mRNA表达水平则明显增高(P<0.05)。Western blotting检测结果显示，与对照组比较，RPDPC处理后HeLa细胞PTEN蛋白表达水平明显增高(P<0.05)，而p-PI3K、PI3K、p-Akt、Akt蛋白表达水平均明显降低(P<0.05)。结论 RPDPC可抑制宫颈癌HeLa细胞增殖并促进其凋亡，其机制可能与抑制miR-21-5P/PTEN/PI3K/Akt信号通路进而降低癌基因E6和E7的表达有关。

宫颈癌  /  海洋生物碱  /  细胞增殖  /  细胞凋亡  /  人乳头瘤病毒

Objective To investigate the effect of Rhopaladins' analogs RPDPC on cell biological properties of human cervical cancer HeLa cells and miR-21-5P/PTEN/PI3K signaling pathway. Methods CCK-8 assay was used to detect the effects of different concentrations of RPDPC on the cell viabilities of HeLa cells treated for different time. DMSO (control), 12.5 μmol/L,25.0 μmol/L and 50.0 μmol/L RPDPC were selected to treat HeLa cells for 48 h. Hoechst 33258 staining and Annexin-FITC/PI double staining were used to detect the effect of RPDPC on HeLa cell apoptosis; The expression levels of miR-21 and mRNA of E6,E7, PTEN, PI3K, Akt were detected by qRT-PCR; The expression levels of PTEN, p-PI3K, p-PI3K, p-Akt and Akt were detected by immunoblotting (WB). Results Compared with the control group, viabilities of HeLa cells decreased significantly treated by RPDPC in different concentration and time (P<0.05); The apoptosis rate of HeLa cells tended to increase with increasing concentration of RPDPC (P<0.05); qRT-PCR results showed that compared with the control group, the expression level of miR-21-5P and mRNA of E6, E7, PI3K, Akt decreased significantly (P<0.05), the expression levels of PTEN mRNA increased significantly(P<0.05). WB results showed that compared with the control group, the expression level of PTEN protein increased significantly(P<0.05); The expression levels of p-PI3K, PI3K, p-Akt and Akt proteins decreased significantly (P<0.05). Conclusions RPDPC could inhibit the proliferation and promote the apoptosis of cervical cancer cells. The mechanism may be the inhibition of expression of E6 and E7, and may be related to mir-21/PTEN/PI3K/Akt signaling pathway.

cervical cancer  /  marine alkaloids  /  cell proliferation  /  apoptosis  /  human papilloma virus
陈凤, 曾小华, 张斌强, 李斌, 王彦娇, 陈琴华, 柯丽娜. RPDPC对宫颈癌HeLa细胞增殖与凋亡的影响及其机制. 解放军医学杂志, 2022 , 47 (9) : 879 -885 . DOI: 10.11855/j.issn.0577-7402.2022.09.0879
Feng Chen, Xiao-Hua Zeng, Bin-Qiang Zhang, Bin Li, Yan-Jiao Wang, Qin-Hua Chen, Li-Na Ke. Effects and mechanism of RPDPC on proliferation and apoptosis of cervical cancer HeLa cells[J]. Medical Journal of Chinese People’s Liberation Army, 2022 , 47 (9) : 879 -885 . DOI: 10.11855/j.issn.0577-7402.2022.09.0879
正文
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宫颈癌为妇科常见癌症，是女性癌症死亡的第四位疾病[1]。全球宫颈癌新发病例数已从2012年的52.8万例增加到2020年的59.8万例，死亡数从2012年的26.6万例增加到2020年的33.8万例，且发展中国家发病率是发达国家的3~10倍[2]。手术及化疗是宫颈癌目前主要的治疗手段，化疗首选以顺铂为主的铂类药物；然而，已有的化疗药物只能使晚期宫颈癌患者的5年生存率略有提高，治疗效果和预后很不理想[3-4]。因此，迫切需要探寻抗宫颈癌安全有效且不易产生耐药性的药物[5]。Hiroyasu研究团队从冲绳被囊类动物Rhopalaea sp.的提取物中分离出4种包含咪唑啉酮结构的双(吲哚)生物碱即Rhopaladins A－D，对人类肿瘤细胞株有显著的细胞毒作用[6]。我们前期合成了海洋生物碱Rhopaladins的类似物RPDPC(化学名：E-N-叔丁基-1-异丙基-4-对氟苄叉基-2-对溴苯甲酰基-5-吡咯烷酮-2-酰胺)，本研究旨在探讨RPDPC对宫颈癌HeLa细胞增殖与凋亡的作用及可能机制。
1 材料与方法
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1.1 细胞、主要试剂及仪器
宫颈癌HeLa细胞、正常肝细胞LO2购自中国武汉普诺赛公司；胎牛血清购自中国CellMax公司；MEM培养基购自美国HyClone公司；胰蛋白酶购自美国Sigma公司；细胞计数试剂盒-8(cell counting kit-8，CCK-8)购自美国Targetmol公司；Annexin V细胞凋亡检测试剂盒购自中国联科生物技术有限公司；TRIzol试剂购自美国Invitrogen公司；SYBR Green Realtime PCR Master Mix购自日本TOYOBO公司；microRNA反转录盒、miScript SYBR Green PCR Kit购自德国QiaGen公司；PCR引物由中国上海生工生物有限公司合成；甘油醛-3-磷酸脱氢酶(GAPDH)购自中国Antgene公司；流式细胞仪购自美国BD公司；荧光定量PCR仪购自德国耶拿公司；抗PTEN抗体、抗p-PI3K抗体、抗PI3K抗体、抗p-Akt抗体、抗Akt抗体购自美国Abcam；二抗购自美国Boster公司；BCA蛋白浓度测定试剂盒购自中国碧云天生物技术公司。
1.2 方法
1.2.1 细胞培养和分组
在含有10%胎牛血清的MEM细胞培养基中培养细胞，1~2 d换液1次，在37 ℃、5% CO2细胞培养箱中孵育培养，待细胞长满瓶底80%~90%时按1:3传代，取对数生长期的细胞进行实验。RPDPC溶于二甲基亚砜(DMSO)中，配成不同浓度的母液后保存在–20 ℃冰箱中。阴性对照组加入等量的DMSO，实验组为不同浓度RPDPC的DMSO溶液。
1.2.2 CCK-8法检测细胞存活率
将HeLa细胞以4×103个/孔的密度种在96孔板中，次日待细胞贴壁后去除原培养基，加入含RPDPC(3.125 μmol/L、6.25 μmol/L、12.5 μmol/L、25.0 μmol/L、50.0 μmol/L、100.0 μmol/L)的培养基200 μl，分别培养24 h、48 h、72 h；以DMSO为阴性对照组，顺铂(PT)为阳性对照组；以正常肝细胞进行细胞毒性实验。每组设置3个复孔，CCK-8与MEM培养基按1:10的比列混合后每孔加入110 μl，放入37 ℃、5%CO2细胞培养箱中避光孵育1.5 h，在酶标仪上测定450 nm波长处的吸光度，计算细胞存活率。细胞存活率(%)=[A实验组–A空白]/[ADMSO–A空白]×100%。
1.2.3 Hoechst 33258染色观察HeLa细胞形态
将HeLa细胞以2×106个/孔的密度接种在6孔板中，次日细胞贴壁后加入试剂，孵育48 h后加入500 μl固定液，固定10 min，PBS冲洗2次，每次3 min。500 μl Hoechst 33258染色5 min后，用PBS清洗细胞2次，每次3 min。荧光显微镜下观察各组细胞。
1.2.4 Annexin V/PI双染法检测HeLa细胞凋亡率
将Hela细胞接种在6孔板中，密度为2×106个/孔；次日细胞贴壁后去除上清培养液，加入不同浓度的RPDPC培养液，每孔2 ml，药物作用48 h后用不含EDTA的胰酶收集细胞悬液，1000 g/min离心5 min，沉淀细胞用孵育缓冲液洗1次，用结合缓冲液重悬细胞后加入Annexin V-FITC 5 μl和PI 10 μl，采用流式细胞仪进行细胞凋亡率检测。实验重复3次。
1.2.5 实时定量反转录聚合酶链反应(qRT-PCR)检测HeLa细胞癌基因E6、E7和PTEN、PI3K、Akt的mRNA及miR-21表达水平
将HeLa细胞以2×106个/孔的密度接种在6孔板中；次日细胞贴壁后去除上清培养液，加入不同浓度的RPDPC培养液，每孔2 ml，药物作用48 h后加入TRIzol试剂裂解细胞，抽提总RNA，测定总RNA浓度，按照反转录试剂盒操作说明书操作，反转录得到双链cDNA。利用SYBR Green PCR Master Mix和miScript SYBR Green PCR Kit扩增并检测mRNA。以GAPDH为内参，利用SYBR Green PCR Master Mix测定E6、E7、PTEN、PI3K和Akt的mRNA表达水平。E6、E7的PCR扩增程序为：95 ℃预变性1 min；95 ℃变性15 s，55 ℃退火15 s，72 ℃延伸45 s，共40个循环。PTEN、PI3K和Akt的PCR扩增程序为：95 ℃预变性1 min；95 ℃变性15 s，60 ℃退火15 s，72 ℃延伸45 s，共40个循环。以U6 RNA作为miR-21的内参对照，miScript SYBR Green PCR Kit检测miR-21的表达水平，PCR扩增程序为：95 ℃预变性15 min；94 ℃变性15 s，55 ℃退火30 s，70 ℃延伸30 s，共40个循环。每个样本设3个复孔，实验重复3次。采用2–ΔΔCt法计算基因的相对表达量。所用引物序列见表1。
1.2.6 Western blotting检测PTEN/PI3K/Akt信号通路蛋白表达水平
将HeLa细胞以2×106个/孔的密度接种在6孔板中；次日细胞贴壁后去除上清培养液，加入不同浓度的RPDPC培养液，每孔2 ml，药物作用48 h后用PBS洗一次，用含有磷酸酶抑制剂和蛋白酶抑制剂的RIPA裂解液在冰上裂解40 min，BCA法测定蛋白浓度，保存在–80 ℃冰箱。以GAPDH作为内参，制备10%的分离胶和5%的浓缩胶进行凝胶电泳分离，蛋白样品上样10 μg。浓缩胶：80V 30 min；分离胶：120V 90 min。在150 mA条件下转膜60 min；37 ℃封闭1 h，加入一抗稀释液GAPDH(1:5000)、PTEN(1:1000)、p-PI3K(1:1000)、PI3K(1:1000)、p-Akt(1:500)、Akt(1:500)，4 ℃过夜，加入二抗稀释液(1:5000)孵育1 h，曝光仪曝光，记录成像结果。使用Image J软件分析蛋白灰度值，计算蛋白相对表达量。
1.3 统计学处理
采用SPSS 22.0软件进行统计分析。数据均符合正态分布，以$\bar{x}±s$表示，采用单因素方差分析进行组间比较，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 对HeLa细胞和肝细胞存活率的影响
CCK-8法检测结果显示，与对照组(DMSO)比较，RPDPC处理后HeLa细胞存活率下降，且随时间和浓度的增加，细胞存活率持续下降，具有明显的时间和浓度依赖性(P<0.05，图1A)。采用GraphPad Prism软件计算，HeLa细胞24 h、48 h、72 h的RPDPC半数抑制浓度(IC50)分别为44.1 μmol/L、28.9 μmol/L、26.1 μmol/L；Hela细胞48 h的顺铂IC50值为32.2 μmol/L(图1B)。据此，后续实验研究选取12.5 μmol/L、25.0 μmol/L、50.0 μmol/L RPDPC分别处理HeLa细胞48 h。药物毒性实验结果显示，RPDPC对正常肝细胞LO2的IC50为200.0 μmol/L(图1C)。
2.2 HeLa细胞的形态观察
Hoechst 33258染色显示，对照组细胞生长良好，细胞数多且形态呈正常的梭形(图2A)；与对照组比较，RPDPC处理48 h后，随RPDPC浓度的递增(12.5 μmol/L、25.0 μmol/L、50.0 μmol/L)，各组细胞数持续减少，细胞间隙增宽，死亡细胞、细胞碎片增多，细胞皱缩、形态失常变化更加明显(图2B－D)。
2.3 各组HeLa细胞凋亡率比较
AnnexinⅤ-FITC/PI双染处理各组细胞并用流式细胞仪检测细胞凋亡情况，结果显示，对照组、RPDPC处理组(12.5 μmol/L、25.0 μmol/L、50.0 μmol/L)的HeLa细胞凋亡率(%)分别为13.2±1.7、21.8±4.5、33.8±3.4、46.7±6.7；与对照组比较，各组HeLa细胞凋亡率均明显增高(P<0.05)；不同浓度RPDPC处理组HeLa细胞凋亡率比较，差异均有统计学意义(P<0.05，图3)。
2.4 HeLa细胞miR-21和E6、E7、PTEN、PI3K、Akt mRNA表达水平的变化
qRT-PCR检测结果显示，与对照组比较，经12.5 μmol/L、25.0 μmol/L、50.0 μmol/L RPDPC处理48 h后，HeLa细胞中E6、E7、PI3K、Akt mRNA及miR-21的相对表达量均降低，PTEN mRNA相对表达量升高，均呈浓度依赖性，差异有统计学意义(P<0.05，图4)。
2.5 HeLa细胞中凋亡相关通路蛋白的表达
Western blotting检测结果显示，与对照组比较，12.5 μmol/L、25.0 μmol/L、50.0 μmol/L RPDPC处理48 h后，各组HeLa细胞中PTEN蛋白表达水平均明显增高(P<0.05)，且不同浓度组间差异明显(P<0.05)；PI3K、p-PI3K、p-Akt和Akt蛋白表达水平均明显降低(P<0.05)，且不同浓度组间差异明显(P<0.05，图5)。
3 讨论
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海洋面积与地球表面的70%，海洋生物特别是海洋无脊椎动物(如海绵、海鞘等)是药用分子的丰富来源，其中部分化合物具有独特的结构，对癌细胞具有细胞毒性。到2020年底，近10种临床批准的抗癌药物是以海洋生物中分离出的小分子化合物为基础开发而来，还有近1000种相关的新结构化合物处于不同临床试验阶段[7-8]。因此，海洋生物用于新药开发具有较大潜力，引起了多个学科的关注；其中部分杂环化合物具有特殊而广泛的作用，部分含吡咯烷酮结构的杂环衍生物在医药、化工等领域有较好的应用前景，已有研究显示部分相关化合物具有显著的抗病毒、抗艾滋病、抗肌肉碱或抗癫痫作用[9]。1998年一类双(吲哚)生物碱从冲绳海洋被囊动物Rhopalaea sp.中被提取，即Rhopaladin A－D四种海洋生物碱，具有staurosporine型骨架或来自被囊动物的哌嗪环，是第一批被报道有咪唑啉酮结构的双(吲哚)生物碱，具有抗肿瘤、抗病毒、抗菌等多种生物活性作用[6]。其中，Rhopaladin B可抑制细胞周期蛋白依赖性激酶(CDK4)和酪氨酸激酶 C-erbB2的表达，而C-erbB2的表达与宫颈癌的发生发展密切相关；Rhopaladins C对黄链球菌和棒状杆菌均有抗菌活性。Rhopaladins的生物学特性使它们有望成为新型抗肿瘤药物，但要大量获取这些生物碱及其类似物，较为可行的途径是化学合成。我们前期合成了Rhopaladins的类似物RPDPC，化学名为E-N-叔丁基-2-对氯苯甲酰基-1-异丙基-4-对氟苄叉基-5-吡咯烷酮-2-酰胺；合成方法为多组分一锅合成法，构建具有与Rhopaladins结构类似的母核及取代芳基(分子式及选择策略见图6)[10-11]。本研究观察了RPDPC对宫颈癌HeLa细胞的作用，初步探讨其可能的作用机制。CCK-8法检测结果显示，与对照组(DMSO)比较，12.5 μmol/L、25.0 μmol/L、50.0 μmol/L RPDPC干预后宫颈癌HeLa细胞的活力受到抑制，且随时间延长和RPDPC浓度增高，抑制作用更加明显；AnnexinⅤ-FITC/PI双染观察RPDPC对HeLa细胞凋亡的影响，结果显示与对照组比较，实验组HeLa细胞凋亡率明显升高，且浓度越高促凋亡作用越明显，提示RPDPC可能抑制宫颈癌细胞的增殖，诱导癌细胞凋亡。
持续感染高危人乳头瘤病毒(HPV)是诱发宫颈癌的主要原因；90.8%的宫颈癌患者感染了高危型HPV，而宫颈鳞癌和腺癌与HPV16、HPV18长期感染密切相关[12]。故本研究选用HPV18阳性的Hela细胞为研究对象。E6和E7是HPV18编码的两种主要病毒癌基因，它们的表达水平决定了HPV的致癌力。有研究显示，在HPV阳性的宫颈癌患者活检组织和HPV阳性细胞中E6和E7是最丰富的病毒转录本，提示E6和E7在HPV病毒复制和致癌进展中发挥关键作用[13-16]。E6和E7序列的开放阅读框直接参与调节宫颈癌细胞的生长，在其增殖中起重要作用，并与宫颈癌细胞的凋亡密切相关[17]。本研究qRT-PCR结果显示，与对照组比较，不同浓度RPDPC处理的HeLa细胞E6和E7 mRNA表达水平均明显降低，且RPDPC浓度越高mRNA表达水平降低越显著，提示RPDPC对宫颈癌细胞的作用可能与E6、E7的低表达密切相关。
MicroRNAs(miRNAs)是一类短小的非编码RNA，是基因表达的关键调控因子。miRNAs的异常表达可影响多种肿瘤细胞的增殖、凋亡、分化及代谢等。miRNAs通过部分序列同源性与靶基因mRNA的3'-非翻译区(3'-UTR)结合，调节mRNA的表达，从而在多种真核生物的基因表达调控和发育动力学中发挥关键作用[18]。miRNAs可参与宫颈癌的发生发展，如miR-21是已知在多种类型的人类癌症中上调的主要肿瘤因子，是宫颈癌细胞系和肿瘤样本中表达较丰富的一种miRNA；过度表达的E6、E7可上调miR-21的表达。已有研究显示抑癌基因PTEN是宫颈癌miR-21的基因靶点；PTEN在肿瘤发展过程中是一种抑制因子，可以负向调节PI3K/Akt轴，而PI3K/Akt信号通路与癌细胞的增殖、凋亡有关[19-20]。本研究结果显示，与对照组比较，RPDPC处理的各组HeLa细胞miR-21表达水平明显下调，PTEN mRNA和PTEN蛋白表达水平明显上调，PI3K mRNA和p-PI3K、PI3K蛋白的表达水平明显下调，Akt mRNA和p-Akt、Akt蛋白表达水平明显下调，提示miR-21/PTEN/PI3K/Akt信号轴可能参与了RPDPC对宫颈癌细胞的抑制作用。
综上所述，本研究结果显示，RPDPC在体外可抑制宫颈癌HeLa细胞增殖，诱导其凋亡；相关作用机制可能是RPDPC通过miR-21/PTEN/PI3K/Akt信号通路抑制HPV的癌基因E6、E7表达；提示RPDPC对于宫颈癌有潜在的抗肿瘤作用，有望用于宫颈癌治疗的研究。但不足之处在于，本研究仅开展了体外细胞实验，仅观察了RPDPC调节E6、E7的表达及对21/PTEN/PI3K/Akt信号通路的影响，是否存在其他相关基因与信号通路的参与，尚待进一步验证，RPDPC的抗肿瘤作用也有待后续动物实验进一步验证。
基金
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  • 国家自然科学基金(81872509)
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2022年第47卷第9期
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doi: 10.11855/j.issn.0577-7402.2022.09.0879
  • 接收时间：2021-10-14
  • 首发时间：2025-12-15
  • 出版时间：2022-09-28
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  • 收稿日期：2021-10-14
  • 录用日期：2022-03-03
基金
National Natural Science Foundation of China(81872509)
国家自然科学基金(81872509)
作者信息
    1锦州医科大学国药东风总医院研究生培养基地，湖北十堰 442008
    2湖北医药学院国药东风总医院妇产科，湖北十堰 442008
    3武当特色中药研究湖北省重点实验室(湖北医药学院)，湖北十堰 442008

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2种不同金属材料的力学参数
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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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