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Article(id=1239222195998749395, tenantId=1146029695717560320, journalId=1205117082300743687, issueId=1239222192311948159, articleNumber=null, orderNo=null, doi=10.14109/j.cnki.xyylc.2024.11.10, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1658160000000, receivedDateStr=2022-07-19, revisedDate=null, revisedDateStr=null, acceptedDate=1723996800000, acceptedDateStr=2024-08-19, onlineDate=1773383195161, onlineDateStr=2026-03-13, pubDate=1732464000000, pubDateStr=2024-11-25, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1773383195161, onlineIssueDateStr=2026-03-13, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1773383195161, creator=13701087609, updateTime=1773383195161, updator=13701087609, issue=Issue{id=1239222192311948159, tenantId=1146029695717560320, journalId=1205117082300743687, year='2024', volume='43', issue='11', pageStart='801', pageEnd='880', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1773383194282, creator=13701087609, updateTime=1773384015681, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1239225637551002124, tenantId=1146029695717560320, journalId=1205117082300743687, issueId=1239222192311948159, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1239225637551002125, tenantId=1146029695717560320, journalId=1205117082300743687, issueId=1239222192311948159, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=852, endPage=859, ext={EN=ArticleExt(id=1239222200436323053, articleId=1239222195998749395, tenantId=1146029695717560320, journalId=1205117082300743687, language=EN, title=MiR-17-5p mediating cisplatin resistance in breast cancer cells by regulating PTEN/Akt pathway, columnId=1207314218647392369, journalTitle=Chinese Journal of New Drugs and Clinical Remedies, columnName=Original Article, runingTitle=null, highlight=null, articleAbstract=
AIM

To investigate the role of miR-17-5p in mediating cisplatin（DDP）resistance in breast cancer cells by regulating the PTEN/Akt pathway.

METHODS

MCF-7/DDP-resistant cell line was cultured with a gradient of increasing DDP concentrations. The content of miR-17-5p was detected in MCF-7 and MCF-7/DDP cells by RT-qPCR. MCF-7 cells were divided into miR-NC and miR-17-5p groups, and transfected with miR-NC and miR-17-5p mimics plasmids,respectively. MCF-7/DDP-resistant cells were divided into anti-miR-NC and anti-miR-17-5p groups, and transfected with anti-miR-NC and anti-miR-17-5p plasmids, respectively. Transfection efficiency was defined by RT-qPCR. The drug sensitivity of DDP in each group of transfected cells was evaluated by MTT. The direct effect of miR-17-5p on the invasive ability was obtained by Transwell assay. DDP-induced apoptosis of MCF-7 and MCF-7/DDP cells after transfection was analyzed by flow cytometry. The targeting relationship between miR-17-5p and PTEN was verified by double luciferase reporter gene assay. The changes of apoptosis and key proteins of PTEN/Akt pathway under the regulation of miR-17-5p were detected by Western blot.

RESULTS

Compared with MCF-7 cells, the miR-17-5p expression in MCF-7/DDP-resistant cells was abnormally increased, while the PTEN expression was reduced（P<0.01）. PTEN was regulated by miR-17-5p as a target gene. Compared with the miR-NC group, the proliferation inhibition rate in the miR-17-5p mimics group was significantly declined, the number of invaded cells was enhanced, and the apoptosis rate was also decreased（P<0.05）, and the expressions of tumor suppressor proteins PTEN, p21 and p27 in the PTEN/Akt pathway were decreased, and the expressions of p-Akt308, p-Akt473 and cyclin D1 were increased（P<0.01）. Compared with the anti-miR-NC group, the proliferation inhibition rate was increased in the anti-miR-17-5p group, the number of invaded cells was decreased, and the apoptosis rate was also increased（P<0.05）, and the expression of tumor suppressor proteins PTEN, p21 and p27 was increased, and the expression of p-Akt308, p-Akt473 and cyclin D1 was decreased（P<0.01）.

CONCLUSION

Knockdown of miR-17-5p can effectively improve the DDP sensitivity of breast cancer cells, attenuate the invasive ability, and induce further apoptosis,which may be related to the regulatory effect of miR-17-5p on the PTEN/Akt pathway.

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目的

探讨miR-17-5p通过调控PTEN/Akt通路介导乳腺癌细胞顺铂（DDP）耐药的作用。

方法

采用DDP浓度梯度递增培养MCF-7/DDP耐药细胞株，通过RT-qPCR检测MCF-7及MCF-7/DDP耐药细胞中miR-17-5p含量。将MCF-7细胞分为miR-NC组和miR-17-5p组，分别转染miR-NC及miR-17-5p mimics质粒；将MCF-7/DDP耐药细胞分为anti-miR-NC组和anti-miR-17-5p组，分别转染anti-miR-NC及anti-miR-17-5p质粒。通过RT-qPCR检测转染效率，MTT法评估转染后各组细胞对DDP的敏感性，Transwell法用于获取miR-17-5p对乳腺癌细胞侵袭能力的直接作用，流式细胞术检测细胞凋亡率。双荧光素酶报告基因实验验证miR-17-5p和PTEN的靶向关系，Western blot法检测miR-17-5p调控下细胞凋亡和PTEN/Akt通路关键蛋白的变化。

结果

相较MCF-7细胞，MCF-7/DDP耐药细胞中miR-17-5p表达量异常升高，PTEN表达量降低（P<0.01），PTEN作为靶基因受miR-17-5p调控。与miR-NC组相比，miR-17-5p组增殖抑制率显著降低，侵袭细胞数增加，凋亡率下降（均P<0.05），PTEN/Akt通路中抑癌蛋白PTEN、p21、p27表达降低, p-Akt308、p-Akt473、cyclin D1表达升高（P<0.01）。与anti-miR-NC组相比，anti-miR-17-5p组增殖抑制率提高，侵袭细胞数减少，凋亡率上升（均P<0.05），抑癌蛋白PTEN、p21、p27表达升高,p-Akt308、p-Akt473、cyclin D1表达降低（P<0.01）。

结论

敲低miR-17-5p可有效提高乳腺癌细胞的DDP敏感性，减弱其侵袭能力，诱导其凋亡，这可能与miR-17-5p对PTEN/Akt通路的调控作用有关。

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武文慧，
赵心宇
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赵妍，女，主管药师，学士，主要从事肿瘤药理学研究，E-mail:

赵心宇，女，正高级实验师，硕士，主要从事医学检验基础研究，E-mail:

武文慧，女，主任药师，硕士，主要从事妇产科药学的研究，E-mail:

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武文慧，女，主任药师，硕士，主要从事妇产科药学的研究，E-mail:

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Role of miR-17-5p in gefitinib resistance in non-small cell lung cancer by targeting PTEN[J]. The J Pract Med, 2019, 35（11）: 1717-1721., articleTitle=Role of miR-17-5p in gefitinib resistance in non-small cell lung cancer by targeting PTEN, refAbstract=null), Reference(id=1239232819751342241, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222195998749395, doi=null, pmid=null, pmcid=null, year=2008, volume=8, issue=3, pageStart=187, pageEnd=198, url=null, language=null, rfNumber=[27], rfOrder=29, authorNames=CARNERO A, BLANCO-APARICIO C, RENNER O, journalName=Curr Cancer Drug Targets, refType=null, unstructuredReference=CARNERO A, BLANCO-APARICIO C, RENNER O, et al.The PTEN/PI3K/AKT signalling pathway in cancer, therapeutic implications[J]. Curr Cancer Drug Targets, 2008, 8（3）: 187-198., articleTitle=The PTEN/PI3K/AKT signalling pathway in cancer, therapeutic implications, refAbstract=null), Reference(id=1239232819831034019, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222195998749395, doi=null, pmid=null, pmcid=null, year=2020, volume=26, issue=6, pageStart=645, pageEnd=648, url=null, language=null, rfNumber=[28], rfOrder=30, authorNames=丁红光, 张星霖, 孙福生, journalName=解剖科学进展, refType=null, unstructuredReference=丁红光, 张星霖, 孙福生, 等. MicroRNA-29a靶向PTEN/AKT信号通路调节结直肠癌耐药敏感性[J]. 解剖科学进展,2020, 26（6）: 645-648., articleTitle=MicroRNA-29a靶向PTEN/AKT信号通路调节结直肠癌耐药敏感性, refAbstract=null), Reference(id=1239232819914920102, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222195998749395, doi=null, pmid=null, pmcid=null, year=2020, volume=26, issue=6, pageStart=645, pageEnd=648, url=null, language=null, rfNumber=[28], rfOrder=31, authorNames=DING HG, ZHANG XL, SUN FS, journalName=Prog Anat Sci, refType=null, unstructuredReference=DING HG, ZHANG XL, SUN FS, et al.MicroRNA-29a regulate resistance to colorectal cancer via targeting on PTEN/AKT signaling pathway[J]. Prog Anat Sci, 2020, 26（6）:645-648., articleTitle=MicroRNA-29a regulate resistance to colorectal cancer via targeting on PTEN/AKT signaling pathway, refAbstract=null), Reference(id=1239232820007194791, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222195998749395, doi=null, pmid=null, pmcid=null, year=2019, volume=2019, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[29], rfOrder=32, authorNames=MA Q, GAO Y, XU P, journalName=Biomed Res Int, refType=null, unstructuredReference=MA Q, GAO Y, XU P, et al. Atorvastatin inhibits breast cancer cells by downregulating PTEN/AKT pathway via promoting ras homolog family member B（RhoB）[J]. Biomed Res Int, 2019, 2019:3235021., articleTitle=Atorvastatin inhibits breast cancer cells by downregulating PTEN/AKT pathway via promoting ras homolog family member B（RhoB）, refAbstract=null), Reference(id=1239232820074303657, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222195998749395, doi=null, pmid=null, pmcid=null, year=2019, volume=176, issue=2, pageStart=291, pageEnd=301, url=null, language=null, rfNumber=[30], rfOrder=33, authorNames=GAO C, YUAN X, JIANG Z, journalName=Breast Cancer Res Treat, refType=null, unstructuredReference=GAO C, YUAN X, JIANG Z, et al. Regulation of AKT phosphorylation by GSK3β and PTEN to control chemoresistance in breast cancer[J]. 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A：MCF-7细胞，B：MCF-7/DDP耐药细胞。经t检验：与miR-NC组或anti-miR-NC组相比，cP<0.01

, figureFileSmall=vTyvw9a4dJVaTj7oinrT4w==, figureFileBig=WejBDvNk/LRrWYyY/cte5Q==, tableContent=null), ArticleFig(id=1239232814760120394, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222195998749395, language=EN, label=null, caption=null, figureFileSmall=/cVWovK9nuQctDR4nLQxeA==, figureFileBig=JLtxfvernfMCM3Lps4JBJQ==, tableContent=null), ArticleFig(id=1239232814835617870, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222195998749395, language=CN, label=图2, caption=miR-17-5p对两种细胞侵袭能力的影响（瑞氏-吉姆萨染色，n=3）

A：MCF-7细胞（miR-NC组、miR-17-5p组），B：MCF-7/DDP耐药细胞（anti-miR-NC组、anti-miR-17-5p组）

, figureFileSmall=/cVWovK9nuQctDR4nLQxeA==, figureFileBig=JLtxfvernfMCM3Lps4JBJQ==, tableContent=null), ArticleFig(id=1239232814944669777, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222195998749395, language=EN, label=null, caption=null, figureFileSmall=1FybSeDrE3+PwtffushmIA==, figureFileBig=yGFXwRwEY7HpBqRdWwdLiQ==, tableContent=null), ArticleFig(id=1239232815028555859, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222195998749395, language=CN, label=图3, caption=miR-17-5p对两种细胞凋亡率的影响（n=3）

A：MCF-7细胞（miR-NC组、miR-17-5p组），B：MCF-7/DDP耐药细胞（anti-miR-NC组、anti-miR-17-5p组）

, figureFileSmall=1FybSeDrE3+PwtffushmIA==, figureFileBig=yGFXwRwEY7HpBqRdWwdLiQ==, tableContent=null), ArticleFig(id=1239232815129219156, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222195998749395, language=EN, label=null, caption=null, figureFileSmall=H2Re7ldhemYK6pC8a4Dw9A==, figureFileBig=Kttm2uyBPlea5Y8sjRSjJg==, tableContent=null), ArticleFig(id=1239232815225688150, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222195998749395, language=CN, label=图4, caption=miR-17-5p对两种细胞凋亡相关蛋白的影响（n=3，）

A：MCF-7细胞，B：MCF-7/DDP耐药细胞。经t检验：与miR-NC组或anti-miR-NC组相比，aP>0.05, cP<0.01

, figureFileSmall=H2Re7ldhemYK6pC8a4Dw9A==, figureFileBig=Kttm2uyBPlea5Y8sjRSjJg==, tableContent=null), ArticleFig(id=1239232815343128663, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222195998749395, language=EN, label=null, caption=null, figureFileSmall=LjQlazd7UkxtjRG+5tsdcw==, figureFileBig=9JMPZvAIWfeCMjzrLliB2Q==, tableContent=null), ArticleFig(id=1239232815414431833, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222195998749395, language=CN, label=图5, caption=miR-17-5p与PTEN的靶向关系（n=3，）

A：miR-17-5p与PTEN结合位点的预测图，B：PTEN在两种细胞中的蛋白表达量，C：双荧光素酶报告基因实验结果（以“+”代表加入，“-”代表未加入）。经t检验：与MCF-7组或Wt-PTEN+miR-NC组相比，aP>0.05，cP<0.01

, figureFileSmall=LjQlazd7UkxtjRG+5tsdcw==, figureFileBig=9JMPZvAIWfeCMjzrLliB2Q==, tableContent=null), ArticleFig(id=1239232815502512220, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222195998749395, language=EN, label=null, caption=null, figureFileSmall=22WaOBN5ZjFXBdsqrhCp+Q==, figureFileBig=Kvl0agvgV92RqRMVEidOJw==, tableContent=null), ArticleFig(id=1239232815561232479, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222195998749395, language=CN, label=图6, caption=miR-17-5p对两种细胞PTEN表达的影响（n=3，）

A：MCF-7细胞，B：MCF-7/DDP耐药细胞。经t检验：与miR-NC组或anti-miR-NC组相比，cP<0.01

, figureFileSmall=22WaOBN5ZjFXBdsqrhCp+Q==, figureFileBig=Kvl0agvgV92RqRMVEidOJw==, tableContent=null), ArticleFig(id=1239232817020850274, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222195998749395, language=EN, label=null, caption=null, figureFileSmall=scHoWEEwwvCRy5kcglhPFA==, figureFileBig=zeOisLfb//j5GFlbIu+yew==, tableContent=null), ArticleFig(id=1239232817121513575, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222195998749395, language=CN, label=图7, caption=miR-17-5p对两种细胞PTEN/Akt信号通路的影响（n=3，）

A：MCF-7细胞，B：MCF-7/DDP耐药细胞。经t检验：与miR-NC组或anti-miR-NC组相比，aP>0.05, cP<0.01

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miR-17-5p通过调控PTEN/Akt通路介导乳腺癌细胞顺铂耐药
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赵妍 1 , 吉柳 1 , 孙成鹏 2a , 赵心宇 2b , 武文慧 1
中国新药与临床杂志 | 论著 2024,43(11): 852-859
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中国新药与临床杂志 | 论著 2024, 43(11): 852-859
miR-17-5p通过调控PTEN/Akt通路介导乳腺癌细胞顺铂耐药
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赵妍1 , 吉柳1, 孙成鹏2a, 赵心宇2b , 武文慧1
作者信息
  • 1.大连市妇女儿童医疗中心（集团）春柳妇产院区 药剂科，辽宁 大连　116000
  • 2a.大连医科大学药学院，辽宁 大连　116000，
  • 2b.大连医科大学检验医学院，辽宁 大连　116000

    • 赵妍，女，主管药师，学士，主要从事肿瘤药理学研究，E-mail:

    赵心宇，女，正高级实验师，硕士，主要从事医学检验基础研究，E-mail:

    武文慧，女，主任药师，硕士，主要从事妇产科药学的研究，E-mail:

通讯作者:

武文慧，
赵心宇
MiR-17-5p mediating cisplatin resistance in breast cancer cells by regulating PTEN/Akt pathway
Yan ZHAO1 , Liu JI1, Cheng-peng SUN2a, Xin-yu ZHAO2b , Wen-hui WU1
Affiliations
  • 1.Pharmacy Department of Chunliu Obstetrics and Gynecology Hospital, Dalian Municipal Women and Children’s Medical Center, Dalian LIAONING 116000, China
  • 2a.College of Pharmacy, Dalian Medical University, Dalian LIAONING 116000, China
  • 2b.College of Laboratory Medicine, Dalian Medical University, Dalian LIAONING 116000, China
出版时间: 2024-11-25 doi: 10.14109/j.cnki.xyylc.2024.11.10
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摘要
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目的

探讨miR-17-5p通过调控PTEN/Akt通路介导乳腺癌细胞顺铂（DDP）耐药的作用。

方法

采用DDP浓度梯度递增培养MCF-7/DDP耐药细胞株，通过RT-qPCR检测MCF-7及MCF-7/DDP耐药细胞中miR-17-5p含量。将MCF-7细胞分为miR-NC组和miR-17-5p组，分别转染miR-NC及miR-17-5p mimics质粒；将MCF-7/DDP耐药细胞分为anti-miR-NC组和anti-miR-17-5p组，分别转染anti-miR-NC及anti-miR-17-5p质粒。通过RT-qPCR检测转染效率，MTT法评估转染后各组细胞对DDP的敏感性，Transwell法用于获取miR-17-5p对乳腺癌细胞侵袭能力的直接作用，流式细胞术检测细胞凋亡率。双荧光素酶报告基因实验验证miR-17-5p和PTEN的靶向关系，Western blot法检测miR-17-5p调控下细胞凋亡和PTEN/Akt通路关键蛋白的变化。

结果

相较MCF-7细胞，MCF-7/DDP耐药细胞中miR-17-5p表达量异常升高，PTEN表达量降低（P<0.01），PTEN作为靶基因受miR-17-5p调控。与miR-NC组相比，miR-17-5p组增殖抑制率显著降低，侵袭细胞数增加，凋亡率下降（均P<0.05），PTEN/Akt通路中抑癌蛋白PTEN、p21、p27表达降低, p-Akt308、p-Akt473、cyclin D1表达升高（P<0.01）。与anti-miR-NC组相比，anti-miR-17-5p组增殖抑制率提高，侵袭细胞数减少，凋亡率上升（均P<0.05），抑癌蛋白PTEN、p21、p27表达升高,p-Akt308、p-Akt473、cyclin D1表达降低（P<0.01）。

结论

敲低miR-17-5p可有效提高乳腺癌细胞的DDP敏感性，减弱其侵袭能力，诱导其凋亡，这可能与miR-17-5p对PTEN/Akt通路的调控作用有关。

顺铂  /  乳腺肿瘤  /  药物敏感性  /  细胞凋亡  /  PTEN/Akt通路
AIM

To investigate the role of miR-17-5p in mediating cisplatin（DDP）resistance in breast cancer cells by regulating the PTEN/Akt pathway.

METHODS

MCF-7/DDP-resistant cell line was cultured with a gradient of increasing DDP concentrations. The content of miR-17-5p was detected in MCF-7 and MCF-7/DDP cells by RT-qPCR. MCF-7 cells were divided into miR-NC and miR-17-5p groups, and transfected with miR-NC and miR-17-5p mimics plasmids,respectively. MCF-7/DDP-resistant cells were divided into anti-miR-NC and anti-miR-17-5p groups, and transfected with anti-miR-NC and anti-miR-17-5p plasmids, respectively. Transfection efficiency was defined by RT-qPCR. The drug sensitivity of DDP in each group of transfected cells was evaluated by MTT. The direct effect of miR-17-5p on the invasive ability was obtained by Transwell assay. DDP-induced apoptosis of MCF-7 and MCF-7/DDP cells after transfection was analyzed by flow cytometry. The targeting relationship between miR-17-5p and PTEN was verified by double luciferase reporter gene assay. The changes of apoptosis and key proteins of PTEN/Akt pathway under the regulation of miR-17-5p were detected by Western blot.

RESULTS

Compared with MCF-7 cells, the miR-17-5p expression in MCF-7/DDP-resistant cells was abnormally increased, while the PTEN expression was reduced（P<0.01）. PTEN was regulated by miR-17-5p as a target gene. Compared with the miR-NC group, the proliferation inhibition rate in the miR-17-5p mimics group was significantly declined, the number of invaded cells was enhanced, and the apoptosis rate was also decreased（P<0.05）, and the expressions of tumor suppressor proteins PTEN, p21 and p27 in the PTEN/Akt pathway were decreased, and the expressions of p-Akt308, p-Akt473 and cyclin D1 were increased（P<0.01）. Compared with the anti-miR-NC group, the proliferation inhibition rate was increased in the anti-miR-17-5p group, the number of invaded cells was decreased, and the apoptosis rate was also increased（P<0.05）, and the expression of tumor suppressor proteins PTEN, p21 and p27 was increased, and the expression of p-Akt308, p-Akt473 and cyclin D1 was decreased（P<0.01）.

CONCLUSION

Knockdown of miR-17-5p can effectively improve the DDP sensitivity of breast cancer cells, attenuate the invasive ability, and induce further apoptosis,which may be related to the regulatory effect of miR-17-5p on the PTEN/Akt pathway.

cisplatin  /  breast neoplasms  /  drug susceptibility  /  apoptosis  /  PTEN/Akt pathway
赵妍, 吉柳, 孙成鹏, 赵心宇, 武文慧. miR-17-5p通过调控PTEN/Akt通路介导乳腺癌细胞顺铂耐药. 中国新药与临床杂志, 2024 , 43 (11) : 852 -859 . DOI: 10.14109/j.cnki.xyylc.2024.11.10
Yan ZHAO, Liu JI, Cheng-peng SUN, Xin-yu ZHAO, Wen-hui WU. MiR-17-5p mediating cisplatin resistance in breast cancer cells by regulating PTEN/Akt pathway[J]. Chinese Journal of New Drugs and Clinical Remedies, 2024 , 43 (11) : 852 -859 . DOI: 10.14109/j.cnki.xyylc.2024.11.10
正文
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乳腺癌一直以来是女性高发的一种癌症，其发病率在绝经前后和青壮年阶段都较高。顺铂（cisplatin,DDP）可用于治疗乳腺癌、卵巢癌、头颈癌、睾丸癌、膀胱癌、结直肠癌和肺癌等多种恶性实体瘤[1]，其可通过多种机制来发挥抗癌活性，但目前广泛认可的机制是DDP可通过与DNA上的嘌呤相互作用，从而激活多个信号通路，最终导致细胞凋亡[2]。然而，在DDP治疗过程中存在部分肿瘤细胞表现出耐药性，极大地影响了后续治疗。微RNAs（miRNA）是一类小的调节性非编码RNA，尽管细胞中miRNA的含量较少，但其在肿瘤发展和介导细胞耐药等方面发挥着关键作用[3]。研究表明，miRNA可通过参与药物运转和代谢[4]、DNA损伤修复[5]、DNA甲基化和组蛋白修饰[6]、自噬和凋亡[7]、上皮-间充质转化[8]等过程调控乳腺癌细胞对DDP的耐药。miR-17-5p是来源于miR-17-92基因簇的一个具有23个核苷酸的miRNA。有研究证实miR-17-5p在卵巢癌细胞中参与介导DDP的耐药性[9]，但其具体机制尚未可知。miR-17-92基因簇已被发现可通过靶向多种抑癌基因促进癌症的发生发展[10,11]。肿瘤抑制基因磷酸酯酶与张力蛋白同源物（PTEN）可在磷脂酰肌醇3激酶（PI3K）/ PTEN /蛋白激酶B（Akt）信号传导途径中发挥负向调节作用，参与细胞分化、增殖及迁移等多种细胞功能[12,13]。最新的研究表明，PTEN/Akt通路的异常激活参与调控肝癌细胞的DDP耐药[14]。本研究通过建立稳定DDP耐药的人乳腺癌MCF-7细胞株，尝试探讨miR-17-5p介导乳腺癌细胞DDP耐药的具体机制，为乳腺癌的诊断和长期治疗寻找新的可行性方案。
材料与方法
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药物、试剂和仪器
DDP（纯度≥99.99%）购自美国Sigma-Aldrich公司。DMEM高糖培养基、特级胎牛血清、青-链霉素双抗（5 000 U·mL-1）、胰酶消化液均购自美国Gibco公司；总RNA小提试剂盒、逆转录试剂盒、荧光定量PCR试剂盒购自德国Qiagen公司；miR-17-5p模拟物、抑制剂，PTEN野生型、突变型质粒及对照质粒购自上海吉玛公司；MTT试剂盒和瑞氏-吉姆萨染液购自上海碧云天生物技术有限公司；胱天蛋白酶3（caspase-3）、cleaved caspase-3、多腺苷二磷酸核糖聚合酶（PARP）、cleaved PARP、PTEN、p27、p21、GAPDH兔单克隆抗体，细胞周期蛋白D1（cyclin D1）兔多克隆抗体购自英国Abcam公司；Akt、p-Akt308、p-Akt473兔单克隆抗体，山羊抗兔IgG均购自美国CST公司；Annexin V-FITC/PI凋亡检测试剂盒购自南京诺唯赞医疗科技有限公司；Lipofectamine 2000转染试剂、RIPA裂解液和ECL化学发光试剂盒购自美国赛默飞世尔科技公司。IX71型倒置荧光生物显微镜（日本Olympus公司），NovoCyte 2040R型流式细胞仪（美国Agilent公司），Cytation5型多功能酶标仪（美国Biotek公司），MA-6000实时荧光定量PCR仪（苏州雅睿生物技术股份有限公司），小型垂直电泳转印仪（美国Bio-Rad公司）。
细胞培养及MCF-7/DDP耐药细胞株的构建
人乳腺癌MCF-7细胞株和人胚肾HEK-293T细胞购自赛百慷生物技术股份有限公司，用含10%特级灭活胎牛血清及1%青-链霉素双抗的DMEM培基培养于37 ℃、5%CO2的恒温恒湿培养箱中。细胞状态良好时，加入DDP终浓度为200 ng·mL-1的DMEM培基液，待3~4 d细胞稳定生长后，以200 ng·mL-1的梯度递增直至DPP终浓度为5 μg·mL-1，细胞仍长势良好，即得MCF-7/DDP耐药细胞株。
分组与转染
将MCF-7及MCF-7/DDP耐药细胞提前1 d铺板，使细胞汇合度达90%，MCF-7细胞分为miR-NC组和miR-17-5p组，使用Lipofectamine 2000转染试剂分别转染miR-NC和miR-17-5p mimics质粒。MCF-7/DDP耐药细胞分为anti-miR-NC组和anti-miR-17-5p组，分别转染anti-miR-NC和anti-miR-17-5p质粒，通过RT-qPCR评估转染效率并进行后续实验。
细胞miR-17-5p表达水平的检测
采用RT-qPCR法进行检测。使用总RNA小提试剂盒从MCF-7细胞及MCF-7/DDP耐药细胞中提取总RNA，并用逆转录试剂盒处理得到cDNA，按照RT-qPCR试剂盒说明体系加样总反应体积为20 μL，反应体系包括2×QuantiTect SYBR Green 10 μL、0.5 μmol·L-1上游引物、0.5 μmol·L-1上游引物、1 μg cDNA模板及适量无RNA酶水。miR-17-5p的上游引物为5?-?GCCGCCAAAGTG CTTACA-3，下游引物为5-CAGAGCAGGGTCCGA GGTA-3，产物长度为64 bp；内参U6的上游引物为5'-CGCTTCGGCAGCACATATAC-3'，下游引物为5-TT CACGAATTTGCGTGTGTCATC-3，产物长度为87 bp。反应条件为95 ℃ 15 min预变性，94 ℃ 15 s、60 ℃ 20 s循环45次，72 ℃ 30 s延伸。采用2-ΔΔCt法计算表达量。
细胞药物敏感度测定
采用MTT法检测不同DDP浓度下各组转染后细胞的增殖情况以评估其对DDP的敏感度。取处于对数生长期的转染后各组细胞，消化后以每孔5×103个接种于96孔板中，显微镜下观察MCF-7细胞贴壁生长的情况。加入DDP，使其终浓度为0、20、40、80、120、160 μg·mL-1，每组设置6个复孔，培养24 h后重新加入含20 μL MTT的新培养基，继续孵育4 h后加入DMSO，摇匀，搅拌10 min，用酶标仪测量490 nm处的吸光度（A）值，以反映细胞活力。计算乳腺癌细胞的增殖抑制率，增殖抑制率=［（A阴性对照孔-A实验孔）/（A阴性对照孔-A空白孔）］×100%，以增殖抑制率为50%时的DDP质量浓度定义为半数抑制浓度（IC50）。
细胞侵袭实验
在通透性支撑物（Transwell小室）上室添加基底胶并等待其脱水。将转染后的各组细胞放入不含血清的培养基中保存1 d，以消除血清对细胞侵袭实验的影响。将细胞悬液均匀放入Transwell小室的上室，将含10%胎牛血清的培养基600 μL放Transwell小室的下室，根据药物敏感度测定中观察到的不同浓度DDP对MCF-7细胞的影响，选择在所用培基中添加DDP使浓度达到20 μg·mL-1，在37 ℃5%CO2的孵箱中继续孵育48 h，取出小室，用75%甲醇固定5 min，用棉签拭去Transwell小室中8.0 μm孔径聚碳酸酯膜上侧未穿过的细胞，待瑞氏-吉姆萨染色完毕，观察侵入膜下方的细胞数量并使用cellSens Dimension软件保存图像。
细胞凋亡检测
采用NovoCyte 2040R型流式细胞仪进行细胞凋亡检测。将形态正常的转染后细胞依次铺在6孔板中，待细胞完全贴壁、形态良好时，以20 μg·mL-1 DDP处理细胞48 h。用100 μL结合缓冲液重悬细胞，加入FITC标记的Annexin Ⅴ 5 μL和PI 5 μL，充分混匀后避光室温孵育10 min，补加上样缓冲液400 μL转移至10 mL塑料软试管，样本上机前用300目滤膜过筛，记录凋亡百分比。
miR-17-5p和PTEN靶向关系的预测和鉴定
使用TargetScanHuman 8.0数据库（https://www.targetscan.org/vert_80/）预测miR-17-5p和PTEN的结合位点，采用双荧光素酶报告基因实验。在96孔板中接种一定数量的HEK-293T细胞，待达到70%~80%的融合度时，使用Lipofectamine 2000转染试剂将Wt-PTEN、Mut-PTEN与miR-NC、miR-17-5p mimics共同转染至HEK-293T细胞细胞中。共转染48 h后，加入报告基因专用裂解液轻缓晃动15 min彻底裂解细胞，取10 μL裂解物上清液与萤火虫荧光素酶底物加入酶标板中混合2 s，测得萤火虫荧光素酶活性值，随后加入海肾荧光素酶底物测得海肾荧光素酶活性值。每组实验重复3次。
凋亡及PTEN/Akt通路相关蛋白的检测
采用Western blot法进行检测。以20 μg·mL-1 DDP处理乳腺癌细胞48 h后收集细胞，使用细胞快速裂解液提取总蛋白，BCA法检测蛋白浓度，取等量蛋白进行聚丙烯酰胺凝胶电泳，转印至聚偏二氟乙烯膜上，以5%脱脂牛奶室温封闭2 h，4 ℃孵育一抗过夜，一抗包括caspase-3（1:1 000）、cleaved caspase-3（1:500）、PARP（1:1 000）、cleaved PARP（1:1 000）、PTEN（1:1 000）、Akt（1:1 000）、p-Akt308（1:1 000）、p-Akt473（1:1 000）、cyclin D1（1:1 000）、p21（1:1 000）、p27（1:1 000）、GAPDH（1:10 000），随后加入HRP标记的山羊抗兔IgG室温孵育1.5 h，用避光EP管配置ECL发光混合液在凝胶仪中曝光成像。
统计学分析
采用SPSS 19.0软件进行统计学分析，数据以均数±标准差表示。每个实验至少重复3次。2组间独立样本比较采用t检验，多组间比较采用单因素方差分析。P<0.05为有显著差异。
结果
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miR-17-5p在两种细胞中的表达量
RT-qPCR结果显示，MCF-7/DDP耐药细胞中miR-17-5p的相对表达量显著高于MCF-7细胞（3.77±0.08 vs. 1.00±0.04,P<0.01）。
转染后miR-17-5p在两种细胞中的表达量
miR-17-5p组细胞中miR-17-5p的相对表达量显著高于miR-NC组（2.96±0.13 vs. 1.00±0.06, P<0.01）。anti-miR-17-5p组细胞的miR-17-5p显著低于anti-miR-NC组（0.34±0.04 vs. 1.00±0.03, P<0.01）。
miR-17-5p对两种细胞DDP敏感性的影响
随着DDP浓度的增加，MCF-7细胞和MCF-7/DDP耐药细胞的增殖抑制率逐渐升高。在同一DDP浓度下，miR-17-5p组细胞的增殖抑制率显著低于miR-NC组，miR-NC组DDP的IC50为33.21 μg·mL-1，miR-17-5p组为102.20 μg·mL-1。anti-miR-17-5p组细胞的增殖抑制率显著高于anti-miR-NC组，anti-miR-NC组DDP的IC50为90.80 μg·mL-1，anti-miR-17-5p组为22.58 μg·mL-1。见图1。
miR-17-5p对两种细胞侵袭能力的影响
miR-17-5p组的侵袭细胞数显著高于miR-NC组（75.67±8.74 vs.26.33±8.50, P<0.01）。anti-miR-17-5p组的侵袭细胞数显著低于anti-miR-NC组（18.00±5.57 vs. 69.75±10.78, P<0.01）。见图2。
miR-17-5p对两种细胞凋亡的影响
相同浓度DDP处理下，miR-17-5p组细胞凋亡率显著低于miR-NC组（8.36±1.55 vs. 14.39±2.96, P<0.05）。anti-miR-17-5p组细胞凋亡率（16.79±3.26）显著高于anti-miR-NC组（9.48±1.03, P<0.05）。见图3。
miR-17-5p对两种细胞中凋亡相关蛋白的影响
在MCF-7细胞2组间caspase-3和PARP蛋白水平无显著差异（P>0.05），而miR-17-5p组cleaved caspase-3和cleaved PARP蛋白水平显著低于miR-NC组（P<0.01）。在MCF-7/DDP耐药细胞2组间caspase-3和PARP蛋白水平无显著差异（P>0.05），而anti-miR-17-5p组cleaved caspase-3和cleaved PARP蛋白水平显著高于anti-miR-NC组（P<0.01）。见图4。
miR-17-5p与PTEN的靶向关系
经检索TargetScan-Human 8.0数据库发现PTEN可能作为miR-17-5p的靶基因，两者存在高度结合的可能性（图5A）。相较MCF-7细胞，MCF-7/DDP耐药细胞PTEN的表达量显著降低（P<0.05，图5B）。双荧光素酶实验证实，miR-17-5p与PTEN存在直接靶向结合关系（P<0.05，图5C）。miR-17-5p组PTEN蛋白表达量显著低于miR-NC组（P<0.01），anti-miR-17-5p组PTEN蛋白表达量显著高于anti-miR-NC组（P<0.01），见图6。
miR-17-5p对两种细胞PTEN/Akt信号通路的影响
miR-17-5p组p-Akt308、 p-Akt473、cyclin D1的表达量显著高于miR-NC组，而抑癌蛋白PTEN、p21、p27的表达量显著低于miR-NC组（P<0.01）。anti-miR-17-5p组p-Akt308、p-Akt473、cyclin D1的表达量显著低于anti-miR-NC组，而PTEN、p21、p27的表达量显著高于anti-miR-NC组（P<0.01）。见图7。
讨论
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乳腺癌的具体发病原因尚不明确，且存在一定的遗传风险，虽然辅助化疗和激素治疗的广泛应用已大幅提高了乳腺癌患者的5年存活率，且早期乳腺癌、局部晚期和局部复发的乳腺癌患者具有一定几率被彻底治愈，但在治疗过程中产生的耐药性仍使患者承受较大的复发和转移风险[15,16]。因此，阐明乳腺癌药物治疗相关的各种生物学行为与分子作用机制，有助于延长乳腺癌患者的存活期并提高治愈率。DDP作为最有效的广谱抗癌药物之一，在《2020乳腺癌NCCN治疗指南》中被列为三阴性乳腺癌的首选治疗方案之一[17]。同时，与非铂类药物相比，铂类药物能显著提高乳腺癌临床治疗有效指标，包括总缓解率、病理完全缓解率、总生存期及无病生存期等[18]。DDP联合其他化疗药物或结合纳米载体递送技术可有效延缓乳腺癌生长同时抑制乳腺癌的转移[19-21]。虽然DDP具有极好的乳腺癌治疗作用，但部分乳腺癌患者因原发性耐药或继发性耐药导致治疗失败。因此，解决乳腺癌细胞对DDP的耐药性是目前应对乳腺癌相关死亡的重要临床问题之一。DDP耐药主要是由于细胞摄取药物的能力和外排能力的改变、还原型谷胱甘肽（GSH）和金属硫蛋白表达的增高、非编码RNA在转录前后对下游基因和通路的调节作用导致的[22]。研究乳腺癌细胞的DDP耐药机制，有助于解决乳腺癌患者的DDP耐药问题，从而改善预后，延长生存期。
据报道，miRNA在调节肿瘤发展和介导细胞耐药性方面发挥着关键作用，调节性miRNA可能作为实现乳腺癌患者治疗效果改善的新靶点[23]。有研究表明，miR-17-5p可通过调控上皮-间充质转化介导三阴性乳腺癌细胞的迁移和侵袭[24]；miR-17-5p可在贲门癌细胞中与长链非编码RNA H19和miR-130a-3p相互作用影响放射抗性和化疗敏感性[25]；miR-17-5p还可通过靶向PTEN促进非小细胞肺癌对吉非替尼的耐药[26]。本研究发现，MCF-7/DDP耐药细胞中的miR-17-5p表达水平显著高于MCF-7细胞，且提高MCF-7细胞中miR-17-5p表达后，其侵袭能力出现显著提升，对DDP的敏感性明显降低，同时凋亡率及凋亡相关蛋白含量也显著下降，提示高水平的miR-17-5p能有效抑制MCF-7细胞的凋亡；而敲低MCF-7/DDP耐药细胞中miR-17-5p的含量后，MCF-7/DDP耐药细胞对DDP的敏感性和凋亡率显著提高，侵袭能力显著下降。上述结果表明，miR-17-5p在乳腺癌DDP耐药中发挥重要作用。
PTEN/Akt信号通路可以调节多种生物活动过程（例如营养代谢、细胞增殖、存活、移动和血管生成等）。在众多恶性肿瘤中，PTEN的活性由于高频的变化、缺失或启动子沉默而不断降低，导致PI3K/Akt信号通路的激活[27]。丁红光等[28]认为，miR-29a可通过靶向PTEN/Akt信号通路增加结直肠癌细胞对5-氟尿嘧啶的耐药性。MA等[29]报道，在乳腺癌中，阿托伐他汀可通过上调Ras同源物基因家族成员B的表达影响PTEN/Akt信号通路的激活进而发挥其抗癌作用。GAO等[30]发现，糖原合成激酶3β和PTEN介导的Akt磷酸化与细胞活力、迁移和凋亡相关，PTEN/Akt信号通路的异常激活促进了乳腺癌的化学耐药性。本研究显示，提高MCF-7细胞中miR-17-5p的表达后，PTEN/Akt信号通路中促癌蛋白p-Akt308、p-Akt473和cyclin D1的活性明显增强，抑癌蛋白PTEN、p21、p27的含量显著下降，敲低MCF-7/DDP耐药细胞中miR-17-5p的含量后PTEN/Akt通路促癌蛋白p-Akt308、 p-Akt473和cyclin D1活性显著下降，而抑癌蛋白PTEN、p21、p27含量显著提高，这些都提示了miR-17-5p可能是通过PTEN/Akt通路介导乳腺癌的DDP耐药。
综上所述，miR-17-5p在乳腺癌DDP耐药中发挥的重要作用，敲低miR-17-5p可有效提高乳腺癌细胞的DDP敏感性，减弱其侵袭能力，诱导其凋亡，可能与miR-17-5p对PTEN/Akt通路的调控作用直接相关。
基金
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  • 辽宁省科学技术基金(2020-MS-256)
文献
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2024年第43卷第11期
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文章信息
doi: 10.14109/j.cnki.xyylc.2024.11.10
  • 接收时间：2022-07-19
  • 首发时间：2026-03-13
  • 出版时间：2024-11-25
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出版历史
  • 收稿日期：2022-07-19
  • 录用日期：2024-08-19
基金
辽宁省科学技术基金(2020-MS-256)
作者信息
    1.大连市妇女儿童医疗中心（集团）春柳妇产院区 药剂科，辽宁 大连　116000
    2a.大连医科大学药学院，辽宁 大连　116000，
    2b.大连医科大学检验医学院，辽宁 大连　116000

通讯作者:

武文慧，
赵心宇
参考文献
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https://castjournals.cast.org.cn/joweb/zgxyylczz/CN/10.14109/j.cnki.xyylc.2024.11.10
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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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