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Article(id=1198558168130351988, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1198558165093675863, articleNumber=null, orderNo=null, doi=10.11855/j.issn.0577-7402.0527.2023.0823, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1681142400000, receivedDateStr=2023-04-11, revisedDate=null, revisedDateStr=null, acceptedDate=1687795200000, acceptedDateStr=2023-06-27, onlineDate=1763688135416, onlineDateStr=2025-11-21, pubDate=1724774400000, pubDateStr=2024-08-28, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1763688135416, onlineIssueDateStr=2025-11-21, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1763688135416, creator=13701087609, updateTime=1763688135416, updator=13701087609, issue=Issue{id=1198558165093675863, tenantId=1146029695717560320, journalId=1189873630562394117, year='2024', volume='49', issue='8', pageStart='855', pageEnd='976', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1763688134691, creator=13701087609, updateTime=1763689174168, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1198562525043327039, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1198558165093675863, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1198562525043327040, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1198558165093675863, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=930, endPage=938, ext={EN=ArticleExt(id=1198558169866793866, articleId=1198558168130351988, tenantId=1146029695717560320, journalId=1189873630562394117, language=EN, title=Effect of flavokawain B downregulates androgen receptor on the proliferation and migration in triple-negative breast cancer, columnId=1190310110212751762, journalTitle=Medical Journal of Chinese People’s Liberation Army, columnName=Basic Research, runingTitle=null, highlight=null, articleAbstract=

Objective To investigate how flavokawain B (FKB) affects the proliferation and migration of triple-negative breast cancer (TNBC) cells by downregulating the androgen receptor (AR). Methods The expression of AR in breast cancer and normal tissues was analyzed using the GEPIA2 database. Expression of estrogen receptor (ER), human epidermal growth factor receptor 2 (HER2), progesterone receptor (PR), and AR was detected in six breast cancer cell lines (SUM159PT, MCF-7, T47D, BT474, Hs-578T, and MDB-MA-231) by Western blotting. The effect of FKB (0, 10, 20, 30, 40, 50, 60 μmoL/L) treatment of 24, 48, and 72 h on the proliferative activity of SUM159PT breast cancer cells was assessed using the CCK-8 assay under normal or androgen deprivation conditions. The mRNA and protein of AR expression was measured by qRT-PCR and Western blotting after 30 μmoL/L FKB treatment of SUM159PT cells for 0, 4 and 8 h. SUM159PT cells were set as control group (treatment with 0.1% DMSO), dihydrotestosterone (DHT) group (treatment with 10 nmol/L DHT), FKB group (treatment with 15 μmol/L FKB), DHT+FKB group (treatment with 10 nmol/L DHT and 15 μmol/L FKB), AR antagonist enzalutamide (ENZA) group (treatment with 40 μmol/L ENZA), and DHT+ENZA group (treatment with 10 nmol/L DHT and 40 μmol/L ENZA) under androgen deprivation conditions. Cell proliferation, migration, and colony formation abilities in the above groups were determined using the CCK-8 method, Transwell assay, and clone formation test. Western blotting was also used to detect the expression levels of EMT-related proteins (N-cadherin, Occludin, Vimentin) and AR protein. Results AR mRNA expression level was significantly higher in breast cancer tissue than in normal breast tissue (P<0.05). AR was expressed at comparable levels in five different breast cancer cell lines (SUM159PT, MCF-7, T47D, BT474, and Hs-578T) in addition to MDB-MA-231. FKB can downregulate AR mRNA and protein levels (P<0.05). Western blotting results showed that DHT could upregulate AR protein levels in SUM159PT cells, but FKB could prevent the DHT-induced upregulation of AR protein levels (P<0.05). FKB and ENZA decreased SUM159PT cell proliferation and migration and DHT-mediated cell proliferation and migration (P<0.05). FKB and ENZA can reduce N-cadherin and Vimentin protein levels and counteract DHT-induced increases in N-cadherin and Vimentin protein levels (P<0.05). In addition, FKB may increase Occludin expression and counteract the DHT-induced decrease in Occludin protein expression (P<0.05). Conclusion Flavokawain B could inhibit the proliferation, migration, and clonogenic ability of TNBC cells by regulating AR expression.

, correspAuthors=Xue-Sen Li, authorNote=null, correspAuthorsNote=
E-mail:
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目的 探讨黄卡瓦胡椒素B(FKB)下调雄激素受体(AR)对三阴性乳腺癌(TNBC)细胞增殖和迁移的影响。方法 基于GEPIA2数据库分析乳腺癌组织及正常乳腺组织中AR的表达情况。采用Western blotting检测6种乳腺癌细胞系(SUM159PT、MCF-7、T47D、BT474、Hs-578T和MDB-MA-231)中雌激素受体(ER)、人表皮生长因子受体2(HER2)、孕激素受体(PR)和AR蛋白的表达情况。在正常或雄激素剥夺条件下，使用CCK-8法检测不同浓度(0、10、20、30、40、50、60 μmoL/L) FKB处理不同时间(24、48、72 h)对SUM159PT细胞增殖活性的影响。利用30 μmoL/L FKB处理SUM159PT细胞0、4和8 h后，采用qRT-PCR和Western blotting检测AR mRNA及蛋白的表达情况。在雄激素剥夺的条件下，取SUM159PT细胞设置对照组(0.1% DMSO处理)、二氢睾酮(DHT)组(10 nmol/L DHT处理)、FKB组(15 μmol/L FKB处理)、DHT+FKB组(10 nmol/L DHT+15 μmol/L FKB处理)、恩杂鲁胺(ENZA)组(40 μmol/L ENZA处理)及DHT+ENZA组(10 nmol/L DHT+40 μmol/L ENZA处理)。采用CCK-8法、Transwell实验和克隆形成实验检测各组细胞增殖、迁移和克隆形成能力，Western blotting检测各组上皮-间质转化(EMT)相关蛋白(N-cadherin、Occludin、Vimentin)及AR蛋白的表达水平。结果 乳腺癌组织中AR mRNA表达水平明显高于正常乳腺组织(P<0.05)。除MDB-MA-231外，AR在其他5种乳腺癌细胞系(SUM159PT、MCF-7、T47D、BT474和Hs-578T)中均有表达。FKB可下调SUM159PT细胞中AR mRNA和蛋白表达水平(P<0.001)。Western blotting检测结果显示，DHT可诱导SUM159PT细胞中AR蛋白表达水平上调，而FKB抑制DHT诱导的AR蛋白表达水平上调(P<0.01)。FKB和ENZA均抑制SUM159PT细胞的增殖和迁移能力，并逆转DHT诱导的细胞增殖和迁移能力增加(P<0.05)。FKB和ENZA均可降低N-cadherin和Vimentin蛋白表达水平，并逆转DHT诱导的N-cadherin和Vimentin蛋白表达水平上调(P<0.05)。此外，FKB还可增加Occludin蛋白的表达，逆转DHT导致的Occludin蛋白表达降低(P<0.05)。结论 FKB可能通过调节AR的表达抑制TNBC细胞的增殖、迁移以及克隆形成能力，从而抑制TNBC的进展。

, correspAuthors=李雪森, authorNote=null, correspAuthorsNote=
李雪森，E-mail：
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杨忠云，硕士研究生，主要从事肿瘤分子生物学方面的研究

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杨忠云，硕士研究生，主要从事肿瘤分子生物学方面的研究

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杨忠云，硕士研究生，主要从事肿瘤分子生物学方面的研究

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AR. 雄激素受体；ER. 雌激素受体；HER2. 人表皮生长因子受体2；PR. 孕激素受体；TNBC. 三阴性乳腺癌；A. GEPIA2数据库分析乳腺癌组织和正常乳腺组织中AR mRNA表达情况；B. CCLE数据库分析乳腺癌细胞中AR mRNA表达情况；C. Western blotting检测不同乳腺癌细胞中AR蛋白的表达情况(n=3)；与正常乳腺组织比较，(1)P<0.05

, figureFileSmall=aD+m/1l9F02LVKqeSLlirg==, figureFileBig=Xn3B2h8jmhwPADyCViDGMw==, tableContent=null), ArticleFig(id=1198578976944911075, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198558168130351988, language=EN, label=Fig.2, caption=Effect of FKB on proliferative activity and the expression of AR in SUM159PT cells (n=3), figureFileSmall=tjhXTgOcbJ2ViFAge4Ud3A==, figureFileBig=1jM0Jtpi1T0VNoab14xp2Q==, tableContent=null), ArticleFig(id=1198578977012019945, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198558168130351988, language=CN, label=图2, caption=FKB对SUM159PT细胞增殖活性及AR表达的影响(n=3)

AR. 雄激素受体；FKB. 黄卡瓦胡椒素B；DHT. 二氢睾酮；A. 不同时间(24、48、72 h)不同浓度(0、10、20、30、40、50、60 μmoL/L) FKB处理对SUM159PT细胞增殖活性的影响；B. FKB对SUM159PT细胞中AR mRNA表达的影响；C. FKB对SUM159PT细胞中AR蛋白表达的影响；D. 在雄激素剥夺的条件下，FKB(15 μmoL/L)和DHT(10 nmol/L)单独或共同处理SUM159PT细胞16 h后，Western blotting检测AR蛋白的表达。与处理24 h比较，(1)P<0.001；与0 μmoL/L FKB比较，(2)P<0.001；与处理0 h比较，(3)P<0.001；与对照组比较，(4)P<0.01；与DHT组比较，(5)P<0.01

, figureFileSmall=tjhXTgOcbJ2ViFAge4Ud3A==, figureFileBig=1jM0Jtpi1T0VNoab14xp2Q==, tableContent=null), ArticleFig(id=1198578977079128812, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198558168130351988, language=EN, label=Fig.3, caption=Effect of FKB on SUM159PT cell proliferative activity (n=3), figureFileSmall=yTGQleVIYlYCMNglxTPMRA==, figureFileBig=9CJYANy4BhNNCKkB0FULCA==, tableContent=null), ArticleFig(id=1198578977158820591, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198558168130351988, language=CN, label=图3, caption=FKB对SUM159PT细胞增殖活性的影响(n=3)

FKB. 黄卡瓦胡椒素B；DHT. 二氢睾酮；AR. 雄激素受体；ENZA. 恩杂鲁胺；A. 在雄激素剥夺的条件下，不同浓度(0、2.5、5、10、15、20 μmol/L)FKB处理不同时间(24、48、72 h)对SUM159PT细胞增殖活性的影响；B. 在雄激素剥夺的条件下，不同浓度(0、10、20、30、40、60 μmol/L)ENZA处理不同时间(24、48、72 h)对SUM159PT细胞增殖活性的影响；C. CCK-8法检测雄激素剥夺的条件下各组SUM159PT细胞的增殖活性；D. 克隆形成实验检测在雄激素剥夺的条件下各组SUM159PT细胞的克隆形成能力；与处理24 h比较，(1)P<0.001；与0 μmol/L FKB或ENZA比较，(2)P<0.05；与对照组比较，(3)P<0.05；与DHT组比较，(4)P<0.05

, figureFileSmall=yTGQleVIYlYCMNglxTPMRA==, figureFileBig=9CJYANy4BhNNCKkB0FULCA==, tableContent=null), ArticleFig(id=1198578977267872500, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198558168130351988, language=EN, label=Fig. 4, caption=Effect of DHT, FKB and ENZA alone or in combination with DHT on the migratory activity of SUM159PT cells, figureFileSmall=v5vLP3ammGUBYVrS3um5iQ==, figureFileBig=UPoQTSxE7VqrVjw7Qkfjfw==, tableContent=null), ArticleFig(id=1198578977343369974, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198558168130351988, language=CN, label=图4, caption=DHT、FKB和ENZA单独或与DHT联用对SUM159PT细胞迁移能力的影响

FKB. 黄卡瓦胡椒素B；DHT. 二氢睾酮；AR. 雄激素受体；ENZA. 恩杂鲁胺；EMT. 上皮-间质转化；A. 在雄激素剥夺的条件下，Transwell实验检测各组SUM159PT细胞的迁移能力；B. 在雄激素剥夺的条件下，Western blotting检测各组SUM159PT细胞中EMT相关标志物蛋白的表达情况(n=3)；与对照组比较，(1)P<0.05；与DHT组比较，(2)P<0.05

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黄卡瓦胡椒素B下调雄激素受体对三阴性乳腺癌增殖和迁移的影响
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杨忠云 , 吴婷 , 李雪森 *
解放军医学杂志 | 基础研究 2024,49(8): 930-938
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解放军医学杂志 | 基础研究 2024, 49(8): 930-938
黄卡瓦胡椒素B下调雄激素受体对三阴性乳腺癌增殖和迁移的影响
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杨忠云, 吴婷, 李雪森*
作者信息
  • 西南医科大学基础医学院肿瘤医学研究所，四川泸州 646000

    • 杨忠云，硕士研究生，主要从事肿瘤分子生物学方面的研究

通讯作者:

李雪森，E-mail：
Effect of flavokawain B downregulates androgen receptor on the proliferation and migration in triple-negative breast cancer
Zhong-Yun Yang, Ting Wu, Xue-Sen Li*
Affiliations
  • Institute of Medical Oncology, School of Basic Medicine, Southwest Medical University, Luzhou, Sichuan 646000, China
出版时间: 2024-08-28 doi: 10.11855/j.issn.0577-7402.0527.2023.0823
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摘要
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目的 探讨黄卡瓦胡椒素B(FKB)下调雄激素受体(AR)对三阴性乳腺癌(TNBC)细胞增殖和迁移的影响。方法 基于GEPIA2数据库分析乳腺癌组织及正常乳腺组织中AR的表达情况。采用Western blotting检测6种乳腺癌细胞系(SUM159PT、MCF-7、T47D、BT474、Hs-578T和MDB-MA-231)中雌激素受体(ER)、人表皮生长因子受体2(HER2)、孕激素受体(PR)和AR蛋白的表达情况。在正常或雄激素剥夺条件下，使用CCK-8法检测不同浓度(0、10、20、30、40、50、60 μmoL/L) FKB处理不同时间(24、48、72 h)对SUM159PT细胞增殖活性的影响。利用30 μmoL/L FKB处理SUM159PT细胞0、4和8 h后，采用qRT-PCR和Western blotting检测AR mRNA及蛋白的表达情况。在雄激素剥夺的条件下，取SUM159PT细胞设置对照组(0.1% DMSO处理)、二氢睾酮(DHT)组(10 nmol/L DHT处理)、FKB组(15 μmol/L FKB处理)、DHT+FKB组(10 nmol/L DHT+15 μmol/L FKB处理)、恩杂鲁胺(ENZA)组(40 μmol/L ENZA处理)及DHT+ENZA组(10 nmol/L DHT+40 μmol/L ENZA处理)。采用CCK-8法、Transwell实验和克隆形成实验检测各组细胞增殖、迁移和克隆形成能力，Western blotting检测各组上皮-间质转化(EMT)相关蛋白(N-cadherin、Occludin、Vimentin)及AR蛋白的表达水平。结果 乳腺癌组织中AR mRNA表达水平明显高于正常乳腺组织(P<0.05)。除MDB-MA-231外，AR在其他5种乳腺癌细胞系(SUM159PT、MCF-7、T47D、BT474和Hs-578T)中均有表达。FKB可下调SUM159PT细胞中AR mRNA和蛋白表达水平(P<0.001)。Western blotting检测结果显示，DHT可诱导SUM159PT细胞中AR蛋白表达水平上调，而FKB抑制DHT诱导的AR蛋白表达水平上调(P<0.01)。FKB和ENZA均抑制SUM159PT细胞的增殖和迁移能力，并逆转DHT诱导的细胞增殖和迁移能力增加(P<0.05)。FKB和ENZA均可降低N-cadherin和Vimentin蛋白表达水平，并逆转DHT诱导的N-cadherin和Vimentin蛋白表达水平上调(P<0.05)。此外，FKB还可增加Occludin蛋白的表达，逆转DHT导致的Occludin蛋白表达降低(P<0.05)。结论 FKB可能通过调节AR的表达抑制TNBC细胞的增殖、迁移以及克隆形成能力，从而抑制TNBC的进展。

雄激素受体  /  黄卡瓦胡椒素B  /  三阴性乳腺癌

Objective To investigate how flavokawain B (FKB) affects the proliferation and migration of triple-negative breast cancer (TNBC) cells by downregulating the androgen receptor (AR). Methods The expression of AR in breast cancer and normal tissues was analyzed using the GEPIA2 database. Expression of estrogen receptor (ER), human epidermal growth factor receptor 2 (HER2), progesterone receptor (PR), and AR was detected in six breast cancer cell lines (SUM159PT, MCF-7, T47D, BT474, Hs-578T, and MDB-MA-231) by Western blotting. The effect of FKB (0, 10, 20, 30, 40, 50, 60 μmoL/L) treatment of 24, 48, and 72 h on the proliferative activity of SUM159PT breast cancer cells was assessed using the CCK-8 assay under normal or androgen deprivation conditions. The mRNA and protein of AR expression was measured by qRT-PCR and Western blotting after 30 μmoL/L FKB treatment of SUM159PT cells for 0, 4 and 8 h. SUM159PT cells were set as control group (treatment with 0.1% DMSO), dihydrotestosterone (DHT) group (treatment with 10 nmol/L DHT), FKB group (treatment with 15 μmol/L FKB), DHT+FKB group (treatment with 10 nmol/L DHT and 15 μmol/L FKB), AR antagonist enzalutamide (ENZA) group (treatment with 40 μmol/L ENZA), and DHT+ENZA group (treatment with 10 nmol/L DHT and 40 μmol/L ENZA) under androgen deprivation conditions. Cell proliferation, migration, and colony formation abilities in the above groups were determined using the CCK-8 method, Transwell assay, and clone formation test. Western blotting was also used to detect the expression levels of EMT-related proteins (N-cadherin, Occludin, Vimentin) and AR protein. Results AR mRNA expression level was significantly higher in breast cancer tissue than in normal breast tissue (P<0.05). AR was expressed at comparable levels in five different breast cancer cell lines (SUM159PT, MCF-7, T47D, BT474, and Hs-578T) in addition to MDB-MA-231. FKB can downregulate AR mRNA and protein levels (P<0.05). Western blotting results showed that DHT could upregulate AR protein levels in SUM159PT cells, but FKB could prevent the DHT-induced upregulation of AR protein levels (P<0.05). FKB and ENZA decreased SUM159PT cell proliferation and migration and DHT-mediated cell proliferation and migration (P<0.05). FKB and ENZA can reduce N-cadherin and Vimentin protein levels and counteract DHT-induced increases in N-cadherin and Vimentin protein levels (P<0.05). In addition, FKB may increase Occludin expression and counteract the DHT-induced decrease in Occludin protein expression (P<0.05). Conclusion Flavokawain B could inhibit the proliferation, migration, and clonogenic ability of TNBC cells by regulating AR expression.

androgen receptor  /  flavokawain B  /  triple-negative breast cancer
杨忠云, 吴婷, 李雪森. 黄卡瓦胡椒素B下调雄激素受体对三阴性乳腺癌增殖和迁移的影响. 解放军医学杂志, 2024 , 49 (8) : 930 -938 . DOI: 10.11855/j.issn.0577-7402.0527.2023.0823
Zhong-Yun Yang, Ting Wu, Xue-Sen Li. Effect of flavokawain B downregulates androgen receptor on the proliferation and migration in triple-negative breast cancer[J]. Medical Journal of Chinese People’s Liberation Army, 2024 , 49 (8) : 930 -938 . DOI: 10.11855/j.issn.0577-7402.0527.2023.0823
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三阴性乳腺癌(triple-negative breast cancer，TNBC)占乳腺癌的15%~20%[1]，其主要表现为雌激素受体(estrogen receptor，ER)、人表皮生长因子受体2(human epidermal growth factor receptor 2，HER2)和孕激素受体(progesterone receptor，PR)的表达均为阴性[2-3]。相较其他类型的乳腺癌，TNBC具有高侵袭、易转移和易复发的特点[4-5]。TNBC患者生存率远低于其他类型乳腺癌，且易产生化疗耐药性，预后较差[6-7]。然而，目前尚未发现有效的TNBC治疗靶点，因此，寻找新的药物靶点对于TNBC的治疗至关重要[8]。研究发现，10%~43%的TNBC组织表达雄激素受体(androgen receptor，AR)[9-10]，临床试验证实AR抑制剂恩杂鲁胺(enzalutamide，ENZA)可用于治疗乳腺癌[11]，表明AR可能是一种新型的TNBC治疗靶点[12-13]。黄卡瓦胡椒素B(flavokawain B，FKB)是一种从卡瓦胡椒中提取的有药用价值的化合物，最初被发现可用于治疗焦虑症[14-15]。进一步研究发现，FKB可通过下调AR的表达来抑制前列腺肿瘤的生长，并减少肿瘤组织中与AR相关的靶基因的表达[16]。然而，FKB是否能够下调TNBC中AR的表达并抑制TNBC进展尚未明确。本研究探讨FKB下调AR的表达对TNBC细胞增殖、迁移和克隆形成的影响，旨在为AR作为TNBC的治疗靶点以及FKB的药物转化研究提供依据。
1 材料与方法
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1.1 主要试剂
ENZA、FKB、二氢睾酮(DHT；上海吉至生化科技有限公司)；DMEM高糖培养基(美国Cytiva公司)；胎牛血清(美国Hyclone公司)；aB-27无血清添加剂(上海白鲨信息科技有限公司)；DMEM无酚红高糖培养基(南京维森特生物技术有限公司)；胰蛋白酶消化液(北京索莱宝科技公司)；CCK-8试剂盒(美国APEXBIO公司)；BCA蛋白浓度测定试剂盒(上海碧云天生物技术有限公司)；HER2抗体、ER抗体、PR抗体、AR抗体、N-cadherin抗体、Vimentin抗体、Occludin抗体、GAPDH抗体(美国Cell Signaling Technology公司)；反转录与实时定量反转录PCR(real-time quantitative reverse transcription PCR，real-time qRT-PCR)试剂盒(日本TaKaRa公司)。
1.2 实验方法
1.2.1 生物信息学分析
基于TCGA和GTEx数据库，使用GEPIA2[17](http://gepia2.cancer-pku.cn/#index)检索并分析1085个乳腺癌样本和291个正常乳腺样本中RNA测序表达数据，以明确乳腺癌组织及正常乳腺组织中AR的表达情况。阈值设置为|log2 FC|>1，P<0.01。基于癌细胞系百科全书(CCLE)[18](https://sites.broadinstitute.org/ccle)数据库，检索分析乳腺癌细胞中AR的表达情况。
1.2.2 常规细胞培养
人乳腺癌细胞系SUM159PT、MDB-MA-231、T47D、MCF-7、BT474和Hs-578T由西南医科大学肿瘤研究所保存，用含10%胎牛血清、1%青霉素-链霉素的DMEM高糖培养基于37 ℃、5% CO2环境中培养。
1.2.3 雄激素剥夺条件下的细胞培养
在常规细胞培养液中培养SUM159PT细胞24 h后，将培养液更换为不含酚红的培养基，并添加aB-27血清替代品使其终浓度为0.5倍；细胞经过8 h饥饿处理以排出雄激素，再次更换培养液为不含酚红的培养基，并添加aB-27血清替代品使其终浓度为1.0倍。细胞在37 ℃、5% CO2恒温箱中继续培养。
1.2.4 qRT-PCR检测AR mRNA的表达
常规培养SUM159PT细胞24 h后，使用30 μmol/L FKB分别处理0、4、8 h，然后使用Trizol试剂提取细胞总RNA，并使用紫外分光光度计检测RNA浓度，分析其质量。取1 μg RNA反转录为cDNA，采用qRT-PCR检测AR mRNA的表达水平。反应条件：95 ℃ 30 s(变性)；95 ℃ 5 s、60 ℃ 34 s(退火)，40个循环。以GAPDH为内参照，使用2-ΔΔCt进行相对定量分析。引物由上海生工有限公司合成。引物序列如下：AR，正向：5'-CTGGCTTCCGCAACTTACAC-3'，反向：5'-TGGTAGAAGCGTCTTGAGCA-3'；GAPDH，正向：5'-GGAGCGAGATCCCTCCAAAAT-3'，反向：5'-GGCTGTTGTCATACTTCTCATGG-3'。对照组(0 h)使用0.1% DMSO处理。
1.2.5 Western blotting检测ER、PR、HER2、AR、Occludin、N-cadherin、Vimentin蛋白表达水平
(1)常规培养SUM159PT细胞24 h后，使用30 μmol/L FKB分别处理0、4和8 h。(2)常规培养SUM159PT、MCF-7、T47D、BT474、Hs-578T和MDB-MA-231细胞24 h。(3)雄激素剥夺条件下培养SUM159PT细胞后，设置对照组(0.1% DMSO处理)、DHT组(10 nmol/L DHT处理)、FKB组(15 μmol/L FKB处理)、DHT+FKB组(10 nmol/L DHT+15 μmol/L FKB处理)、ENZA组(40 μmol/L ENZA处理)及DHT+ENZA组(10 nmol/L DHT+40 μmol/L ENZA处理)，加入相应药物处理16 h。
使用含有蛋白酶抑制剂的裂解液裂解上述细胞，提取细胞总蛋白。利用BCA试剂盒检测蛋白浓度，行SDS-PAGE电泳并转膜；以5%牛血清白蛋白作为封闭缓冲液室温封闭膜1 h；加入一抗ER(1∶1000)、PR(1∶1000)、HER2(1∶1000)、AR(1∶1000)、Occludin(1∶1000)、N-cadherin(1∶1000)、Vimentin(1∶1000)和GAPDH(1∶1000)4 ℃孵育过夜；加入抗鼠或抗兔二抗常温孵育2 h，采用Odessey成像仪扫描成像，ImageJ软件进行灰度值分析。
1.2.6 细胞迁移实验
雄激素剥夺条件下培养SUM159PT细胞后，设置对照组(0.1% DMSO处理)、DHT组(10 nmol/L DHT处理)、FKB组(15 μmol/L FKB处理)、DHT+FKB组(10 nmol/L DHT+15 μmol/L FKB处理)、ENZA组(40 μmol/L ENZA处理)及DHT+ENZA组(10 nmol/L DHT+40 μmol/L ENZA处理)。收集SUM159PT细胞重悬于无血清无酚红培养基中，进行细胞计数并稀释细胞；在Transwell上室中加入100 μl含6×104个细胞的混悬液，并加入100 μl对应实验分组的药物培养基混合溶液；在下室中加入600 μl含20% FBS的细胞培养液，并将Transwell置于37 ℃、5% CO2孵箱中孵育16 h。孵育结束后，取出小室，倒掉上室的培养基，PBS洗2次，轻轻用棉签擦去上室的细胞。然后使用70%甲醇固定、晾干、1%结晶紫染色，随机选取3个视野拍照和采集数据，对细胞进行计数并取平均值。
1.2.7 克隆形成实验
雄激素剥夺条件下培养SUM159PT细胞后，设置对照组(0.1% DMSO处理)、DHT组(10 nmol/L DHT处理)、FKB组(5 μmol/L FKB处理)、DHT+FKB组(10 nmol/L DHT+5 μmol/L FKB处理)、ENZA组(40 μmol/L ENZA处理)及DHT+ENZA组(10 nmol/L DHT+40 μmol/L ENZA处理)。为减少细胞活性抑制对细胞克隆能力的影响，该实验选取抑制细胞活性较小的5 μmol/L FKB进行处理。接种SUM159PT细胞于6孔板(8×103个/孔)中，按照分组处理细胞并每隔2~3 d换液1次。培养10~14 d后，肉眼可见克隆团时终止培养。PBS洗涤细胞后，用70%甲醛溶液固定、1%结晶紫染色(上海碧云天生物技术有限公司)，拍照保存。随后使用33%冰乙酸洗脱结晶紫，采用酶标仪检测590 nm波长处的吸光度(OD)值，计算克隆细胞数。实验均独立重复3次。
1.2.8 CCK-8法检测细胞增殖活性
(1)在正常培养条件下，采用CCK-8法检测FKB对SUM159PT细胞增殖活性的影响。接种SUM159PT细胞于96孔板中(1×105个/孔)并培养24 h后，使用不同浓度的FKB(0、10、20、30、40、50、60 μmol/L)处理。每个处理设置5个复孔，于常规培养箱中培养。分别培养24、48、72 h后，采用CCK-8法检测细胞增殖活性。(2)在雄激素剥夺的条件下，采用CCK-8法检测不同浓度(0、2.5、5、10、15、20 μmol/L)FKB处理不同时间(24、48、72 h)对SUM159PT细胞增殖活性的影响，不同浓度(0、10、20、30、40、60 μmol/L)ENZA处理不同时间(24、48、72 h)对SUM159PT细胞增殖活性的影响；取SUM159PT细胞，设置对照组(0.1% DMSO处理)、DHT组(10 nmol/L DHT处理)、FKB组(10 μmol/L FKB处理)、DHT+FKB组(10 nmol/L DHT+10 μmol/L FKB处理)、ENZA组(40 μmol/L ENZA处理)及DHT+ENZA组(10 nmol/L DHT+40 μmol/L ENZA处理)，加入相应药物处理24、48、72 h，采用CCK-8法检测细胞增殖活性。
配制含CCK-8试剂的培养液(CCK-8∶培养基=1∶10)备用。弃去培养基，PBS洗2次；每孔加入100 μl CCK-8溶液，并设置含CCK-8溶液但无细胞的孔作为空白对照孔；继续培养2 h后，采用酶标仪检测450 nm处的OD值，并计算细胞增殖活性。实验独立重复3次。细胞增殖活性(%)=(实验组-空白组)/(对照组-空白组)×100%。对照组使用0.1% DMSO处理。
1.3 统计学处理
采用GraphPad Prism 9软件进行统计分析。定量资料以$\bar{x}±s$表示，两组间比较采用t检验，多组间比较采用单因素方差分析，进一步两两比较采用Dunnett's检验。P<0.05为差异有统计学意义。
2 结果
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2.1 AR在乳腺癌中的表达情况
GEPIA2检索分析结果显示，与正常乳腺组织相比，乳腺癌组织中AR mRNA表达水平明显升高(P<0.05，图1A)。CCLE数据库分析结果显示，AR在大多数乳腺癌细胞中均有表达，在TNBC中呈偏态分布，且不同细胞之间表达量差异较大；在其余两种亚型(Lumial和HER2+)乳腺癌细胞中的表达较均衡，不同细胞之间表达量差异较小(图1B)。
Western blotting检测结果显示，除MDB-MA-231细胞外，AR在其余ER阳性MCF-7、T47D，HER2阳性BT474，以及三阴性Hs-578T、SUM159PT等5种乳腺癌细胞中均有表达(图1C)，在两种三阴性细胞中，AR mRNA在SUM59PT细胞中表达较高，因此选取SUM159PT细胞进行后续实验。
2.2 FKB对AR的表达及SUM159PT细胞增殖活性的影响
CCK-8法检测结果显示，FKB以浓度和时间依赖性抑制SUM159PT细胞的增殖活性。FKB处理24、48、72 h的IC50值分别为44.36、13.92、10.06 μmoL/L(图2A)。30 μmoL/L FKB处理对细胞增殖活性有一定抑制作用，但对细胞状态没有明显影响，因此选择30 μmoL/L FKB进行后续实验。
qRT-PCR检测结果显示，与处理0 h相比，30 μmoL/L FKB处理4 h后，SUM159PT细胞中AR mRNA表达水平降低60%；处理8 h后，SUM159PT细胞中AR mRNA表达水平降低84%(P<0.001，图2B)。
Western blotting检测结果显示，与处理0 h相比，30 μmoL/L FKB处理4 h后，SUM159PT细胞中AR蛋白表达水平降低41%；处理8 h后，SUM159PT细胞中AR蛋白表达水平降低57%(P<0.001，图2C)。
在雄激素剥夺的条件下，与对照组相比，DHT组SUM159PT细胞中AR蛋白表达水平增高(P<0.01)；与DHT组相比，DHT+FKB组SUM159PT细胞中AR蛋白表达水平降低(P<0.01，图2D)。
2.3 FKB抑制AR的表达对SUM159PT细胞增殖活性和克隆形成能力的影响
CCK-8法检测结果显示，在雄激素剥夺的条件下，不同浓度(0、2.5、5、10、15、20 μmol/L)FKB处理24、48、72 h后，SUM159PT细胞增殖活性均受到明显抑制，且呈浓度和时间依赖性(P<0.05，图3A)。FKB处理24、48、72 h的IC50值分别为24.8、16.1和13.6 μmol/L。
在雄激素剥夺的条件下，不同浓度(0、10、20、30、40、60 μmol/L)ENZA处理SUM159PT细胞，处理24 h时IC50值超出其线性范围，处理48、72 h 的IC50值分别为58.07、47.86 μmol/L(图3B)。
CCK-8法检测结果显示，处理24 h、48 h和72 h，DHT组SUM159PT细胞增殖活性明显高于对照组，FKB组与ENZA组SUM159PT细胞增殖活性明显低于对照组(P<0.05)；DHT+FKB组和DHT+ENZA组SUM159PT细胞增殖活性明显低于DHT组(P<0.05，图3C)。克隆形成实验结果显示，DHT组SUM159PT细胞克隆数明显多于对照组，FKB组和ENZA组SUM159PT细胞克隆数明显少于对照组(P<0.05)；DHT+FKB组和DHT+ENZA组SUM159PT细胞克隆数明显少于DHT组(P<0.05，图3D)。
2.4 FKB抑制AR的表达对SUM159PT细胞迁移的影响
Transwell实验结果显示，DHT组迁移细胞数明显多于对照组，FKB组和ENZA组迁移细胞数明显少于对照组(P<0.05)；DHT+FKB组和DHT+ENZA组迁移细胞数明显少于DHT组(P<0.05，图4A)。
Western blotting检测结果显示，DHT激活AR可使N-cadherin和Vimentin蛋白表达水平明显升高(P<0.05)，Occludin蛋白表达水平明显降低(P<0.05)；与对照组比较，FKB组和ENZA组N-cadherin和Vimentin蛋白表达水平明显降低(P<0.05)，FKB组Occludin蛋白表达水平明显升高(P<0.05)，而ENZA组Occludin蛋白表达水平无明显变化(P>0.05)；与DHT组比较，DHT+FKB组及DHT+ENZA组N-cadherin和Vimentin蛋白表达水平明显降低(P<0.05)，DHT+FKB组Occludin蛋白表达水平明显升高(P<0.05)，DHT+FKB组Occludin蛋白表达水平无明显变化(P>0.05，图4B)。
3 讨论
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目前，乳腺癌已成为威胁全球女性健康的第一大杀手，其中TNBC恶性程度远高于其他类型乳腺癌[19-23]。AR在包括乳房在内的多种组织中均有表达[24]，参与多种生物学过程，如骨骼和生殖功能的发育和维持，在女性生育能力和乳房发育中必不可缺[25-26]。AR可直接与DNA结合并调节多种基因的转录[27-28]。
除在前列腺癌中起重要作用外，AR高表达也与肾癌的低肿瘤分级和早期肾细胞癌相关[28]，食管鳞状细胞癌(esophageal squamous cell carcinoma，ESCC)患者中AR呈高表达，且与较短的总生存期(overall survival，OS)和无病生存期密切相关[29]。利用阻止雄激素产生和(或)阻断AR的药物进行雄激素阻断可抑制前列腺癌的生长[27]。AR在乳腺癌中广泛表达，且与TNBC预后相关，因此其是潜在的乳腺癌治疗靶点[29]。AR抑制剂ENZA可使TNBC患者的临床获益率(clinical benefit rate，CBR)提高至33%，并改善AR阳性TNBC患者的中位无进展生存期(progression-free survival，PFS)和OS[11]。
FKB提取自卡瓦胡椒的根部，是一种天然的查耳酮类化合物[14,30]。FKB可下调AR及其靶基因(PSA和TMPRSS2)的表达，同时降低Sp1蛋白的表达，导致AR转录水平下调[16]。既往临床前研究发现，雄激素可导致表达AR的乳腺癌细胞增殖，并促进动物模型中的肿瘤形成[该动物模型不添加致癌物质，使用睾酮(T)联合17β-雌二醇(E2)在几个月内即可诱发乳腺癌][31]；而FKB可抑制乳腺癌细胞的增殖活性[32]。有动物研究发现，降解AR蛋白可抑制小鼠体内异种移植物的生长[33]。Anestis等[34]发现，ENZA可抑制乳腺癌细胞MDA-MB-453的生长，也可抑制DHT介导的乳腺癌细胞生长；AR抑制剂比卡鲁胺可降低TNBC中AR的表达，并具有抗增殖作用[35]。本研究结果显示，FKB和ENZA可抑制DHT促进的SUM159PT细胞增殖活性和克隆形成能力。FKB和ENZA在功能上具有相似的作用，均通过作用于AR抑制SUM159PT细胞的增殖活性和克隆形成能力。值得注意的是，DHT具有激活AR的作用，与FKB和ENZA的作用方式可能不同。
由于AR的表达与OS有关，因此AR有利于乳腺癌的发展和侵袭[36]。AR可促进TNBC细胞的存活以及侵袭相关基因的表达，从而促进转移[35]。本研究发现，FKB与AR抑制剂ENZA类似[37-38]，均可抑制SUM159PT细胞的迁移。上皮-间质转化(epithelial-mesenchymal transition，EMT)与肿瘤细胞迁移及侵袭密切相关[39-40]，其中上皮型标志物紧密连接蛋白(Occludin)表达下调可促进EMT的发生，从而促进肿瘤细胞转移[41]；间质型标志物N-钙黏蛋白(N-cadherin)和波形蛋白(Vimentin)表达下调可抑制EMT的发生，从而抑制肿瘤细胞转移[42-43]。DHT激活的AR可与去甲基酶LSD1相互作用，抑制AR阳性MCF7乳腺癌细胞中E-cadherin转录，并激活Vimentin转录，导致EMT发生，最终促进癌症转移[29]。研究发现，AR抑制剂ENZA可通过抑制细胞迁移和增殖，影响细胞迁移相关蛋白的表达，从而影响细胞生长[34]。本研究发现，FKB通过影响Occludin、N-cadherin和Vimentin蛋白的表达从而影响细胞迁移，提示DHT可诱导细胞迁移，而FKB和ENZA可抑制细胞迁移，同时可抑制DHT诱导的细胞迁移。
ENZA可与AR结合，竞争性抑制AR的活性，因此容易受到AR突变的影响，ENZA对AR剪接变异体7(androgen receptor splice variant-7，AR-V7)具有明显的耐药性[44]。FKB可下调全长AR和AR-V7的表达[16]，从而下调AR mRNA和蛋白水平，进而避免AR突变产生的耐药性。本研究发现，SUM159PT细胞中，FKB IC50值及抑制AR活性的浓度均低于ENZA。研究发现，FKB可在体内抑制前列腺癌、骨肉瘤和胆管癌等多种癌细胞的生长[16，45-46]。因此，FKB具有治疗AR+ TNBC的潜力，有望成为一种治疗AR+ TNBC的化疗药物。此外，FKB也被用于治疗焦虑症，并被列入《美国药典》中[15]。FKB应用于乳腺癌的治疗中，还需对其剂量、给药方案以及治疗持续时间等参数进行优化。因此，将FKB引入临床试验以治疗TNBC仍任重道远。多项研究发现，FKB可与其他药物联合治疗癌症，从而起到协同作用[46-47]，因此，未来研究应深入探索FKB在TNBC发生发展中的确切作用，并研究FKB与其他治疗手段的联合应用，以期提高治疗效果。
综上所述，本研究结果表明，FKB可抑制高表达AR的TNBC细胞的增殖、克隆形成和迁移，其机制可能与FKB抑制AR的表达有关，为高表达AR的TNBC的治疗提供了一种新的策略和方向。但本研究仍存在不足之处：(1)仅基于细胞层面，缺乏对乳腺癌实体瘤和动物模型的实验验证；(2)仅初步证实FKB通过调节AR的表达来抑制TNBC细胞的恶性进展，仍需要进一步深入探讨FKB抑制乳腺癌细胞生物学活性与AR表达之间的关系。
基金
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  • 四川省科技计划联合创新专项(2022YFS0623)
文献
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参考文献 引证文献
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doi: 10.11855/j.issn.0577-7402.0527.2023.0823
  • 接收时间：2023-04-11
  • 首发时间：2025-11-21
  • 出版时间：2024-08-28
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  • 收稿日期：2023-04-11
  • 录用日期：2023-06-27
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Sichuan Provincial Science and Technology Program(2022YFS0623)
四川省科技计划联合创新专项(2022YFS0623)
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    西南医科大学基础医学院肿瘤医学研究所，四川泸州 646000

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李雪森，E-mail：
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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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