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Article(id=1308842581342126390, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308842471539442166, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2025-1535, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1766246400000, receivedDateStr=2025-12-21, revisedDate=1773331200000, revisedDateStr=2026-03-13, acceptedDate=null, acceptedDateStr=null, onlineDate=1789981988511, onlineDateStr=2026-09-21, pubDate=1786464000000, pubDateStr=2026-08-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1789981988511, onlineIssueDateStr=2026-09-21, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1789981988511, creator=13701087609, updateTime=1789981988511, updator=13701087609, issue=Issue{id=1308842471539442166, tenantId=1146029695717560320, journalId=1189982191388893191, year='2026', volume='61', issue='8', pageStart='2821', pageEnd='3220', issueExtLink='null', onlineDate='null', pubDate='1786464000000', pubDateStr='2026-08-12', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1789981962332, creator='13701087609', updateTime=1789984137222, updator='13701087609', preIssue=null, nextIssue=null, articleTotal=null, ext={EN=IssueExt(id=1308851593773150481, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308842471539442166, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1308851593773150482, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308842471539442166, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null, downloadFileDto=null}, startPage=2998, endPage=3005, ext={EN=ArticleExt(id=1308842581577007415, articleId=1308842581342126390, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Anti-tumor study of liquidambaric acid inhibiting the interaction of TRAF2/CRLF2 to regulate the STAT3 signaling pathway, columnId=1190335348761793317, journalTitle=Acta Pharmaceutica Sinica, columnName=Original Articles, runingTitle=null, highlight=null, articleAbstract=

Tumor necrosis factor receptor-associated factor 2 (TRAF2) is a central signaling adaptor that integrates multiple oncogenic pathways and represents potential target for cancer therapy. In this study, leveraging the extensive protein-protein interaction network of TRAF2, 100 "undruggable" key tumor-associated proteins were selected to screen for TRAF2 interactors. It was found that cytokine receptor-like factor 2 (CRLF2) is a novel interacting protein of TRAF2, and the liquidambaric acid (LDA), which can directly target TRAF2, can inhibit the TRAF2/CRLF2 interaction. Binding site studies revealed that CRLF2 binds to the TRAF domain of TRAF2 and can be blocked by LDA. Functional studies of CRLF2 indicated that TRAF2 is a key protein in the CRLF2-STAT3 (signal transducer and activator of transcription 3) signaling pathway, and LDA can regulate CRLF2-related STAT3 phosphorylation. In summary, this study reveals the TRAF2-mediated tumor protein interaction network and elucidates a new mechanism by which LDA exerts antitumor effects by inhibiting TRAF2/CRLF2 interaction to regulate the STAT3 signaling pathway. It also provides new theoretical guidance and potential strategies for the development of anti-tumor drugs targeting undruggable targets.

, authors=Hui-hui LI, Shi-cheng ZHENG, Tian-yi ZHANG, Yan YANG, Hong-yan ZHU, Yi QU, Xi-song KE, Rong YAN*, authorsList=Hui-hui LI, Shi-cheng ZHENG, Tian-yi ZHANG, Yan YANG, Hong-yan ZHU, Yi QU, Xi-song KE, Rong YAN, authorCompany=null, correspAuthors=Rong YAN, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2026 Acta Pharmaceutica Sinica. All rights reserved., copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, fund=null), CN=ArticleExt(id=1308842584357830976, articleId=1308842581342126390, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=路路通酸抑制TRAF2/CRLF2互作调控STAT3信号通路的抗肿瘤研究, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

肿瘤坏死因子受体相关因子2 (tumor necrosis factor receptor-associated factor 2, TRAF2) 是典型的信号转接因子, 广泛参与肿瘤信号通路, 是潜在的肿瘤治疗靶标。本研究根据TRAF2广泛参与蛋白互作的特征, 选择100个“不可成药”肿瘤关键蛋白, 进行TRAF2互作蛋白筛选, 发现细胞因子受体样因子2 (cytokine receptor-like factor 2, CRLF2) 是TRAF2的新型互作蛋白, 且TRAF2的靶向小分子路路通酸(liquidambaric acid, LDA) 可阻断TRAF2/CRLF2蛋白互作; 通过结合位点研究发现, CRLF2结合在TRAF2的TRAF结构域, 且可以被LDA阻断; CRLF2功能研究发现, TRAF2是CRLF2-STAT3 (signal transducer and activator of transcription 3) 信号通路的关键蛋白, 且LDA可以调控CRLF2相关的STAT3磷酸化。综上, 本研究揭示了TRAF2介导的肿瘤蛋白互作网络, 并阐明了LDA通过抑制TRAF2/CRLF2互作调控STAT3信号通路抗肿瘤的新机制, 并为突破难以成药靶点的抗肿瘤药物研发提供了新的理论依据与潜在策略。

, authors=李慧慧, 郑诗成, 张天艺, 杨彦, 朱红岩, 屈祎, 柯细松, 闫蓉*, authorsList=李慧慧, 郑诗成, 张天艺, 杨彦, 朱红岩, 屈祎, 柯细松, 闫蓉, authorCompany=null, correspAuthors=闫蓉, authorNote=

作者贡献:

闫蓉和李慧慧负责课题总体设计; 李慧慧、郑诗成、张天艺、杨彦和朱红岩负责完成实验的具体实施; 李慧慧负责实验数据分析、文章撰写; 屈祎、柯细松和闫蓉对课题进行及论文撰写进行指导。

, correspAuthorsNote=
闫蓉, Tel: 86-21-51323190, E-mail:
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Cell Death Dis, 2025, 16: 292., articleTitle=null, refAbstract=null)], funds=null, companyList=[AuthorCompany(id=1308842584575934785, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308842581342126390, xref=null, ext=[AuthorCompanyExt(id=1308842584584323394, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308842581342126390, companyId=1308842584575934785, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China), AuthorCompanyExt(id=1308842584588517699, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308842581342126390, companyId=1308842584575934785, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=上海中医药大学交叉科学研究院, 上海 201203)])], figs=[ArticleFig(id=1308842588917039478, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308842581342126390, language=EN, label=null, caption=null, figureFileSmall=PKy0ags2mnV2fmDMBVPVZA==, figureFileBig=5lvMsi9ELGBE5cgHnWGBYA==, tableContent=null), ArticleFig(id=1308842588979954039, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308842581342126390, language=CN, label=Fig.1, caption=CRLF2 was a novel interacting protein of TRAF2. A: Screening flowchart of the screening process for tumor-associated proteins that interact with TRAF2 (created in BioRender, https://BioRender.com/70267hq); B: Representative images of single and co-transfection of TRAF2-mCherry and CRLF2-GFP after transfection for 24 h in HEK293T; C: Representative FRET efficiency images of TRAF2-mCherry and CRLF2-GFP after co-transfection for 24 h in HEK293T; D: FRET efficiency statistics of TRAF2-mCherry and CRLF2-GFP after co-transfection for 24 h in HEK293T; E: Co-immunoprecipitation (Co-IP) assay of TRAF2/CRLF2 interactions in NCI-H1975/HCT116 cells; F: Representative proximity ligation assay (PLA) images of TRAF2/CRLF2 interactions in NCI-H1975/HCT116 cells. Scale bars: 5 and 10 μm. n = 8, $ \overline{x}\pm s $. **P < 0.01. TRAF2: Tumor necrosis factor receptor-associated factor 2; CRLF2: Cytokine receptor-like factor 2; FRET: Fluorescence resonance energy transfer, figureFileSmall=PKy0ags2mnV2fmDMBVPVZA==, figureFileBig=5lvMsi9ELGBE5cgHnWGBYA==, tableContent=null), ArticleFig(id=1308842589177086328, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308842581342126390, language=EN, label=null, caption=null, figureFileSmall=oldMBYuhgp2XgvpOxTM/gw==, figureFileBig=smXU58x8BrCfHrDR4T9IUA==, tableContent=null), ArticleFig(id=1308842589240000889, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308842581342126390, language=CN, label=Fig.2, caption=LDA inhibited the interaction of TRAF2 and CRLF2. A: Chemical structures of LDA; B: Representative FRET efficiency images of TRAF2-mCherry and CRLF2-GFP after co-transfection for 36 h in HEK293T upon the treatment of LDA (0, 5, 10 and 20 μmol·L-1) for 12 h; C: FRET efficiency statistics of TRAF2-mCherry and CRLF2-GFP after co-transfection for 36 h in HEK293T upon the treatment of LDA (0, 5, 10 and 20 μmol·L-1) for 12 h; D: Representative PLA images and duolink spot quantitation of TRAF2/CRLF2 interactions in NCI-H1975/HCT116 cells upon the treatment of LDA (10 μmol·L-1) for 12 h; E: Co-IP assay of TRAF2/CRLF2 interactions in NCI-H1975/HCT116 cells upon the treatment of LDA (10 μmol·L-1) for 12 h. n = 3, $ \overline{x}\pm s $. *P < 0.05, **P < 0.01, ***P < 0.001. Scale bars: 5 and 10 μm. LDA: Liquidambaric acid, figureFileSmall=oldMBYuhgp2XgvpOxTM/gw==, figureFileBig=smXU58x8BrCfHrDR4T9IUA==, tableContent=null), ArticleFig(id=1308842589311304058, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308842581342126390, language=EN, label=null, caption=null, figureFileSmall=R2tJTuSX9/xrEY9QgCkd1Q==, figureFileBig=5KvKQNTDmITFBR08qqqV0g==, tableContent=null), ArticleFig(id=1308842589370024315, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308842581342126390, language=CN, label=Fig.3, caption=CRLF2 bound to the TRAF2-TRAF domain and was specifically blocked by LDA. A: Diagram of TRAF2 truncation; B: Co-IP assay of the association of GFP-tagged TRAF2 truncations and mCherry-tagged CRLF2 in HEK293T; C: Co-IP assay of TRAF2-GFP/CRLF2-mCherry interactions after co-transfection for 48 h in 293T cells upon the treatment of LDA (10 μmol·L-1) for 12 h; D: Co-IP assay of TRAF2-M3-GFP/CRLF2-mCherry interactions after co-transfection for 48 h in HEK293T cells upon the treatment of LDA (10 μmol·L-1) for 12 h, figureFileSmall=R2tJTuSX9/xrEY9QgCkd1Q==, figureFileBig=5KvKQNTDmITFBR08qqqV0g==, tableContent=null), ArticleFig(id=1308842589428744572, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308842581342126390, language=EN, label=null, caption=null, figureFileSmall=a2YmSUdw+iQUxdn3P7PqIw==, figureFileBig=ELZcCI2hZ+4HvIIsAb1Y6Q==, tableContent=null), ArticleFig(id=1308842589504242045, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308842581342126390, language=CN, label=Fig.4, caption=LDA exerted anti-lung cancer activity by inhibiting the STAT3 signaling pathway. A: Colony formation assay of NCI-H460/HCC827/NCI-H1975 upon the treatment of LDA (2.5, 5 and 10 μmol·L-1); B: CCK8 assay of NCI-H1975 upon the treatment of LDA with dose course (0, 0.312 5, 0.625, 1.25, 2.5, 5, 10, 20, 40 and 80 μmol·L-1) for 48 h (n = 3); C: Western blot analysis of STAT3/pSTAT3 in NCI-H1975 cells upon the treatment of LDA (10 μmol·L-1) for 12 h; D: Western blot analysis of STAT3/pSTAT3/TRAF2 in NCI-H1975 cells containing siRNA against TRAF2 upon the treatment of LDA (10 μmol·L-1) for 12 h (n = 3); E: Western blot analysis of STAT3/pSTAT3/CRLF2 in NCI-H1975 cells containing siRNA against CRLF2 upon the treatment of LDA (10 μmol·L-1) for 12 h (n = 3); F: Mechanism diagram of LDA (created in BioRender, https://BioRender.com/o4dmaro). $ \overline{x}\pm s $. *P < 0.05. ns indicated no significance. 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路路通酸抑制TRAF2/CRLF2互作调控STAT3信号通路的抗肿瘤研究
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李慧慧 , 郑诗成 , 张天艺 , 杨彦 , 朱红岩 , 屈祎 , 柯细松 , 闫蓉 *
药学学报 | 研究论文 2026,61(8): 2998-3005
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药学学报 |研究论文 2026 , 61 (8) : 2998 -3005
路路通酸抑制TRAF2/CRLF2互作调控STAT3信号通路的抗肿瘤研究
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李慧慧, 郑诗成, 张天艺, 杨彦, 朱红岩, 屈祎, 柯细松, 闫蓉*
作者信息
  • 上海中医药大学交叉科学研究院, 上海 201203
通讯作者:
闫蓉, Tel: 86-21-51323190, E-mail:
作者简介:

作者贡献:

闫蓉和李慧慧负责课题总体设计; 李慧慧、郑诗成、张天艺、杨彦和朱红岩负责完成实验的具体实施; 李慧慧负责实验数据分析、文章撰写; 屈祎、柯细松和闫蓉对课题进行及论文撰写进行指导。

Anti-tumor study of liquidambaric acid inhibiting the interaction of TRAF2/CRLF2 to regulate the STAT3 signaling pathway
Hui-hui LI, Shi-cheng ZHENG, Tian-yi ZHANG, Yan YANG, Hong-yan ZHU, Yi QU, Xi-song KE, Rong YAN*
Affiliations
  • Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
出版时间: 2026-08-12 doi: 10.16438/j.0513-4870.2025-1535
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摘要
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肿瘤坏死因子受体相关因子2 (tumor necrosis factor receptor-associated factor 2, TRAF2) 是典型的信号转接因子, 广泛参与肿瘤信号通路, 是潜在的肿瘤治疗靶标。本研究根据TRAF2广泛参与蛋白互作的特征, 选择100个“不可成药”肿瘤关键蛋白, 进行TRAF2互作蛋白筛选, 发现细胞因子受体样因子2 (cytokine receptor-like factor 2, CRLF2) 是TRAF2的新型互作蛋白, 且TRAF2的靶向小分子路路通酸(liquidambaric acid, LDA) 可阻断TRAF2/CRLF2蛋白互作; 通过结合位点研究发现, CRLF2结合在TRAF2的TRAF结构域, 且可以被LDA阻断; CRLF2功能研究发现, TRAF2是CRLF2-STAT3 (signal transducer and activator of transcription 3) 信号通路的关键蛋白, 且LDA可以调控CRLF2相关的STAT3磷酸化。综上, 本研究揭示了TRAF2介导的肿瘤蛋白互作网络, 并阐明了LDA通过抑制TRAF2/CRLF2互作调控STAT3信号通路抗肿瘤的新机制, 并为突破难以成药靶点的抗肿瘤药物研发提供了新的理论依据与潜在策略。

路路通酸  /  蛋白互作  /  肿瘤坏死因子受体相关因子2  /  细胞因子受体样因子2  /  STAT3信号通路

Tumor necrosis factor receptor-associated factor 2 (TRAF2) is a central signaling adaptor that integrates multiple oncogenic pathways and represents potential target for cancer therapy. In this study, leveraging the extensive protein-protein interaction network of TRAF2, 100 "undruggable" key tumor-associated proteins were selected to screen for TRAF2 interactors. It was found that cytokine receptor-like factor 2 (CRLF2) is a novel interacting protein of TRAF2, and the liquidambaric acid (LDA), which can directly target TRAF2, can inhibit the TRAF2/CRLF2 interaction. Binding site studies revealed that CRLF2 binds to the TRAF domain of TRAF2 and can be blocked by LDA. Functional studies of CRLF2 indicated that TRAF2 is a key protein in the CRLF2-STAT3 (signal transducer and activator of transcription 3) signaling pathway, and LDA can regulate CRLF2-related STAT3 phosphorylation. In summary, this study reveals the TRAF2-mediated tumor protein interaction network and elucidates a new mechanism by which LDA exerts antitumor effects by inhibiting TRAF2/CRLF2 interaction to regulate the STAT3 signaling pathway. It also provides new theoretical guidance and potential strategies for the development of anti-tumor drugs targeting undruggable targets.

liquidambaric acid  /  protein-protein interaction  /  tumor necrosis factor receptor-associated factor 2  /  cytokine receptor-like factor 2  /  STAT3 signaling pathway
李慧慧, 郑诗成, 张天艺, 杨彦, 朱红岩, 屈祎, 柯细松, 闫蓉. 路路通酸抑制TRAF2/CRLF2互作调控STAT3信号通路的抗肿瘤研究. 药学学报, 2026 , 61 (8) : 2998 -3005 . DOI: 10.16438/j.0513-4870.2025-1535
Hui-hui LI, Shi-cheng ZHENG, Tian-yi ZHANG, Yan YANG, Hong-yan ZHU, Yi QU, Xi-song KE, Rong YAN. Anti-tumor study of liquidambaric acid inhibiting the interaction of TRAF2/CRLF2 to regulate the STAT3 signaling pathway[J]. Acta Pharmaceutica Sinica, 2026 , 61 (8) : 2998 -3005 . DOI: 10.16438/j.0513-4870.2025-1535
正文
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肿瘤的发生与发展是一个多因素、多通路共同作用的复杂过程, 其中蛋白质相互作用(protein-protein interaction, PPI) 在维持细胞稳态、调控信号传导及决定细胞命运中发挥关键作用[1]。肿瘤坏死因子受体相关因子2 (tumor necrosis factor receptor-associated factor 2, TRAF2) 是一个广泛参与蛋白互作的衔接子(adaptor), 在结直肠癌和肺癌等多种肿瘤中TRAF2有异常激活, 是潜在的抗肿瘤治疗靶点[2, 3]。TRAF2结构是由1个环指结构域(ring)、5个锌指结构域(Zn fingers) 和TRAF结构域组成[3], TRAF结构域具有支架活性作用, 是TRAF2形成三聚体以及广泛参与蛋白互作的结构基础。
TRAF2的结构解析已经超过20年[4, 5], 本课题组报道的路路通酸(liquidambaric acid, LDA) 是首个基于表型筛选得到的TRAF2直接靶向小分子, 且发现LDA结合在TRAF结构域, 可以阻断多种与TRAF2结合蛋白的PPI[6, 7], 并在多种肿瘤细胞模型中表现出显著的抗肿瘤活性。LDA可通过破坏TRAF2/β-catenin/TCF4/TNIK复合体发挥抗结直肠癌作用[6]; 由Wnt/β-catenin过度激活驱动的结直肠癌(colorectal cancer, CRC) 依赖于β-catenin的入核, 而LDA可通过阻断TRAF2/Nups相互作用, 抑制β-catenin核转位[7]。然而, TRAF2作为超级适配体蛋白, 其在肿瘤相关信号网络调控中的具体机制以及LDA对其的调控作用尚不完全清楚, 有待进一步阐明。
本研究选择具有“难以靶向”特点的100个肿瘤关键相关蛋白与TRAF2蛋白互作筛选, 发现细胞因子受体样因子2 (cytokine receptor-like factor 2, CRLF2) 是TRAF2的新型互作蛋白。CRLF2是一种I型跨膜蛋白, 主要作为细胞因子受体参与信号转导, 在多种肿瘤中存在异常表达[8, 9]。LDA可以阻断TRAF2/CRLF2的PPI, 提示LDA靶向TRAF2抗肿瘤的新机制, 并为“难以靶向”的肿瘤相关蛋白提供了新的治疗策略。
材料与方法
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细胞  正常人胚胎肾细胞HEK293T、人结肠癌细胞HCT116和人非小细胞肺癌细胞NCI-H1975均购自中国科学院细胞库。HEK293T细胞使用DMEM培养基培养, HCT116细胞和NCI-H1975细胞均使用RPMI 1640培养基培养, 培养基中均含有10%胎牛血清和1%双抗, 所有细胞均在37 ℃、5% CO2的培养箱中培养。
药物与试剂  二甲基亚砜(DMSO, 货号: D2650)、胎牛血清(货号: F0193)、Duolink PLA试剂(货号: DUO092101) 和抗体IgG (货号: 15381) 均购自德国Sigma公司; LDA (货号: HY-N1451)、Hoechst 33342 (货号: HY-15559)、磷酸酶抑制剂(货号: HY-K0021) 和蛋白酶抑制剂(货号: HY-K0010) 均购自美国Med Chem Express公司; DMEM培养基(货号: C11995500)、RPMI1640培养基(货号: C22400500) 及青霉素-链霉素溶液(货号: 15140122) 均购自美国Gibco Life Technologies生物试剂有限公司; IP裂解缓冲液(货号: 87787) 购自美国Thermo Fisher公司; LipoFiter 3.0 (货号: HB-LF3-1000) 购自HANBIO公司; siRNA Mate Plus (货号: G04026) 购自GenePharma公司; DynabeadsTM蛋白G磁珠(货号: 10004D) 购自美国Promega公司; CCK-8试剂(货号: K1018) 购自美国APExBIO公司; RIPA裂解液(货号: 9806) 及抗体: TRAF2 (货号: 4724)、信号转导和转录激活因子3 (signal transducer and activator of transcription 3, STAT3, 货号: 9137)、pSTAT3 (货号: 9145) 和GAPDH (货号: 60004-1-Ig) 均购自美国Cell Signaling Technology公司; 抗体GFP (货号: 66002-1-IgG) 和抗体GFP (货号: 50430-2-AP) 均购自中国Proteintech公司; 抗体CRLF2 (货号: A10152) 购自中国ABclonal公司; 4%多聚甲醛固定液(货号: P0099-3L)、免疫染色通透液(货号: P0095) 和PBS缓冲液(货号: ST476) 均购自上海碧云天生物技术有限公司。
质粒  与mCherry基因融合的Flag标记的TRAF2质粒, 以及所有GFP融合基因的质粒均基于mEmerald-Calreticulin-N-16制备, 由南京GenScript Biotechnology公司制作。
仪器  Spark多功能酶标仪(美国TECAN公司); TCS SP8单光子激光共聚焦显微镜(德国徕卡公司); ChemiDoc MP核酸凝胶及蛋白质印迹成像系统(美国Bio-Rad公司)。
细胞转染  在质粒转染前, 细胞需培养24 h到50%密度。按照制造商操作指南, 使用LipoFiter 3.0进行转染, 根据以下比例配制质粒转染混合液: 100 μL基础培养基、1 μg质粒和2 μL Lipo3.0, 轻轻混匀, 室温孵育15 min后缓慢且均匀地加入细胞中, 培养6 h后更换新鲜培养基, 转染24 h后进行后续实验。对于siRNA的转染, 使用GenePharma公司合成的小干扰RNA (siRNA), 通过siRNA Mate Plus试剂进行转染, 严格遵循标准化操作流程。基因敲低效果通过蛋白质水平验证。TRAF2基因的siRNA靶向序列是5'-GUCAAGACUUGUG GCAAGUTT-3', CRLF2基因的siRNA靶向序列是5'-GAUGCCGAGAAGUG UUACUTT-3'。
荧光共振能量转移实验(fluorescence resonance energy transfer, FRET)  FRET效率的测定采用受体漂白法。向HEK293T细胞中同时转染GFP和mCherry标记蛋白。颗粒形成后, 使用配备Leica FRET AB模块的Leica Stellaris 5显微镜进行成像。具体操作如下: 首先选定颗粒内的目标区域(ROI), 使用561 nm激光(设置为100%强度, 连续漂白3次) 对受体(mCherry) 进行光漂白。在光漂白前后分别采集两个通道的图像。所有实验均选取至少5个独立细胞中的约10个颗粒进行测量, FRET效率计算公式为FRET efficiency = (Dpost - Dpre) /Dpost, 其中Dpre和Dpost分别表示光漂白前后的供体(GFP) 荧光强度。
免疫共沉淀实验(co-immunoprecipitation, Co-IP)  将等密度的细胞接种在2个6 cm培养皿中, 细胞密度达到80%时, 分别给予LDA 10 μmol·L-1和等体积的DMSO处理12 h。然后用含有蛋白酶抑制剂和磷酸酶抑制剂的IP裂解缓冲液裂解细胞, 冰上裂解30 min, 在4 ℃、14 000 r·min-1的条件下离心15 min。取蛋白上清液进行BCA定量, 根据蛋白浓度取适量的蛋白加入5×SDS缓冲液, 于100 ℃金属浴加热10 min进行Input组样品制备; 取出1 mg蛋白裂解液与一抗在4 ℃旋转器上孵育12 h, 然后与蛋白G磁珠在4 ℃旋转器上孵育3 h。通过磁力架将磁珠复合物分离, 并用0.02% PBST缓冲液洗涤磁珠5次, 最后将从磁珠复合物上洗脱下的液体收集到新的EP管中, 加入5×SDS缓冲液, 于100 ℃金属浴中加热10 min进行IP组样品制备。平行使用小鼠IgG抗体作为阴性对照, 然后进行SDS-PAGE和Western blot分析。
邻位连接实验(proximity ligation assay, PLA)  将等密度的细胞接种于共聚焦皿中, 贴壁24 h后, 分别给予LDA 10 μmol·L-1和等体积的DMSO处理12 h。然后用1×PBS缓冲液洗涤细胞, 4%多聚甲醛固定10 min, 细胞免疫染色通透液通透10 min, 每个步骤间用1×PBS缓冲液洗涤, PLA封闭液37 ℃封闭1 h后, 4 ℃孵育一抗12 h。然后按照Sigma-Aldrich提供的步骤操作, 用单光子激光共聚焦显微镜拍照成像。
Western blot实验  用含有蛋白酶抑制剂和磷酸酶抑制剂的RIPA裂解液裂解细胞, 冰上裂解30 min后, 在4 ℃、14 000 r·min-1的条件下离心15 min。取蛋白的上清液进行BCA定量, 根据蛋白浓度取适量的蛋白加入5×SDS缓冲液, 置于100 ℃金属浴中加热10 min, 进行样品制备。每个样品以20 μg蛋白量进行电泳后转移到PVDF膜上, 5%脱脂奶粉室温封闭1 h, 依次孵育一抗和二抗, 化学发光法检测条带。
克隆形成实验(colony formation)  将细胞以每孔500个的密度接种于24孔板中。铺板第二天更换培养基同时给予LDA (10 μmol·L-1) 处理。每3天更换培养基同时给予LDA处理。经LDA处理9天后收板, 用1×PBS缓冲液洗涤细胞, 用4%多聚甲醛固定10 min, 1×PBS缓冲液洗弃后, 用结晶紫溶液染色10 min, 1×PBS缓冲液润洗并干燥后, 扫描图像。
CCK8实验  将NCI-H1975细胞接种至96孔板中, 使每孔细胞数为1×104个, 等细胞贴壁24 h后给予LDA处理, LDA终浓度为0.312 5、0.625、1.25、2.5、5、10、20、40、80 μmol·L-1, 对照组加入等量DMSO。给药48 h后, 每孔按培养基∶CCK8试剂= 10∶1的比例加入CCK8试剂, 37 ℃孵育约1 h, 孵育完成后使用酶标仪在450 nm波长下测定各孔的吸光度(A) 值。通过公式“细胞活力(%) = (A实验组-A空白组) / (A对照组-A空白组) ×100%”计算细胞活力。
统计学方法  所有数据统计分析均采用Image J软件和GraphPad Prism软件, 数值以$ \overline{x}\pm s $表示, P < 0.05被认为差异具有统计学意义。
结果
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1　CRLF2是TRAF2的新型互作蛋白
为了筛选与TRAF2互作的肿瘤相关蛋白, 本研究基于以下特点选出100个肿瘤相关的关键蛋白: ①蛋白在肿瘤发生过程中的重要性: 肿瘤相关蛋白通过多种途径参与肿瘤发生的各个环节, 其中关键蛋白的功能异常是肿瘤细胞获得增殖、生存、侵袭和转移的核心机制; ②无临床靶向药物: 尽管现有多种靶向药物已被开发用于治疗多种类型的肿瘤, 但仍有大量的肿瘤相关蛋白缺乏有效的临床靶向药物, 选择这些缺乏靶向药物的肿瘤相关蛋白进行深入研究, 有助于发现新的潜在治疗靶点; ③难以靶向: 由于许多肿瘤相关蛋白具有内在的无序区域或缺乏明显的小分子结合口袋等特征, 这些蛋白难以被靶向[10], 研究“难以靶向”的肿瘤相关蛋白为开发创新的抗肿瘤药物提供了新的方向。
本研究采用了共表达方法进行筛选, 将带有mCherry标签的TRAF2 (TRAF2-mCherry) 与带有GFP标签的各肿瘤相关蛋白分别共转染至HEK293T细胞, 通过荧光共定位分析筛选潜在互作蛋白(图1A)。通过筛选发现, 单独转染TRAF2时, TRAF2分布在细胞质; 在共表达条件下, TRAF2与CRLF2在细胞质中存在共定位信号, 且在细胞膜出现明显重叠信号(图1B), 提示CRLF2的存在可影响TRAF2的亚细胞定位, 使其部分分布由胞质向膜相关区域转移。为了验证筛选得到的TRAF2与CRLF2的互作, 本研究通过FRET实验发现TRAF2-mCherry与CRLF2-GFP之间存在较高的荧光共振能量转移效率(图1C、D), 证实外源性TRAF2与CRLF2存在PPI。
在非小细胞肺癌细胞NCI-H1975和结肠癌细胞HCT116上, 通过Co-IP证明两者在细胞内可形成复合物(图1E); 并通过PLA验证了TRAF2与CRLF2的内源性蛋白相互作用(图1F)。以上结果证明, 在肺癌和结肠癌细胞中存在TRAF2/CRLF2的PPI。
2　LDA抑制TRAF2/CRLF2蛋白互作
LDA是TRAF2的直接靶向小分子, 属于五环三萜类化合物(图2A), 且能阻断与TRAF2互作蛋白的PPI[6, 7]。为了研究LDA是否对TRAF2/CRLF2的蛋白互作具有调控作用, 本研究首先采用FRET实验, 在HEK293T细胞中共表达TRAF2-mCherry与CRLF2-GFP, 分别给予LDA (5、10和20 μmol·L-1) 处理后, TRAF2/CRLF2的荧光共振能量转移效率较DMSO组均显著降低(图2B、C), 提示LDA可直接抑制TRAF2/CRLF2的蛋白互作。
随后, 在NCI-H1975和HCT116细胞上, PLA和Co-IP结果显示, 给予LDA 10 μmol·L-1处理后可显著抑制TRAF2/CRLF2的蛋白互作(图2D、E)。以上结果表明, LDA对内源性及外源性TRAF2/CRLF2的蛋白互作均有抑制作用。
3　CRLF2结合在TRAF2-TRAF结构域且被LDA特异性阻断
为了明确TRAF2/CRLF2的具体结合位点, 本研究构建了TRAF2全长(TRAF2-FL) 及不同功能结构域的截断体: TRAF2-M1 (1~97, ring结构域)、TRAF2-M2 (98~250, 锌指结构域) 和TRAF2-M3 (251~501, TRAF结构域) (图3A)。将各TRAF2截断体分别与CRLF2共转染至HEK293T细胞后, 通过Co-IP实验检测发现, 在转入TRAF2全长及TRAF结构域截短体的样本中, 可免疫沉淀出CRLF2, 说明CRLF2与TRAF2的结合主要依赖于TRAF2的C端TRAF结构域(图3B)。
前期研究证实, LDA结合在TRAF2-TRAF结构域[6], 为探究LDA是否能阻断TRAF2-TRAF结合位点与CRLF2互作, 本研究将CRLF2-mCherry分别与TRAF2-FL及TRAF结构域共同转染至HEK293T细胞36 h后, 再给予LDA 10 μmol·L-1处理12 h, 进行Co-IP实验。结果显示, 与对照组相比, LDA显著减弱CRLF2与TRAF2全长及TRAF结构域的互作(图3C、D), 证明LDA可特异性地阻断CRLF2与TRAF2的TRAF结构域之间的结合。
4　LDA通过抑制STAT3信号通路发挥抗肺癌活性
作为胸腺基质淋巴细胞生成素(thymic stromal lymphopoietin, TSLP) 的关键受体[11, 12], CRLF2可招募并磷酸化JAK家族激酶, 进而磷酸化STAT3, 最终通过pSTAT3入核调控靶基因表达[8]。在肺癌中, STAT3信号通路常处于持续活化状态[13], 其过度激活会显著促进肺癌细胞的增殖、抗凋亡及转移能力, 因此成为肺癌治疗的重要干预靶点。
为了探究LDA抗肺癌的作用, 本研究通过多细胞克隆形成实验对小分子作用于肺癌细胞的增殖情况进行了观察, NCI-H460/HCC827/NCI-H1975细胞经LDA (2.5、5和10 μmol·L-1) 处理, 发现LDA对非小细胞肺癌细胞NCI-H1975具有特异性抑制作用(图4A)。进一步通过CCK8实验发现, NCI-H1975细胞在LDA处理后细胞活力降低(图4B), 表明LDA可有效抑制NCI-H1975细胞的增殖能力。本研究进一步探究LDA对STAT3信号通路的调控作用。将NCI-H1975细胞经LDA 10 μmol·L-1处理12 h后, 通过Western blot检测发现, 细胞内STAT3的磷酸化水平较对照组显著降低, 而总STAT3蛋白水平无明显变化(图4C), 表明LDA可通过抑制STAT3的磷酸化过程, 直接阻断STAT3信号通路的激活。
为明确LDA对STAT3信号通路的抑制是否依赖TRAF2和CRLF2的互作, 本研究进一步开展了基因敲低实验。在NCI-H1975细胞中通过siRNA分别敲低TRAF2和CRLF2后, 再经LDA 10 μmol·L-1处理12 h后, 结果显示: 与siNC组相比, 敲低TRAF2后, STAT3的磷酸化水平下降, 且LDA对pSTAT3的抑制作用显著降低(图4D); 类似地, 敲低CRLF2后, STAT3的磷酸化水平亦显著下降, 在此背景下LDA对pSTAT3的抑制作用明显受损(图4E)。上述结果表明, TRAF2与CRLF2的互作参与下游STAT3的磷酸化, 且LDA对STAT3信号通路的调控作用, 需以TRAF2与CRLF2的正常表达及互作轴的完整性为前提, 即LDA抑制STAT3信号通路依赖于TRAF2/CRLF2的蛋白互作(图4F)。
讨论
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近年来, 越来越多的研究关注“不可成药”靶点的药物干预策略。这类蛋白多存在结构无序、缺乏小分子结合口袋等特点, 传统药物难以直接作用, 成为肿瘤治疗中的重要挑战[14-16]。TRAF2是典型的信号适配体蛋白, 通过其C端TRAF结构域介导多种蛋白互作, 参与NF-κB、MAPK及JAK/STAT等关键信号通路[2-4, 17], 在多种肿瘤中呈现异常激活状态, 是潜在的治疗靶点。尽管TRAF2本身缺乏酶活性, 但其“衔接子”功能使其在调控复杂信号网络中具有关键地位。
本研究基于TRAF2广泛的蛋白互作特性, 从100个“难以靶向”的肿瘤相关蛋白中筛选发现CRLF2为其新型互作蛋白, 且该互作依赖于TRAF结构域。CRLF2作为TSLP受体复合体的重要组成部分, 可激活JAK家族激酶并启动STAT3信号通路, 其在多种肿瘤中存在异常表达[8, 9, 11-13]。前期研究发现, LDA为首个直接靶向TRAF2的小分子, 具有显著抗肿瘤活性[6]。本研究进一步证实LDA通过结合TRAF2的TRAF结构域, 阻断其与CRLF2之间的蛋白互作, 进而抑制STAT3的磷酸化, 最终发挥抗肺癌作用。
值得强调的是, LDA并未直接作用于CRLF2或STAT3, 而是通过靶向TRAF2这一“衔接蛋白”间接调控下游信号通路, 展示了小分子破坏关键PPI来干预“不可成药”靶点的可行性与优势, 拓展了抗肿瘤药物设计的新思路[14]。该策略为中药来源的天然小分子在复杂信号网络中的作用机制提供了理论支持, 也为未来“难靶点”抗肿瘤药物的研发提供了新的方向。
然而, 本研究尚存在一定局限: 目前数据主要基于细胞模型, TRAF2/CRLF2/STAT3轴在体内肿瘤模型中的功能与机制仍有待进一步验证; 此外, TRAF2的互作网络较为庞大, 尽管本研究已经发现LDA对CRLF2/TRAF2互作的抑制作用, 但是否存在其他蛋白通过与TRAF2相互作用而调控STAT3活性, 及其在肿瘤信号网络中的相对贡献, 仍需在后续研究中进一步探讨。

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doi: 10.16438/j.0513-4870.2025-1535
  • 接收时间：2025-12-21
  • 首发时间：2026-09-21
  • 出版时间：2026-08-12
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  • 收稿日期：2025-12-21
  • 修回日期：2026-03-13
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    上海中医药大学交叉科学研究院, 上海 201203

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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
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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
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