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Article(id=1320440940049843091, tenantId=1146029695717560320, journalId=1319373162502258839, issueId=1320440935603880850, articleNumber=null, orderNo=null, doi=10.16016/j.2097-0927.202510068, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1761148800000, receivedDateStr=2025-10-23, revisedDate=1768838400000, revisedDateStr=2026-01-20, acceptedDate=null, acceptedDateStr=null, onlineDate=1792747252713, onlineDateStr=2026-10-23, pubDate=1773504000000, pubDateStr=2026-03-15, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1792747252713, onlineIssueDateStr=2026-10-23, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1792747252713, creator=13701087609, updateTime=1792747252713, updator=13701087609, issue=Issue{id=1320440935603880850, tenantId=1146029695717560320, journalId=1319373162502258839, year='2026', volume='48', issue='5', pageStart='523', pageEnd='662', issueExtLink='null', onlineDate='null', pubDate='1773504000000', pubDateStr='2026-03-15', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1792747251654, creator='13701087609', updateTime=1792749737175, updator='13701087609', preIssue=null, nextIssue=null, articleTotal=null, ext={EN=IssueExt(id=1320451360810713528, tenantId=1146029695717560320, journalId=1319373162502258839, issueId=1320440935603880850, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1320451360810713529, tenantId=1146029695717560320, journalId=1319373162502258839, issueId=1320440935603880850, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null, downloadFileDto=null}, startPage=530, endPage=542, ext={EN=ArticleExt(id=1320440940989367188, articleId=1320440940049843091, tenantId=1146029695717560320, journalId=1319373162502258839, language=EN, title=IL-1β serves as a biomarker for poor prognosis in osteosarcoma and drives tumor cell proliferation through the IL-1R1/NF-κB signaling axis, columnId=1320434418116837551, journalTitle=Journal of Army Medical University, columnName=Basic Medicine, runingTitle=null, highlight=null, articleAbstract=
Objective

To investigate the expression profile of interleukin-1β (IL-1β) in osteosarcoma tissues, explore its correlation with clinical prognosis, and to elucidate the underlying molecular mechanisms of IL-1β regulating the proliferation of osteosarcoma cells.

Methods

Four osteosarcoma patients admitted to Department of Orthopedics of our hospital from December 2020 to January 2024 were enrolled, and their tumor and adjacent tissues were collected to detect differential mRNA and protein expression of IL-1β by immunohistochemistry, reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR), and Western blotting. Additionally, 15 paraffin-embedded osteosarcoma specimens collected between March 2018 and August 2021 were immunohistochemically stained and scored using ImageJ, and then divided into high IL-1β expression group (3+, 2+) and low expression group (1+, 0). Kaplan-Meier analysis was used to determine the association between the scoring results and patient survival rates. In in vitro experiments, osteosarcoma cell line U2OS was subjected and treated with 0 to 100 ng/mL recombinant IL-1β protein. EdU incorporation assay, flow cytometry, CCK-8 assay and colony formation assay were performed to screen the optimal proliferation-stimulating concentration. Transcriptome sequencing was carried out on the U2OS cells with 40 ng/mL IL-1β treatment and untreated cells to analyze significantly up-regulated signals involved in regulating U2OS proliferation. The obtained key regulatory molecule, nuclear factor kappa B (NF-κB) was then verified by RT-qPCR, Western blotting, and immunofluorescence staining. After IL-1 receptor type 1 (IL-1R1) was knocked down by lentiviral transfection, or the cells were treated with NF-κB inhibitor embelin, the changes in cell proliferation were detected with EdU incorporation assay, flow cytometry, CCK-8 assay, and colony formation assay. In in vivo experiments, 12 female nude mice (5 weeks old) were randomly divided into control group, IL-1R1 knockdown group, and IL-1R1 inhibitor (anakinra) injection group, with 4 animals in each group. An orthotopic osteosarcoma model was established by intratibial injection, and tumor growth was compared across groups.

Results

Immunohistochemical staining and survival analysis demonstrated that osteosarcoma patients with high IL-1β expression level had poorer prognosis (P<0.05). In vitro experiments showed that IL-1β treatment significantly increased the EdU incorporation rate (P<0.05), enhanced G2/M cell cycle arrest (P<0.05), and improved the colony formation ability (P<0.05) in U2OS cells, indicating that IL-1β promotes osteosarcoma cell proliferation. Transcriptome data analysis revealed 4 165 differentially expressed genes (1 688 up-regulated and 2 477 down-regulated) between IL-1β-treated and untreated U2OS cells. IL-1β treatment obviously promoted cell cycle and up-regulated the proteins related to NF-κB signaling pathway in U2OS cells. RT-qPCR confirmed the mRNA levels of cell cycle-related molecules were enhanced by IL-1β treatment, which was further confirmed by Western blotting at protein level. IL-1R1 knockdown resulted in notably decreased proliferation ability in U2OS cells compared with the control cells (P<0.05). Both RT-qPCR and Western blotting confirmed that IL-1R1 knockdown reduced the expression levels of cell cycle-related proteins and NF-κB. Addition of NF-κB inhibitor, embelin, significantly inhibited the IL-1β-induced EdU incorporation rate (P<0.05), G2/M phase arrest (P<0.05), and colony formation ability (P<0.05) in U2OS cells, and suppressed the expression of cell cycle-related proteins. In vivo experimental results showed that the tumor weight in the IL-1R1 knockdown group (0.75±0.10 g) and anakinra injection group (0.93±0.06 g) was statistically lower than that in the control group (1.46±0.09 g) (both P<0.05).

Conclusion

Intratumoral IL-1β level is positively correlated with poor prognosis in osteosarcoma patients. IL-1β promotes the proliferation ability of osteosarcoma cells through the IL-1R1/NF-κB signaling axis.

, authors=Chuanchuan LIN, Yonghao YANG, Jiawu YU, Zhongjun LI, Qian RAN, Yang XIANG, authorsList=Chuanchuan LIN, Yonghao YANG, Jiawu YU, Zhongjun LI, Qian RAN, Yang XIANG, authorCompany=null, correspAuthors=Yang XIANG, authorNote=null, correspAuthorsNote=null, copyrightStatement=© 2026 Journal of Army Medical University, copyrightOwner=Editorial Office of Journal of Army Medical University, 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=1320440951034725285, articleId=1320440940049843091, tenantId=1146029695717560320, journalId=1319373162502258839, language=CN, title=IL-1β作为骨肉瘤不良预后的生物标志物并通过IL-1R1/NF-κB信号轴驱动肿瘤细胞增殖, columnId=1320434418343329969, journalTitle=陆军军医大学学报, columnName=论著·基础医学, runingTitle=null, highlight=null, articleAbstract=
目的

解析骨肉瘤组织中白介素-1β（interleukin-1β，IL-1β）的表达特征，揭示其表达水平与患者临床预后的关联性，并阐明IL-1β在调控骨肉瘤细胞增殖中的核心分子机制。

方法

收集2020年12月至2024年1月陆军军医大学第二附属医院骨科收治的4例骨肉瘤患者的肿瘤及癌旁组织，通过免疫组化、实时荧光定量反转录聚合酶链式反应（reverse transcription quantitative real-time polymerase chain reaction，RT-qPCR）和Western blot检测IL-1β的mRNA和蛋白表达差异；另收集2018年3月至2021年8月期间15例骨肉瘤石蜡标本，经免疫组化染色及Image J软件评分后分为IL-1β高表达组（3+、2+）和低表达组（1+、0）；采用Kaplan-Meier法分析评分高低与患者生存率的关联。在体外实验中，以0~100 ng/mL IL-1β重组蛋白处理骨肉瘤细胞系U2OS后，通过EdU掺入、流式细胞术、CCK-8实验及单克隆形成实验筛选最佳增殖刺激浓度；对40 ng/mL IL-1β重组蛋白处理和未处理的U2OS细胞进行转录组测序，分析重组蛋白处理调控U2OS增殖的显著上调信号，并结合RT-qPCR、Western blot、免疫荧光染色验证关键调控分子核因子κB（nuclear factor kappa B，NF-κB）。通过慢病毒转染敲低IL-1受体1（interleukin-1 receptor type 1，IL-1R1）；或者以NF-κB抑制剂恩贝林（embelin）处理后，采用EdU掺入实验、流式细胞术、CCK-8实验和单克隆形成实验检测各组细胞增殖变化。体内实验：将12只5周龄雌性裸鼠随机分为3组：对照组、IL-1R1敲低组和IL-1R1抑制剂（阿那白滞素）注射组，每组4只，采用胫骨髓内注射原位骨肉瘤模型，比较各组肿瘤生长情况。

结果

免疫组化染色和生存分析表明，IL-1β高表达骨肉瘤患者的临床预后较差（P<0.05）。体外细胞实验表明，与未处理组相比，IL-1β处理可显著提高骨肉瘤细胞系U2OS的EdU掺入比例（P<0.05）、增加细胞周期G2/M期占比（P<0.05）、提高单克隆形成能力（P<0.05），表明IL-1β可上调骨肉瘤细胞增殖能力。分析转录组数据表明，IL-1β处理与未处理组之间共存在4 165个差异表达基因，包括1 688个上调表达基因和2 477个下调表达基因；IL-1β可显著上调U2OS中细胞周期和NF-κB信号通路。RT-qPCR结果表明IL-1β处理可显著上调细胞周期相关分子在mRNA水平的表达，该结果在蛋白水平上得到进一步证实。敲低IL-1R1后，与敲低对照组比较，U2OS的增殖能力明显下降（P<0.05），且RT-qPCR和Western blot数据均证实敲低IL-1R1降低了细胞周期相关蛋白和NF-κB的表达水平。Embelin的加入能够显著抑制IL-1β诱导的U2OS细胞中EdU掺入比例（P<0.05）、细胞周期G2/M期占比（P<0.01）和单克隆形成能力（P<0.05），同时抑制细胞周期相关蛋白的表达。动物实验结果表明，敲低IL-1R1组［（0.75±0.10）g， P<0.05］和阿那白滞素注射组［（0.93±0.06）g， P<0.05］小鼠肿瘤质量显著低于对照组（1.46±0.09）g。

结论

临床上IL-1β的瘤内水平与骨肉瘤患者的不良预后呈正相关；IL-1β通过IL-1R1/NF-κB信号轴上调骨肉瘤细胞的增殖能力。

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向 阳，E-mail：
XIANG Yang， E-mail：
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A： Representative images of immunohistochemical staining of IL-1β in osteosarcoma sections； B： High IL-1β expression is correlated with poor patient survival （n=15）； C and D： mRNA levels of IL-1β（C） and IL-1R1（D）in para-cancerous vs tumor tissues （n=3， x¯±s）； E： Protein abundances of IL-1R1 and IL-1β in para-cancerous vs tumor tissues

, figureFileSmall=VchDyZNk7FFllsvbOImR6g==, figureFileBig=pD9CMDNRzs80BwEVHWGdpQ==, tableContent=null), ArticleFig(id=1320440966213911510, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1320440940049843091, language=EN, label=Figure 2, caption=IL-1β treatment promotes the proliferation of osteosarcoma U2OS cells, figureFileSmall=gOGkJ77toNtRSeFM/pvdBQ==, figureFileBig=kXdCG01lb0RhmyGuDMKqGw==, tableContent=null), ArticleFig(id=1320440966574621655, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1320440940049843091, language=CN, label=图2, caption=IL-1β处理促进骨肉瘤细胞U2OS增殖

A： Representative images of EdU-positive U2OS cells treated with recombinant IL-1β protein at different concentrations； B： Proportion of EdU-positive U2OS cells after IL-1β treatment （n=5， x¯±s）； C： Cell cycle profiles of U2OS cells treated with different concentrations of IL-1β； D： Cell cycle distribution of U2OS cells after IL-1β treatment （n=3， x¯±s）； E： Colony formation of U2OS cells after IL-1β treatment； F： Cell viability of U2OS cells after IL-1β treatment （n=8， x¯±s）

, figureFileSmall=gOGkJ77toNtRSeFM/pvdBQ==, figureFileBig=kXdCG01lb0RhmyGuDMKqGw==, tableContent=null), ArticleFig(id=1320440966918554584, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1320440940049843091, language=EN, label=Figure 3, caption=IL-1β treatment significantly activates cell cycle and NF-κB-enriched signaling in U2OS cells, figureFileSmall=3lBOTtehbhVHd298v1Ytvw==, figureFileBig=2Xwk59AjCw+lXOAMnHJMgQ==, tableContent=null), ArticleFig(id=1320440967006634969, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1320440940049843091, language=CN, label=图3, caption=IL-1β处理显著激活U2OS细胞周期及NF-κB富集信号

A： Hierarchical clustering heatmap of differential expression genes （DEGs） in U2OS cells； B： Volcano plot of gene expression in U2OS cells； C： Gene Ontology enrichment bubble plot of DEGs in U2OS cells； D： Heatmap of DEGs enriched in cell cycle signaling pathway in U2OS cells； E： mRNA levels of key cell cycle molecules in U2OS cells detected by RT-qPCR （n=3， x¯±s）； F： Heatmap of DEGs enriched in NF-κB signaling pathway in U2OS cells； G： NF-κB mRNA levels in para-cancerous （N） and tumor （T） tissues of osteosarcoma patients detected by RT-qPCR （n=3， x¯±s）； H： NF-κB protein levels in para-cancerous （N） and tumor （T） tissues detected by Western blotting

, figureFileSmall=3lBOTtehbhVHd298v1Ytvw==, figureFileBig=2Xwk59AjCw+lXOAMnHJMgQ==, tableContent=null), ArticleFig(id=1320440967329596378, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1320440940049843091, language=EN, label=Figure 4, caption=IL-1R1 knockdown inhibits cell proliferation, figureFileSmall=fr1x9/7qf8eO4TgsXsFuWw==, figureFileBig=MNHFvbxXs14f5eS6kbX3dQ==, tableContent=null), ArticleFig(id=1320440969015706588, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1320440940049843091, language=CN, label=图4, caption=IL-1R1敲低抑制细胞增殖

A： Validation of IL-1R1 knockout in U2OS cells by RT-qPCR and Western blot （n=4， x¯±s）； B： EdU-positive U2OS cells after different treatments； C： Proportion of EdU-positive U2OS cells after different treatments （n=5， x¯±s）； D： Cell cycle distribution plots of U2OS cells after different treatments； E： Cell cycle distribution of U2OS cells after different treatments （n=3， x¯±s）； F： Colony formation of U2OS cells after different treatments； G： Cell viability of U2OS cells after different treatments （n=8， x¯±s）； H： mRNA levels of key cell cycle molecules in U2OS cells of different treatment groups （n=3， x¯±s）； I： Expression of cell cycle-related proteins and NF-κB p65 in U2OS cells of different treatment groups

, figureFileSmall=fr1x9/7qf8eO4TgsXsFuWw==, figureFileBig=MNHFvbxXs14f5eS6kbX3dQ==, tableContent=null), ArticleFig(id=1320440969137341405, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1320440940049843091, language=EN, label=Figure 5, caption=Embelin inhibits IL-1β-induced cell proliferation, figureFileSmall=Qhi/ZqeBt/hO5wB1fOpgMg==, figureFileBig=qBX4tfI+uzwVUdh3IuB6fQ==, tableContent=null), ArticleFig(id=1320440969854567390, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1320440940049843091, language=CN, label=图5, caption=Embelin抑制IL-1β诱导的细胞增殖

A： Effects of IL-1β and embelin treatment on NF-κB p65 and p-NF-κB p65 levels in U2OS cells； B： EdU-positive U2OS cells after different treatments； C： Proportion of EdU-positive U2OS cells after different treatments （n=5， x¯±s）； D： Cell cycle profiles of U2OS cells after different treatments； E： Cell cycle distribution of U2OS cells after different treatments （n=3， x¯±s）； F： Colony formation of U2OS cells after different treatments； G： Cell viability of U2OS cells after different treatments （n=8， x¯±s）； H： Expression of cell cycle-related proteins in U2OS cells of different treatment groups

, figureFileSmall=Qhi/ZqeBt/hO5wB1fOpgMg==, figureFileBig=qBX4tfI+uzwVUdh3IuB6fQ==, tableContent=null), ArticleFig(id=1320440969917481951, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1320440940049843091, language=EN, label=Figure 6, caption=In vivo blockade of IL-1β signaling effectively reduces osteosarcoma tumor growth, figureFileSmall=f3VPEiwOYeIN3MfaLrA6lw==, figureFileBig=VmfkxNrO1vin0fkmM1x9aA==, tableContent=null), ArticleFig(id=1320440970253026272, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1320440940049843091, language=CN, label=图6, caption=体内阻断IL-1β信号可有效降低骨肉瘤瘤体生长

A： Flowchart of the experimental procedure； B： Gross observation of osteosarcoma in the tibia of nude mice after different treatments； C： Tumor weight of osteosarcoma in nude mice after different treatments； D： Representative images of HE stained osteosarcoma tissues in different groups

, figureFileSmall=f3VPEiwOYeIN3MfaLrA6lw==, figureFileBig=VmfkxNrO1vin0fkmM1x9aA==, tableContent=null), ArticleFig(id=1320440970328523745, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1320440940049843091, language=EN, label=Table 1, caption=

Primer sequences for qPCR

, figureFileSmall=null, figureFileBig=null, tableContent=
GenePrimer sequence（5′→3′）
IL-1BForward：ATGATGGCTTATTACAGTGGCAA
Reverse：GTCGGAGATTCGTAGCTGGA
IL-1R1Forward：ATGAAATTGATGTTCGTCCCTGT
Reverse：ACCACGCAATAGTAATGTCCTG
NF-κBForward：AACAGAGAGGATTTCGTTTCCG
Reverse：TTTGACCTGAGGGTAAGACTTCT
PCNAForward：CCTGCTGGGATATTAGCTCCA
Reverse：CAGCGGTAGGTGTCGAAGC
CHEK1Forward：ATATGAAGCGTGCCGTAGACT
Reverse：TGCCTATGTCTGGCTCTATTCTG
CDC7Forward：GAGGCGTCTTTGGGGATTCAG
Reverse：GGTCCTACTTGTAACTGTGCTG
CCNE2Forward：TCAAGACGAAGTAGCCGTTTAC
Reverse：TGACATCCTGGGTAGTTTTCCTC
CDC6Forward：CCAGGCACAGGCTACAATCAG
Reverse：AACAGGTTACGGTTTGGACATT
CDKN2DForward：AGTCCAGTCCATGACGCAG
Reverse：ATCAGGCACGTTGACATCAGC
CDC25AForward：GTGAAGGCGCTATTTGGCG
Reverse：TGGTTGCTCATAATCACTGCC
CDC25BForward：ACGCACCTATCCCTGTCTC
Reverse：CTGGAAGCGTCTGATGGCAA
CDC25CForward：TCTACGGAACTCTTCTCATCCAC
Reverse：TCCAGGAGCAGGTTTAACATTTT
CDK1Forward：AAACTACAGGTCAAGTGGTAGCC
Reverse：TCCTGCATAAGCACATCCTGA
CDK2Forward：CCAGGAGTTACTTCTATGCCTGA
Reverse：TTCATCCAGGGGAGGTACAAC
CDK4Forward：ATGGCTACCTCTCGATATGAGC
Reverse：CATTGGGGACTCTCACACTCT
CDK6Forward：GCTGACCAGCAGTACGAATG
Reverse：GCACACATCAAACAACCTGACC
E2F1Forward：ACGCTATGAGACCTCACTGAA
Reverse：TCCTGGGTCAACCCCTCAAG
MYCForward：GGCTCCTGGCAAAAGGTCA
Reverse：CTGCGTAGTTGTGCTGATGT
CCND1Forward：GCTGCGAAGTGGAAACCATC
Reverse：CCTCCTTCTGCACACATTTGAA
GAPDHForward：GGAGCGAGATCCCTCCAAAAT
Reverse：GGCTGTTGTCATACTTCTCATGG
), ArticleFig(id=1320440970706011106, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1320440940049843091, language=CN, label=表1, caption=

qPCR引物

, figureFileSmall=null, figureFileBig=null, tableContent=
GenePrimer sequence（5′→3′）
IL-1BForward：ATGATGGCTTATTACAGTGGCAA
Reverse：GTCGGAGATTCGTAGCTGGA
IL-1R1Forward：ATGAAATTGATGTTCGTCCCTGT
Reverse：ACCACGCAATAGTAATGTCCTG
NF-κBForward：AACAGAGAGGATTTCGTTTCCG
Reverse：TTTGACCTGAGGGTAAGACTTCT
PCNAForward：CCTGCTGGGATATTAGCTCCA
Reverse：CAGCGGTAGGTGTCGAAGC
CHEK1Forward：ATATGAAGCGTGCCGTAGACT
Reverse：TGCCTATGTCTGGCTCTATTCTG
CDC7Forward：GAGGCGTCTTTGGGGATTCAG
Reverse：GGTCCTACTTGTAACTGTGCTG
CCNE2Forward：TCAAGACGAAGTAGCCGTTTAC
Reverse：TGACATCCTGGGTAGTTTTCCTC
CDC6Forward：CCAGGCACAGGCTACAATCAG
Reverse：AACAGGTTACGGTTTGGACATT
CDKN2DForward：AGTCCAGTCCATGACGCAG
Reverse：ATCAGGCACGTTGACATCAGC
CDC25AForward：GTGAAGGCGCTATTTGGCG
Reverse：TGGTTGCTCATAATCACTGCC
CDC25BForward：ACGCACCTATCCCTGTCTC
Reverse：CTGGAAGCGTCTGATGGCAA
CDC25CForward：TCTACGGAACTCTTCTCATCCAC
Reverse：TCCAGGAGCAGGTTTAACATTTT
CDK1Forward：AAACTACAGGTCAAGTGGTAGCC
Reverse：TCCTGCATAAGCACATCCTGA
CDK2Forward：CCAGGAGTTACTTCTATGCCTGA
Reverse：TTCATCCAGGGGAGGTACAAC
CDK4Forward：ATGGCTACCTCTCGATATGAGC
Reverse：CATTGGGGACTCTCACACTCT
CDK6Forward：GCTGACCAGCAGTACGAATG
Reverse：GCACACATCAAACAACCTGACC
E2F1Forward：ACGCTATGAGACCTCACTGAA
Reverse：TCCTGGGTCAACCCCTCAAG
MYCForward：GGCTCCTGGCAAAAGGTCA
Reverse：CTGCGTAGTTGTGCTGATGT
CCND1Forward：GCTGCGAAGTGGAAACCATC
Reverse：CCTCCTTCTGCACACATTTGAA
GAPDHForward：GGAGCGAGATCCCTCCAAAAT
Reverse：GGCTGTTGTCATACTTCTCATGG
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IL-1β作为骨肉瘤不良预后的生物标志物并通过IL-1R1/NF-κB信号轴驱动肿瘤细胞增殖
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林川川 , 杨永浩 , 于加武 , 李忠俊 , 冉茜 , 向阳
陆军军医大学学报 | 论著·基础医学 2026,48(5): 530-542
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陆军军医大学学报 |论著·基础医学 2026 , 48 (5) : 530 -542
IL-1β作为骨肉瘤不良预后的生物标志物并通过IL-1R1/NF-κB信号轴驱动肿瘤细胞增殖
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林川川, 杨永浩, 于加武, 李忠俊, 冉茜, 向阳
作者信息
  • 1陆军军医大学（第三军医大学）第二附属医院输血科，教育部骨髓型急性放射综合征医药基础创新中心，重庆
通讯作者:
向 阳，E-mail：
XIANG Yang， E-mail：
IL-1β serves as a biomarker for poor prognosis in osteosarcoma and drives tumor cell proliferation through the IL-1R1/NF-κB signaling axis
Chuanchuan LIN, Yonghao YANG, Jiawu YU, Zhongjun LI, Qian RAN, Yang XIANG
Affiliations
  • 1Department of Blood Transfusion， Hematopoietic Acute Radiation Syndrome Medical and Pharmaceutical Basic Research Innovation Center of Ministry of Education， Second Affiliated Hospital， Army Medical University （Third Military Medical University）， Chongqing， China
出版时间: 2026-03-15 doi: 10.16016/j.2097-0927.202510068
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摘要
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目的

解析骨肉瘤组织中白介素-1β（interleukin-1β，IL-1β）的表达特征，揭示其表达水平与患者临床预后的关联性，并阐明IL-1β在调控骨肉瘤细胞增殖中的核心分子机制。

方法

收集2020年12月至2024年1月陆军军医大学第二附属医院骨科收治的4例骨肉瘤患者的肿瘤及癌旁组织，通过免疫组化、实时荧光定量反转录聚合酶链式反应（reverse transcription quantitative real-time polymerase chain reaction，RT-qPCR）和Western blot检测IL-1β的mRNA和蛋白表达差异；另收集2018年3月至2021年8月期间15例骨肉瘤石蜡标本，经免疫组化染色及Image J软件评分后分为IL-1β高表达组（3+、2+）和低表达组（1+、0）；采用Kaplan-Meier法分析评分高低与患者生存率的关联。在体外实验中，以0~100 ng/mL IL-1β重组蛋白处理骨肉瘤细胞系U2OS后，通过EdU掺入、流式细胞术、CCK-8实验及单克隆形成实验筛选最佳增殖刺激浓度；对40 ng/mL IL-1β重组蛋白处理和未处理的U2OS细胞进行转录组测序，分析重组蛋白处理调控U2OS增殖的显著上调信号，并结合RT-qPCR、Western blot、免疫荧光染色验证关键调控分子核因子κB（nuclear factor kappa B，NF-κB）。通过慢病毒转染敲低IL-1受体1（interleukin-1 receptor type 1，IL-1R1）；或者以NF-κB抑制剂恩贝林（embelin）处理后，采用EdU掺入实验、流式细胞术、CCK-8实验和单克隆形成实验检测各组细胞增殖变化。体内实验：将12只5周龄雌性裸鼠随机分为3组：对照组、IL-1R1敲低组和IL-1R1抑制剂（阿那白滞素）注射组，每组4只，采用胫骨髓内注射原位骨肉瘤模型，比较各组肿瘤生长情况。

结果

免疫组化染色和生存分析表明，IL-1β高表达骨肉瘤患者的临床预后较差（P<0.05）。体外细胞实验表明，与未处理组相比，IL-1β处理可显著提高骨肉瘤细胞系U2OS的EdU掺入比例（P<0.05）、增加细胞周期G2/M期占比（P<0.05）、提高单克隆形成能力（P<0.05），表明IL-1β可上调骨肉瘤细胞增殖能力。分析转录组数据表明，IL-1β处理与未处理组之间共存在4 165个差异表达基因，包括1 688个上调表达基因和2 477个下调表达基因；IL-1β可显著上调U2OS中细胞周期和NF-κB信号通路。RT-qPCR结果表明IL-1β处理可显著上调细胞周期相关分子在mRNA水平的表达，该结果在蛋白水平上得到进一步证实。敲低IL-1R1后，与敲低对照组比较，U2OS的增殖能力明显下降（P<0.05），且RT-qPCR和Western blot数据均证实敲低IL-1R1降低了细胞周期相关蛋白和NF-κB的表达水平。Embelin的加入能够显著抑制IL-1β诱导的U2OS细胞中EdU掺入比例（P<0.05）、细胞周期G2/M期占比（P<0.01）和单克隆形成能力（P<0.05），同时抑制细胞周期相关蛋白的表达。动物实验结果表明，敲低IL-1R1组［（0.75±0.10）g， P<0.05］和阿那白滞素注射组［（0.93±0.06）g， P<0.05］小鼠肿瘤质量显著低于对照组（1.46±0.09）g。

结论

临床上IL-1β的瘤内水平与骨肉瘤患者的不良预后呈正相关；IL-1β通过IL-1R1/NF-κB信号轴上调骨肉瘤细胞的增殖能力。

骨肉瘤  /  白介素1β  /  细胞增殖  /  核因子κB
Objective

To investigate the expression profile of interleukin-1β (IL-1β) in osteosarcoma tissues, explore its correlation with clinical prognosis, and to elucidate the underlying molecular mechanisms of IL-1β regulating the proliferation of osteosarcoma cells.

Methods

Four osteosarcoma patients admitted to Department of Orthopedics of our hospital from December 2020 to January 2024 were enrolled, and their tumor and adjacent tissues were collected to detect differential mRNA and protein expression of IL-1β by immunohistochemistry, reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR), and Western blotting. Additionally, 15 paraffin-embedded osteosarcoma specimens collected between March 2018 and August 2021 were immunohistochemically stained and scored using ImageJ, and then divided into high IL-1β expression group (3+, 2+) and low expression group (1+, 0). Kaplan-Meier analysis was used to determine the association between the scoring results and patient survival rates. In in vitro experiments, osteosarcoma cell line U2OS was subjected and treated with 0 to 100 ng/mL recombinant IL-1β protein. EdU incorporation assay, flow cytometry, CCK-8 assay and colony formation assay were performed to screen the optimal proliferation-stimulating concentration. Transcriptome sequencing was carried out on the U2OS cells with 40 ng/mL IL-1β treatment and untreated cells to analyze significantly up-regulated signals involved in regulating U2OS proliferation. The obtained key regulatory molecule, nuclear factor kappa B (NF-κB) was then verified by RT-qPCR, Western blotting, and immunofluorescence staining. After IL-1 receptor type 1 (IL-1R1) was knocked down by lentiviral transfection, or the cells were treated with NF-κB inhibitor embelin, the changes in cell proliferation were detected with EdU incorporation assay, flow cytometry, CCK-8 assay, and colony formation assay. In in vivo experiments, 12 female nude mice (5 weeks old) were randomly divided into control group, IL-1R1 knockdown group, and IL-1R1 inhibitor (anakinra) injection group, with 4 animals in each group. An orthotopic osteosarcoma model was established by intratibial injection, and tumor growth was compared across groups.

Results

Immunohistochemical staining and survival analysis demonstrated that osteosarcoma patients with high IL-1β expression level had poorer prognosis (P<0.05). In vitro experiments showed that IL-1β treatment significantly increased the EdU incorporation rate (P<0.05), enhanced G2/M cell cycle arrest (P<0.05), and improved the colony formation ability (P<0.05) in U2OS cells, indicating that IL-1β promotes osteosarcoma cell proliferation. Transcriptome data analysis revealed 4 165 differentially expressed genes (1 688 up-regulated and 2 477 down-regulated) between IL-1β-treated and untreated U2OS cells. IL-1β treatment obviously promoted cell cycle and up-regulated the proteins related to NF-κB signaling pathway in U2OS cells. RT-qPCR confirmed the mRNA levels of cell cycle-related molecules were enhanced by IL-1β treatment, which was further confirmed by Western blotting at protein level. IL-1R1 knockdown resulted in notably decreased proliferation ability in U2OS cells compared with the control cells (P<0.05). Both RT-qPCR and Western blotting confirmed that IL-1R1 knockdown reduced the expression levels of cell cycle-related proteins and NF-κB. Addition of NF-κB inhibitor, embelin, significantly inhibited the IL-1β-induced EdU incorporation rate (P<0.05), G2/M phase arrest (P<0.05), and colony formation ability (P<0.05) in U2OS cells, and suppressed the expression of cell cycle-related proteins. In vivo experimental results showed that the tumor weight in the IL-1R1 knockdown group (0.75±0.10 g) and anakinra injection group (0.93±0.06 g) was statistically lower than that in the control group (1.46±0.09 g) (both P<0.05).

Conclusion

Intratumoral IL-1β level is positively correlated with poor prognosis in osteosarcoma patients. IL-1β promotes the proliferation ability of osteosarcoma cells through the IL-1R1/NF-κB signaling axis.

osteosarcoma  /  interleukin-1β  /  cell proliferation  /  NF-κB
林川川, 杨永浩, 于加武, 李忠俊, 冉茜, 向阳. IL-1β作为骨肉瘤不良预后的生物标志物并通过IL-1R1/NF-κB信号轴驱动肿瘤细胞增殖. 陆军军医大学学报, 2026 , 48 (5) : 530 -542 . DOI: 10.16016/j.2097-0927.202510068
Chuanchuan LIN, Yonghao YANG, Jiawu YU, Zhongjun LI, Qian RAN, Yang XIANG. IL-1β serves as a biomarker for poor prognosis in osteosarcoma and drives tumor cell proliferation through the IL-1R1/NF-κB signaling axis[J]. Journal of Army Medical University, 2026 , 48 (5) : 530 -542 . DOI: 10.16016/j.2097-0927.202510068
正文
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骨肉瘤（osteosarcoma，OS）是高发于青少年的原发性骨恶性肿瘤，不仅严重威胁患者生命健康，更因肿瘤好发于四肢骨骼而导致肢体功能障碍，常须通过截肢手术控制病情，为患者带来生理及心理的双重负担。在临床治疗中，尽管当前已经形成了化疗、手术切除及辅助放疗的标准化治疗模式，但受限于肿瘤细胞对于放化疗的耐受性，治疗效果均不理想，转移患者的5年生存率低于30%。骨肉瘤的发生与进展过程复杂，主要涉及遗传易感性和环境风险因素，其机制有待进一步阐明［1］。因此，揭示推动骨肉瘤发生发展的关键分子机制，明确具有临床转化价值的调控靶点，已成为当前骨肉瘤基础研究与临床转化领域的核心需求。
白介素-1β（interleukin-1β，IL-1β）作为白介素-1（interleukin-1， IL-1）家族中最具代表性的促炎因子，是介导炎症反应与免疫调节的核心分子，其生物学功能主要通过与细胞膜表面的IL-1受体1（interleukin-1 receptor 1， IL-1R1）结合，激活下游信号通路。近年来，多项研究证实IL-1β在癌症进展中扮演“促癌因子”角色［2］，如在乳腺癌、肺癌和胰腺癌等相关疾病中，IL-1β可通过促进肿瘤细胞增殖、上皮-间质转化等方式加快转移过程［3-5］。与此同时，IL-1β的特异性拮抗剂，阿那白滞素（anakinra）可通过竞争性结合IL-1R1，阻断IL-1β介导的信号通路激活，也被大量用于多种肿瘤的临床前研究，且展现出良好的应用前景［6-7］。这些研究结果为IL-1β拮抗剂的肿瘤治疗应用提供了重要的理论支撑。
基于上述研究背景，结合骨肉瘤领域对关键调控分子的需求，本研究围绕IL-1β展开以下探索：通过检测骨肉瘤细胞在IL-1β处理前后的转录组水平表达差异，阐明IL-1β参与骨肉瘤细胞增殖的分子机制；同时，通过阿那白滞素，考察IL-1β拮抗剂对于骨肉瘤治疗的潜在可能性，以期为骨肉瘤的靶向治疗提供新的思路。
1　材料与方法
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1.1　骨肉瘤临床样本
收集2020年12月至2024年1月陆军军医大学第二附属医院骨科收治的4例骨肉瘤患者的新鲜骨肉瘤组织及癌旁组织。同时，收集2018年3月至2021年8月期间15例骨肉瘤患者石蜡包埋存档骨肉瘤组织。纳入标准如下：①病理学诊断为普通型骨肉瘤；②无其他慢性疾病。排除标准：不配合患者。所有纳入的患者均签署了知情同意书，本研究已获得陆军军医大学第二附属医院医学伦理委员会的批准（2022-研第476-01），所有患者均由经过培训的医生根据指南进行单独诊断和随访。
1.2　实验动物
12只5周龄雌性BALB/c nu/nu裸鼠，体质量18~22 g，购自北京维通利华实验动物有限公司。动物饲养于陆军军医大学实验动物中心，本研究过程均遵循实验动物伦理规定，并通过陆军军医大学实验动物福利伦理委员会审查（AMUWEC2020065）。
1.3　主要试剂及仪器
RPMI 1640培养基、胎牛血清、青霉素-链霉素购自美国Gibco公司；RIPA裂解液购自中国上海碧云天生物技术有限公司；兔抗IL-1β抗体、兔抗IL-1R1抗体、兔抗NF-κB p65抗体、兔抗磷酸化NF-κB p65抗体均购自美国Abcam公司；小鼠抗CDC25C抗体、兔抗GAPDH抗体、HRP标记抗兔IgG抗体、HRP标记抗小鼠IgG抗体均购自中国武汉三鹰生物技术有限公司；兔抗CDC25A抗体、兔抗Cyclin E1抗体、兔抗CDK2-T14抗体、兔抗CDK2-Y15抗体、兔抗CDK2-p16抗体、兔抗CDK2抗体购自美国CST公司；TRIzol裂解液购自美国赛默飞世尔科技公司；EdU-594细胞增殖检测试剂盒、细胞周期检测试剂盒购自中国上海碧云天生物技术有限公司；10%结晶紫染液购自中国北京索莱宝科技有限公司；CCK-8、恩贝林（embelin，Em）、PMA购自美国MCE公司；定量PCR专用反转录试剂盒、快速qPCR试剂购自日本TaKaRa Bio公司；兔二步法通用检测试剂盒购自中国北京中杉金桥生物技术有限公司；免疫组化染色试剂盒购自中国武汉赛维尔生物科技有限公司。
1.4　免疫组化染色检测组织中IL-1β蛋白水平表达
石蜡切片进行脱蜡处理后，进行抗原修复并阻断内源性过氧化物酶活性。抗原封闭后，加入兔抗IL-1β抗体工作液（1∶200）在4 ℃环境中孵育过夜。用PBS洗涤后，滴加辣根过氧化物酶（horseradish peroxidase， HRP）标记的二抗工作液，37 ℃孵育30 min。PBS洗涤后，滴加3，3'-二氨基联苯胺四盐酸盐（diaminobenzidine， DAB）染色5 min。最后用苏木精复染3 min，并用大量自来水冲洗，盐酸酒精分化2 s，返蓝处理10 min。脱水透明处理后采用中性树脂封片。使用正置光学显微镜（Olympus BX53）进行切片观察和图像采集。将采集的图像导入Image J软件中，利用IHC Profiler插件对图片进行评分，其中，评分为Negative（0）和Low Positive（1+）被划分为IL-1β低表达组；评分为Positive（2+）和High Positive（3+）被划分为IL-1β高表达组。
1.5　U2OS细胞体外培养
U2OS细胞购自美国典型培养物保藏中心，采用含10%胎牛血清（fetal bovine serum， FBS）和100 U/mL青霉素-链霉素的RPMI 1640培养基进行培养。细胞在37 ℃、含5%CO₂的细胞培养箱中培养。
1.6　 IL-1R1基因敲低模型的构建
携带shIL-1R1和NT shRNA的慢病毒由上海吉玛制药技术有限公司构建。其中，IL-1R1靶序列：GGTGGAGGATTCAGGACATTA；非靶向对照序列（NT shRNA）：TTCTCCGAACGTGTCACGT。将病毒转染至U2OS细胞中，48 h后，加入嘌呤霉素以清除未转染的细胞，获得敲低目标基因的细胞。
1.7　转录组测序检测差异基因
不同处理组的U2OS细胞采用TRIzol裂解液裂解后提取样品RNA，质检合格后进行mRNA的分离与片段化。合成cDNA后进行PCR富集文库，质检后上机测序。按照P<0.05和Fold Change>2.3或Fold Change<-2.3筛选差异表达基因，随后利用基因本体（gene ontology，GO）数据库对差异表达基因进行富集分析。
1.8　Western blot检测目标蛋白表达
使用RIPA裂解液裂解组织或细胞后提取总蛋白，蛋白定量后加入5×SDS上样缓冲液，煮沸5 min后，按照每孔10 μg总蛋白量上样至PAGE胶样孔内。以80 V、30 min浓缩样品，随后转至120 V电泳2 h。电泳结束后以恒定电流250 mA将胶上的蛋白转印至0.22 μm的PVDF膜上。经5%牛血清白蛋白封闭液室温封闭1 h后，加入对应的一抗（1∶1 000）工作液进行4 ℃过夜孵育。采用TBST洗去一抗后，加入HRP-二抗，室温孵育1 h，TBST洗膜后加入化学发光显影液，并置于显影成像设备（AcuronBio FluorQuant AC600）中进行显影并拍照。
1.9　流式细胞术检测U2OS细胞周期分布
将不同处理的U2OS细胞采用胰蛋白酶消化液消化后获取单细胞悬液，使用70%乙醇4 ℃固定过夜。800 ×g离心5 min除去乙醇后，向细胞中加入10 μg/mL的4，6-二脒基-2-苯基吲哚（4，6-diamidino-2-phenylindole， DAPI）染色液，室温染色30 min。以800 ×g离心5 min后去上清收集细胞，重悬于200 μL的PBS上，使用贝克曼流式细胞仪（CytoFLEX LX）进行周期分析。数据采用FlowJo V1 10.8软件进行分析和处理。
1.10　荧光定量PCR检测目标基因表达
提取细胞或组织的RNA后，采用定量PCR反转录试剂盒将mRNA反转录为cDNA。使用12.5 μL的TB Green Premix、1 μL的上游引物、1 μL的下游引物、8.5 μL的DEPC水和2 μL的cDNA配置定量PCR反应体系，并通过荧光定量PCR仪器（ThermoFisher，Quantstudio Ⅰ）进行检测，涉及引物见表1。
1.11　U2OS细胞克隆形成能力检测
将细胞按照1 000个/孔接种到6孔板中，或按照500个/孔接种到12孔板中。细胞接受不同条件的培养直至细胞群落逐渐汇聚。弃去培养基后加入4%多聚甲醛固定10 min，再以PBS清洗后加入结晶紫染液染色2 min。采用PBS冲洗后晾干并拍照。
1.12　U2OS细胞增殖活性检测
将细胞接种于6孔板中，经过不同处理后，加入终浓度为10 μmol/L的EdU工作液，继续在37 ℃孵箱中孵育2 h。加入4%多聚甲醛固定细胞后按说明书比例加入荧光反应液，室温避光孵育30 min。弃去反应液后采用PBS洗涤3次，并加入DAPI染色液，室温避光染色10 min。获得的样品置于倒置荧光显微镜（Leica DMI3000B）下拍照。
1.13　裸鼠骨肉瘤原位模型建立及动物实验
将2×10⁶个U2OS细胞、表达非靶向shRNA的U2OS细胞或shIL-1R1的U2OS细胞注射到裸鼠膝关节的胫骨。10 d后，根据实验组设计，对荷瘤小鼠进行腹腔注射，阿那白滞素的注射剂量为10 mg/kg，每4天注射1次，共计注射4次，停药后第6天收集肿瘤及主要脏器。使用游标卡尺测量肿瘤长短径并计算肿瘤体积（V），记录膝关节的前后径（AP）和沿胫骨轴的纵径（L），并使用以下公式计算：V=4π/3×［（AP+L）/4］2。
1.14　IL-1β表达水平与骨肉瘤患者预后相关性分析
根据收集的患者生存相关信息数据，利用Kaplan-Meier法对低表达组和高表达组的总生存率进行单因素生存分析，对数秩检验（Log-rank）比较IL-1β高低表达组的生存曲线差异，P<0.05表示差异有统计学意义。
1.15　统计学分析
除非另有说明，所示数据均为至少3次独立实验得出的x¯±s。统计分析采用Origin 2023软件进行。对于多组间的比较，使用单因素方差分析（one-way ANOVA），参数数据辅以Tukey检验，非参数数据则辅以Kruskal-Wallis检验。P<0.05表示差异有统计学意义。
2　结果
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2.1　IL-1β在骨肉瘤组织中的高表达与患者不良预后相关
对收集到的骨肉瘤病理石蜡标本切片并进行免疫组化染色后发现，IL-1β在部分患者的肿瘤组织中高表达（图1A），且与患者的不良预后相关（P<0.05，图1B）。在4例骨肉瘤患者手术切除的新鲜癌旁及肿瘤组织中，RT-qPCR结果提示IL-1β在肿瘤组织中的表达显著高于配对的癌旁组织（P<0.05，图1C）；IL-1R1的表达趋势与IL-1β相似（P<0.05，图1D）。此外，Western blot结果也证实，在蛋白水平上，肿瘤组织中IL-1β和IL-1R1的表达均远高于对应癌旁组织（图1E）。
2.2　IL-1β处理可上调骨肉瘤细胞增殖能力
EdU掺入实验结果提示，随着重组蛋白IL-1β浓度的升高，U2OS的EdU掺入率显著提升（图2A），并于40 ng/mL时达到峰值。更高浓度的IL-1β处理后并未观察到较40 ng/mL组更高的EdU阳性细胞比例（图2B）。此外，细胞周期检测结果也提示，随着IL-1β作用浓度的增加，U2OS中处于G2/M和S期的细胞比例显著上调，并于40 ng/mL后进入上升平台期（图2C、D）。单克隆形成实验结果如图2E所示，随着IL-1β作用浓度的升高，克隆数量和大小显示出明显的上调趋势；同时，CCK-8实验结果也提示了相似的趋势（图2F）。上述实验结果提示，IL-1β重组蛋白的添加可有效上调骨肉瘤细胞U2OS的增殖能力，且40 ng/mL是其最佳作用浓度。
2.3　IL-1β处理可显著上调骨肉瘤细胞周期及NF-κB信号
基因表达热图和火山图提示IL-1β处理组和未处理组细胞的转录组表达发生了明显的改变（图3A、B），其中，IL-1β处理组与未处理组之间共存在4 165个差异表达基因，包括1 688个上调表达基因和2 477个下调表达基因。通过将IL-1β处理组中的显著上调基因进行GO富集分析后发现，与未处理组的细胞相比，IL-1β处理组能显著上调NF-κB信号通路（I-kappa B kinase/NF-kappa B signaling）、IL-1产生及应答（interleukin-1 production）、细胞周期（cell cycle）等相关信号通路（图3C）。对富集于细胞周期信号通路的基因进行热图分析提示，IL-1β处理组能够显著上调细胞周期相关分子的转录水平表达（图3D）。利用RT-qPCR验证细胞周期关键分子的mRNA表达表明，IL-1β处理组显著上调了细胞周期检查点激酶1（checkpoint kinase 1， CHEK1）、周期蛋白依赖性激酶2（cyclin-dependent kinases， CDK2）、细胞分裂周期25A（cell division cycle 25A， CDC25A）等关键分子的mRNA表达水平（P<0.05，图3E）。此外，基因热图提示IL-1β处理组可显著上调NF-κB通路相关基因的表达（图3F）；而在4例骨肉瘤患者的肿瘤组织中，NF-κB的mRNA和蛋白表达水平均高于癌旁组织（P<0.05，图3G、H）。综上所述，IL-1β可上调骨肉瘤细胞中细胞周期相关信号通路，且NF-κB信号在其中可能起到关键调控作用。
2.4　阻断IL-1β信号传导可有效抑制骨肉瘤细胞增殖
如图4A所示，慢病毒载体转染后可显著降低U2OS内IL-1R1的mRNA和蛋白水平。增殖检测实验结果表明，较之对照组而言，shIL-1R1组显著降低了EdU阳性细胞率（P<0.05，图4B、C）和处于G2/M期和S期（P<0.05，图4D、E）的细胞比例；同时下调了骨肉瘤细胞的单克隆形成能力（图4F），显著降低了U2OS的细胞活性（P<0.05，图4G），且IL-1β的额外添加并不能有效刺激shIL-1R1组的细胞增殖。RT-qPCR结果证实IL-1R1敲低可显著下调U2OS中细胞周期相关分子的表达（P<0.05，图4H）；Western blot结果表明，敲低IL-1R1显著下调了细胞周期中CDC25C、CDC25A、Cyclin E1的表达和CDK2-p160的磷酸化水平（图4I）。以上结果表明IL-1R1是IL-1β诱导的骨肉瘤细胞增殖的关键受体。此外，NF-κB的表达也在IL-1R1敲低组中明显降低，且IL-1β的添加不能逆转这种下降趋势，提示NF-κB的表达受到IL-1β/IL-1R1信号轴的调控（图4I）。
2.5　NF-κB是IL-1β/IL-1R1信号轴下游重要调控分子
NF-κB小分子抑制剂embelin阻断NF-κB信号后，可观察到NF-κB p65的磷酸化水平被抑制，蛋白活性降低（图5A），以及相应的IL-1β对骨肉瘤细胞U2OS增殖的促进作用被阻断（图5B）。embelin处理抑制了IL-1β对EdU阳性细胞占比的促进作用（P<0.05，图5C）。细胞周期检测结果提示，embelin处理显著减少了IL-1β诱导增加的处于G2/M期的细胞占比（P<0.05，图5D、E）。单克隆形成实验结果表明，embelin的加入抑制了IL-1β诱导的克隆数量增加和克隆体积增大（图5F）。细胞活力实验中也观察到类似的现象（P<0.05，图5G）。此外，CDC25C、CDC25A、Cyclin E1和CDK2-p160等细胞周期正调控分子也因embelin的添加而显著下调（图5H）。上述结果提示，NF-κB是IL-1β调控骨肉瘤细胞增殖的重要作用分子。
2.6　阻断IL-1β/IL-1R1信号传导可抑制体内骨肉瘤的生长
通过IL-1R1稳定低表达的U2OS建立原发性骨肉瘤裸鼠模型，实验流程如图6A所示。IL-1R1敲低以及IL-1R1拮抗剂阿那白滞素的腹腔注射均可显著降低骨肉瘤的瘤体大小和质量（P<0.05，图6B、C）。通过HE染色对收集的肿瘤组织进行病理学分析证实本研究的原位骨肉瘤模型符合典型的骨肉瘤病理特征（图6D）。
3　讨论
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骨肉瘤作为青少年中常见的原发性恶性骨肿瘤，尤其好发于四肢长骨的干骺端等骨骼生长发育过程中细胞增殖活跃、代谢旺盛的区域，提示异常增殖信号通路的紊乱可能是疾病发生的核心驱动因素［1］。骨肉瘤以高恶性程度、快速疾病进展和高转移倾向为特征［8］，尽管近年来手术切除联合新辅助化疗、放疗等综合治疗策略的进步显著提高了患者的肿瘤局部控制率，但晚期或转移性骨肉瘤患者的5年生存率仍长期停滞在20%~30%，未能实现突破性提升［9］。治疗抵抗与远处转移的高发率，仍是导致患者高死亡率和高致残率的重要原因，严重威胁青少年群体的生命健康与生活质量。因此，深入阐明骨肉瘤发生发展的关键分子机制，挖掘具有临床转化潜力的治疗靶点，对于开发新型精准救治策略、进一步改善患者预后具有重要的理论与实践意义。
3.1　IL-1β在骨肉瘤进展中的关键作用及临床转化潜力
炎症微环境在肿瘤发生、增殖及转移中的调控作用已成为癌症研究的热点，其中IL-1β作为一种核心促炎细胞因子，被证实参与多种实体瘤的病理进程［10］。已有研究表明，IL-1β的高表达可通过促进肿瘤血管生成、抑制抗肿瘤免疫应答等机制，加速胰腺癌、乳腺癌等肿瘤的生长，且其表达水平与患者的生存率密切相关［3，5］。此外，阿那白滞素作为IL-1β拮抗剂的重组蛋白药物，已经在乳腺癌、肺癌、结直肠癌等多种肿瘤的临床前研究中显示出抗肿瘤活性，为炎症相关肿瘤的治疗提供了新的思路［3，6-7］。本研究通过临床样本分析、体外细胞实验及体内动物模型验证，系统探讨了IL-1β在骨肉瘤中的作用及机制。临床病理数据显示，部分骨肉瘤患者肿瘤组织中IL-1β呈高表达状态，且该表达特征与患者的不良预后显著相关，提示IL-1β可能作为骨肉瘤预后评估的潜在生物标志物；体外实验证实，重组IL-1β蛋白刺激可显著增强骨肉瘤U2OS细胞的增殖能力，而通过敲低IL-1R1或使用特异性抑制剂阻断IL-1β信号传导，可有效逆转其诱导的细胞增殖效应；裸鼠胫骨骨肉瘤模型进一步验证，体内阻断IL-1β信号可显著降低瘤体重量与体积，抑制肿瘤的体内生长。上述结果共同表明，IL-1β在骨肉瘤的进展过程中发挥关键的促癌作用，而其拮抗剂阿那白滞素可能具有转化为骨肉瘤新型治疗药物的潜力，为临床治疗提供了新的候选方案。
3.2　IL-1β/IL-1R1/NF-κB信号轴是调控骨肉瘤增殖的关键分子机制
IL-1β的生物学功能主要通过与细胞膜表面的IL-1R1结合启动信号传导，二者结合后引发IL-1R1构象改变，进而招募IL-1受体辅助蛋白（IL-1 receptor accessory proteins，IL-1RAcP）、髓系分化初级反应基因88（myeloid differentiation primary response，MyD88）及IL-1受体激活蛋白激酶4（interleukin-1 receptor associated kinase 4，IRAK4）形成稳定的初始信号复合物［2，10］。该复合物的形成可诱导IRAK4磷酸化，进而激活下游IL-1受体激活蛋白激酶1/2（interleukin-1 receptor-associated kinase 1/2，IRAK1/2）的磷酸化级联反应，并通过衔接分子传递信号至下游效应通路，其中丝裂原活化蛋白激酶（mitogen-activated protein kinase，MAPK）和NF-κB信号通路的激活是其主要的下游调控机制［2］。本研究进一步揭示，IL-1β在骨肉瘤中的促增殖作用依赖于NF-κB信号通路的激活：临床样本分析显示，骨肉瘤组织中IL-1β的高表达与NF-κB通路的激活状态呈正相关；体外实验证实，IL-1β刺激可显著上调骨肉瘤细胞中IL-1R1的表达，并进一步激活NF-κB信号通路，而敲低IL-1R1可有效阻断IL-1β介导的NF-κB激活。NF-κB作为炎症反应与肿瘤发生中的关键转录因子，激活后可通过调控细胞周期相关基因的表达、抑制凋亡相关分子的功能、促进上皮-间质转化等多种途径，参与肿瘤细胞增殖、迁移、侵袭及治疗抵抗的调控。例如，RODRIGUEZ-BAENA等［11］的研究报道，NF-κB的p65亚基是黑色素瘤脑转移中的关键驱动因子，敲除或药物抑制p65可显著减少肿瘤转移灶的形成；TAN等［12］的研究也证实，NF-κB的异常激活可维持结直肠癌干细胞样特性，进而加速肿瘤进展。本研究中，我们发现IL-1β/IL-1R1轴激活的NF-κB信号可上调p65的磷酸化水平，进而促进骨肉瘤细胞的增殖，提示经典NF-κB通路可能是IL-1β调控骨肉瘤进展的核心下游分子机制，为理解骨肉瘤的发病机理提供了新的分子视角。
3.3　不足与展望
综上所述，本研究通过多层面实验证实，IL-1β在骨肉瘤组织中高表达且与患者不良预后呈正相关，其通过与IL-1R1结合激活下游NF-κB信号通路，进而促进骨肉瘤细胞增殖及体内肿瘤生长。此外，IL-1β拮抗剂阿那白滞素已在其他肿瘤中显示出明确的抗肿瘤活性，本研究为其应用于骨肉瘤治疗提供了实验依据，提示阿那白滞素可能成为骨肉瘤精准治疗的潜力药物。
然而，本研究仍存在一定局限性：①临床样本量相对有限，IL-1β作为骨肉瘤预后标志物的可靠性仍需大样本、多中心队列研究进一步验证；②IL-1β/IL-1R1/NF-κB轴调控骨肉瘤增殖的下游靶基因尚未完全明确，需通过转录组测序等技术进一步筛选关键效应分子。

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doi: 10.16016/j.2097-0927.202510068
  • 接收时间：2025-10-23
  • 首发时间：2026-10-23
  • 出版时间：2026-03-15
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  • 收稿日期：2025-10-23
  • 修回日期：2026-01-20
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    1陆军军医大学（第三军医大学）第二附属医院输血科，教育部骨髓型急性放射综合征医药基础创新中心，重庆

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鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
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