IL1RAP在恶性肿瘤中作用的研究进展
Research Progress of the Role of IL1RAP in Malignant Tumors
DOI: 10.12677/wjcr.2025.152007, PDF,   
作者: 张雪鸥, 徐建红：浙江大学医学院附属第四医院麻醉疼痛科，浙江 金华；郁丽娜*：浙江大学医学院附属第二医院麻醉手术部，浙江 杭州
关键词: IL1RAP；恶性肿瘤；信号通路；IL-1；IL1RAP； Malignant Tumors； Signaling Pathway； IL-1
摘要: 白介素1受体辅助蛋白(IL1RAP)是白介素1 (IL-1)家族的共受体，通过与白介素1受体(IL-1R)结合形成多聚复合物并激活下游信号通路发挥生物学效应。IL1RAP介导的信号通路在各类恶性肿瘤中表现出促增殖和促侵袭、迁移的特性，包括血液系统肿瘤、消化道肿瘤、乳腺癌、宫颈癌等。本综述旨在阐明IL1RAP介导的信号通路的生物学效应，以及IL1RAP在各类恶性肿瘤中作用机制的研究进展。
Abstract: Interleukin 1 receptor accessory protein (IL1RAP) is a co-receptor of the interleukin 1 (IL-1) family, which exerts biological effects by binding to the interleukin 1 receptor (IL-1R) to form a multimeric complex and activating the downstream signaling pathway. The signaling pathway mediated by IL1RAP shows pro-proliferative, pro-invasive, and migratory properties in various types of malignant tumors, including hematological tumors, gastrointestinal tract tumors, breast cancers, cervical cancer, etc. The aim of this review is to elucidate the biological effects of IL1RAP-mediated signaling pathway and the progress of the research on the mechanism of IL1RAP in various malignant tumors.
文章引用：张雪鸥, 徐建红, 郁丽娜. IL1RAP在恶性肿瘤中作用的研究进展[J]. 世界肿瘤研究, 2025, 15(2): 53-60. https://doi.org/10.12677/wjcr.2025.152007

参考文献

[1] Højen, J.F., Kristensen, M.L.V., McKee, A.S., Wade, M.T., Azam, T., Lunding, L.P., et al. (2019) IL-1R3 Blockade Broadly Attenuates the Functions of Six Members of the IL-1 Family, Revealing Their Contribution to Models of Disease. Nature Immunology, 20, 1138-1149. [Google Scholar] [CrossRef] [PubMed]
[2] Li, X., Commane, M., Jiang, Z. and Stark, G.R. (2001) IL-1-Induced NF-κB and C-Jun N-Terminal Kinase (JNK) Activation Diverge at IL-1 Receptor-Associated Kinase (IRAK). Proceedings of the National Academy of Sciences, 98, 4461-4465. [Google Scholar] [CrossRef] [PubMed]
[3] Fields, J.K., Günther, S. and Sundberg, E.J. (2019) Structural Basis of IL-1 Family Cytokine Signaling. Frontiers in Immunology, 10, Article 1412. [Google Scholar] [CrossRef] [PubMed]
[4] Greenfeder, S.A., Nunes, P., Kwee, L., Labow, M., Chizzonite, R.A. and Ju, G. (1995) Molecular Cloning and Characterization of a Second Subunit of the Interleukin 1 Receptor Complex. Journal of Biological Chemistry, 270, 13757-13765. [Google Scholar] [CrossRef] [PubMed]
[5] Frenay, J., Bellaye, P., Oudot, A., Helbling, A., Petitot, C., Ferrand, C., et al. (2022) IL-1RAP, a Key Therapeutic Target in Cancer. International Journal of Molecular Sciences, 23, Article 14918. [Google Scholar] [CrossRef] [PubMed]
[6] Wesche, H., Korherr, C., Kracht, M., Falk, W., Resch, K. and Martin, M.U. (1997) The Interleukin-1 Receptor Accessory Protein (IL-1RACP) Is Essential for IL-1-Induced Activation of Interleukin-1 Receptor-Associated Kinase (IRAK) and Stress-Activated Protein Kinases (SAP Kinases). Journal of Biological Chemistry, 272, 7727-7731. [Google Scholar] [CrossRef] [PubMed]
[7] Jensen, L.E. and Whitehead, A.S. (2003) Expression of Alternatively Spliced Interleukin-1 Receptor Accessory Protein mRNAs Is Differentially Regulated during Inflammation and Apoptosis. Cellular Signalling, 15, 793-802. [Google Scholar] [CrossRef] [PubMed]
[8] Krumm, B., Xiang, Y. and Deng, J. (2014) Structural Biology of the IL-1 Superfamily: Key Cytokines in the Regulation of Immune and Inflammatory Responses. Protein Science, 23, 526-538. [Google Scholar] [CrossRef] [PubMed]
[9] Casadio, R., Frigimelica, E., Bossù, P., Neumann, D., Martin, M.U., Tagliabue, A., et al. (2001) Model of Interaction of the IL-1 Receptor Accessory Protein IL-1RACP with the IL-1β/IL-1RI Complex. FEBS Letters, 499, 65-68. [Google Scholar] [CrossRef] [PubMed]
[10] Zarezadeh Mehrabadi, A., Aghamohamadi, N., Khoshmirsafa, M., Aghamajidi, A., Pilehforoshha, M., Massoumi, R., et al. (2022) The Roles of Interleukin-1 Receptor Accessory Protein in Certain Inflammatory Conditions. Immunology, 166, 38-46. [Google Scholar] [CrossRef] [PubMed]
[11] Jensen, L.E., Muzio, M., Mantovani, A. and Whitehead, A.S. (2000) IL-1 Signaling Cascade in Liver Cells and the Involvement of a Soluble Form of the IL-1 Receptor Accessory Protein. The Journal of Immunology, 164, 5277-5286. [Google Scholar] [CrossRef] [PubMed]
[12] Yilmaz-Elis, S., Aartsma-Rus, A., Vroon, A., van Deutekom, J., de Kimpe, S., Hoen, P.A.C., et al. (2012) Antisense Oligonucleotide Mediated Exon Skipping as a Potential Strategy for the Treatment of a Variety of Inflammatory Diseases Such as Rheumatoid Arthritis. Annals of the Rheumatic Diseases, 71, i75-i77. [Google Scholar] [CrossRef] [PubMed]
[13] Gabay, C., Lamacchia, C. and Palmer, G. (2010) IL-1 Pathways in Inflammation and Human Diseases. Nature Reviews Rheumatology, 6, 232-241. [Google Scholar] [CrossRef] [PubMed]
[14] Smith, D.E., Lipsky, B.P., Russell, C., Ketchem, R.R., Kirchner, J., Hensley, K., et al. (2009) A Central Nervous System-Restricted Isoform of the Interleukin-1 Receptor Accessory Protein Modulates Neuronal Responses to Interleukin-1. Immunity, 30, 817-831. [Google Scholar] [CrossRef] [PubMed]
[15] Acuner Ozbabacan, S.E., Gursoy, A., Nussinov, R. and Keskin, O. (2014) The Structural Pathway of Interleukin 1 (IL-1) Initiated Signaling Reveals Mechanisms of Oncogenic Mutations and SNPS in Inflammation and Cancer. PLOS Computational Biology, 10, e1003470. [Google Scholar] [CrossRef] [PubMed]
[16] Huang, J., Gao, X., Li, S. and Cao, Z. (1997) Recruitment of IRAK to the Interleukin 1 Receptor Complex Requires Interleukin 1 Receptor Accessory Protein. Proceedings of the National Academy of Sciences, 94, 12829-12832. [Google Scholar] [CrossRef] [PubMed]
[17] Bozaoglu, K., Attard, C., Kulkarni, H., Cummings, N., Diego, V.P., Carless, M.A., et al. (2014) Plasma Levels of Soluble Interleukin 1 Receptor Accessory Protein Are Reduced in Obesity. The Journal of Clinical Endocrinology & Metabolism, 99, 3435-3443. [Google Scholar] [CrossRef] [PubMed]
[18] Weber, A., Wasiliew, P. and Kracht, M. (2010) Interleukin-1 (IL-1) Pathway. Science Signaling, 3, 1-6. [Google Scholar] [CrossRef] [PubMed]
[19] Towne, J.E., Garka, K.E., Renshaw, B.R., Virca, G.D. and Sims, J.E. (2004) Interleukin (IL)-1F6, IL-1F8, and IL-1F9 Signal through IL-1RRP2 and IL-1RACP to Activate the Pathway Leading to NF-κB and MAPKS. Journal of Biological Chemistry, 279, 13677-13688. [Google Scholar] [CrossRef] [PubMed]
[20] Drube, S., Heink, S., Walter, S., Löhn, T., Grusser, M., Gerbaulet, A., et al. (2010) The Receptor Tyrosine Kinase C-Kit Controls IL-33 Receptor Signaling in Mast Cells. Blood, 115, 3899-3906. [Google Scholar] [CrossRef] [PubMed]
[21] Schmitz, J., Owyang, A., Oldham, E., Song, Y., Murphy, E., McClanahan, T.K., et al. (2005) IL-33, an Interleukin-1-Like Cytokine That Signals via the IL-1 Receptor-Related Protein ST2 and Induces T Helper Type 2-Associated Cytokines. Immunity, 23, 479-490. [Google Scholar] [CrossRef] [PubMed]
[22] Liang, Y., Seymour, R.E. and Sundberg, J.P. (2011) Inhibition of NF-κB Signaling Retards Eosinophilic Dermatitis in Sharpin-Deficient Mice. Journal of Investigative Dermatology, 131, 141-149. [Google Scholar] [CrossRef] [PubMed]
[23] Chen, R., Li, M., Zhang, Y., Zhou, Q. and Shu, H. (2012) The E3 Ubiquitin Ligase MARCH8 Negatively Regulates IL-1β-Induced NF-κB Activation by Targeting the IL1RAP Coreceptor for Ubiquitination and Degradation. Proceedings of the National Academy of Sciences, 109, 14128-14133. [Google Scholar] [CrossRef] [PubMed]
[24] Kobayashi, K., Hernandez, L.D., Galán, J.E., Janeway, C.A., Medzhitov, R. and Flavell, R.A. (2002) IRAK-M Is a Negative Regulator of Toll-Like Receptor Signaling. Cell, 110, 191-202. [Google Scholar] [CrossRef] [PubMed]
[25] Muzio, M., Ni, J., Feng, P. and Dixit, V.M. (1997) IRAK (Pelle) Family Member IRAK-2 and Myd88 as Proximal Mediators of IL-1 Signaling. Science, 278, 1612-1615. [Google Scholar] [CrossRef] [PubMed]
[26] Burns, K., Janssens, S., Brissoni, B., Olivos, N., Beyaert, R. and Tschopp, J. (2003) Inhibition of Interleukin 1 Receptor/Toll-Like Receptor Signaling through the Alternatively Spliced, Short Form of Myd88 Is Due to Its Failure to Recruit IRAK-4. The Journal of Experimental Medicine, 197, 263-268. [Google Scholar] [CrossRef] [PubMed]
[27] Koeppel, M., van Heeringen, S.J., Kramer, D., Smeenk, L., Janssen-Megens, E., Hartmann, M., et al. (2011) Crosstalk between C-Jun and Tap73α/β Contributes to the Apoptosis-Survival Balance. Nucleic Acids Research, 39, 6069-6085. [Google Scholar] [CrossRef] [PubMed]
[28] Lockett, A., Goebl, M.G. and Harrington, M.A. (2008) Transient Membrane Recruitment of IRAK-1 in Response to LPS and IL-1β Requires TNF R1. American Journal of Physiology-Cell Physiology, 295, C313-C323. [Google Scholar] [CrossRef] [PubMed]
[29] Ågerstam, H., Lilljebjörn, H., Rissler, M., Sandén, C. and Fioretos, T. (2022) IL1RAP Is Expressed in Several Subtypes of Pediatric Acute Lymphoblastic Leukemia and Can Be Used as a Target to Eliminate ETV6::RUNX1-Positive Leukemia Cells in Preclinical Models. Haematologica, 108, 599-604. [Google Scholar] [CrossRef] [PubMed]
[30] Eisenwort, G., Sadovnik, I., Keller, A., Ivanov, D., Peter, B., Berger, D., et al. (2021) Phenotypic Characterization of Leukemia-Initiating Stem Cells in Chronic Myelomonocytic Leukemia. Leukemia, 35, 3176-3187. [Google Scholar] [CrossRef] [PubMed]
[31] Mitchell, K., Barreyro, L., Todorova, T.I., Taylor, S.J., Antony-Debré, I., Narayanagari, S., et al. (2018) IL1RAP Potentiates Multiple Oncogenic Signaling Pathways in Aml. Journal of Experimental Medicine, 215, 1709-1727. [Google Scholar] [CrossRef] [PubMed]
[32] De Boer, B., Sheveleva, S., Apelt, K., Vellenga, E., Mulder, A.B., Huls, G., et al. (2020) The IL1-IL1RAP Axis Plays an Important Role in the Inflammatory Leukemic Niche That Favors Acute Myeloid Leukemia Proliferation over Normal Hematopoiesis. Haematologica, 106, 3067-3078. [Google Scholar] [CrossRef] [PubMed]
[33] Herrmann, H., Sadovnik, I., Cerny-Reiterer, S., Rülicke, T., Stefanzl, G., Willmann, M., et al. (2014) Dipeptidylpeptidase IV (CD26) Defines Leukemic Stem Cells (LSC) in Chronic Myeloid Leukemia. Blood, 123, 3951-3962. [Google Scholar] [CrossRef] [PubMed]
[34] Järås, M., Johnels, P., Hansen, N., Ågerstam, H., Tsapogas, P., Rissler, M., et al. (2010) Isolation and Killing of Candidate Chronic Myeloid Leukemia Stem Cells by Antibody Targeting of IL-1 Receptor Accessory Protein. Proceedings of the National Academy of Sciences, 107, 16280-16285. [Google Scholar] [CrossRef] [PubMed]
[35] Ågerstam, H., Hansen, N., von Palffy, S., Sandén, C., Reckzeh, K., Karlsson, C., et al. (2016) IL1RAP Antibodies Block IL-1-Induced Expansion of Candidate CML Stem Cells and Mediate Cell Killing in Xenograft Models. Blood, 128, 2683-2693. [Google Scholar] [CrossRef] [PubMed]
[36] Landberg, N., Hansen, N., Askmyr, M., Ågerstam, H., Lassen, C., Rissler, M., et al. (2015) IL1RAP Expression as a Measure of Leukemic Stem Cell Burden at Diagnosis of Chronic Myeloid Leukemia Predicts Therapy Outcome. Leukemia, 30, 255-258. [Google Scholar] [CrossRef] [PubMed]
[37] Robbrecht, D., Jungels, C., Sorensen, M.M., Spanggaard, I., Eskens, F., Fretland, S.Ø., et al. (2021) First-in-Human Phase 1 Dose-Escalation Study of CAN04, a First-In-Class Interleukin-1 Receptor Accessory Protein (IL1RAP) Antibody in Patients with Solid Tumours. British Journal of Cancer, 126, 1010-1017. [Google Scholar] [CrossRef] [PubMed]
[38] Zhang, Y., Chen, X., Wang, H., Gordon-Mitchell, S., Sahu, S., Bhagat, T.D., et al. (2022) Innate Immune Mediator, Interleukin-1 Receptor Accessory Protein (IL1RAP), Is Expressed and Pro-Tumorigenic in Pancreatic Cancer. Journal of Hematology & Oncology, 15, Article No. 70. [Google Scholar] [CrossRef] [PubMed]
[39] Herremans, K.M., Szymkiewicz, D.D., Riner, A.N., Bohan, R.P., Tushoski, G.W., Davidson, A.M., et al. (2022) The Interleukin-1 Axis and the Tumor Immune Microenvironment in Pancreatic Ductal Adenocarcinoma. Neoplasia, 28, Article ID: 100789. [Google Scholar] [CrossRef] [PubMed]
[40] Lv, Q., Xia, Q., Li, A. and Wang, Z. (2021) The Potential Role of IL1RAP on Tumor Microenvironment-Related Inflammatory Factors in Stomach Adenocarcinoma. Technology in Cancer Research & Treatment, 20, 1-11. [Google Scholar] [CrossRef] [PubMed]
[41] Rehman, A., Olsson, P.O., Akhtar, A., Padhiar, A.A., Liu, H., Dai, Y., et al. (2022) Systematic Molecular Analysis of the Human Secretome and Membrane Proteome in Gastrointestinal Adenocarcinomas. Journal of Cellular and Molecular Medicine, 26, 3329-3342. [Google Scholar] [CrossRef] [PubMed]
[42] Liu, F., Dai, M., Xu, Q., Zhu, X., Zhou, Y., Jiang, S., et al. (2018) SRSF10-Mediated IL1RAP Alternative Splicing Regulates Cervical Cancer Oncogenesis via mIL1RAP-NF-κB-Cd47 Axis. Oncogene, 37, 2394-2409. [Google Scholar] [CrossRef] [PubMed]
[43] Ghittoni, R., Accardi, R., Hasan, U., Gheit, T., Sylla, B. and Tommasino, M. (2009) The Biological Properties of E6 and E7 Oncoproteins from Human Papillomaviruses. Virus Genes, 40, 1-13. [Google Scholar] [CrossRef] [PubMed]
[44] Kozlovski, I., Siegfried, Z., Amar-Schwartz, A. and Karni, R. (2017) The Role of RNA Alternative Splicing in Regulating Cancer Metabolism. Human Genetics, 136, 1113-1127. [Google Scholar] [CrossRef] [PubMed]
[45] Venables, J.P., Klinck, R., Koh, C., Gervais-Bird, J., Bramard, A., Inkel, L., et al. (2009) Cancer-Associated Regulation of Alternative Splicing. Nature Structural & Molecular Biology, 16, 670-676. [Google Scholar] [CrossRef] [PubMed]
[46] Wang, Y., Cheng, S., Fleishman, J.S., Chen, J., Tang, H., Chen, Z., et al. (2024) Targeting Anoikis Resistance as a Strategy for Cancer Therapy. Drug Resistance Updates, 75, Article ID: 101099. [Google Scholar] [CrossRef] [PubMed]
[47] Mendoza-Naranjo, A., El-Naggar, A., Wai, D.H., Mistry, P., Lazic, N., Ayala, F.R.R., et al. (2013) ERBB4 Confers Metastatic Capacity in Ewing Sarcoma. EMBO Molecular Medicine, 5, 1087-1102. [Google Scholar] [CrossRef] [PubMed]
[48] Zhang, H., Hughes, C.S., Li, W., He, J., Surdez, D., El-Naggar, A.M., et al. (2021) Proteomic Screens for Suppressors of Anoikis Identify IL1RAP as a Promising Surface Target in Ewing Sarcoma. Cancer Discovery, 11, 2884-2903. [Google Scholar] [CrossRef] [PubMed]
[49] Alcantara Llaguno, S.R. and Parada, L.F. (2016) Cell of Origin of Glioma: Biological and Clinical Implications. British Journal of Cancer, 115, 1445-1450. [Google Scholar] [CrossRef] [PubMed]
[50] Li, F., Zhang, W., Wang, M. and Jia, P. (2020) IL1RAP Regulated by PRPRD Promotes Gliomas Progression via Inducing Neuronal Synapse Development and Neuron Differentiation in Vitro. Pathology—Research and Practice, 216, Article ID: 153141. [Google Scholar] [CrossRef] [PubMed]
[51] He, J., Li, X., Zhu, W., Yu, Y. and Gong, J. (2017) Research of Differential Expression of Sil1rap in Low-Grade Gliomas between Children and Adults. Brain Tumor Pathology, 35, 19-28. [Google Scholar] [CrossRef] [PubMed]
[52] Zheng, P., Zhang, Y., Zhang, B., Wang, Y., Wang, Y. and Yang, L. (2018) Synthetic Human Monoclonal Antibody Targets Hil1 Receptor Accessory Protein Chain with Therapeutic Potential in Triple-Negative Breast Cancer. Biomedicine & Pharmacotherapy, 107, 1064-1073. [Google Scholar] [CrossRef] [PubMed]

为你推荐