ERO1在肿瘤生物学机制和治疗中的研究进展
Research Advances of ERO1 in Tumor Biology: Mechanisms and Therapeutic Target
DOI: 10.12677/wjcr.2025.153017, PDF,   
作者: 姜东岳, 吴 亮*:中国药科大学多靶标天然药物全国重点实验室,江苏 南京
关键词: ERO1肿瘤内质网免疫药物ERO1 Tumor Endoplasmic Reticulum Immunology Drug
摘要: 内质网氧化还原酶1 (ERO1)家族是一类定位于内质网的黄素氧化还原酶,主要负责接受蛋白质内二硫键成键时所产生的电子,从而维持内质网中氧化还原稳态,在蛋白质氧化折叠、维持钙离子稳态等过程中发挥重要的作用。已有研究发现相较于正常组织,ERO1在多种肿瘤中的表达均发生明显上调,并通过调节内质网应激、细胞死亡和肿瘤微环境等机制,增强肿瘤细胞的应激抗性,促进肿瘤的恶性进展,因此,ERO1有可能成为抗肿瘤药物研发的重要靶点。本文将对近年来ERO1家族相关的结构功能,ERO1在肿瘤发展中的作用和靶向ERO1的抗肿瘤机制等方向的研究进行综述。
Abstract: The endoplasmic reticulum oxidoreductase 1 (ERO1) family represents a class of flavoprotein oxidoreductases localized primarily in the endoplasmic reticulum (ER). These enzymes function as critical electron acceptors during disulfide bond formation in protein folding, thereby maintaining ER redox homeostasis and playing essential roles in oxidative protein folding and calcium ion homeostasis regulation. Emerging studies have demonstrated significant upregulation of ERO1 expression across multiple tumor types compared to normal tissues. Mechanistically, ERO1 enhances tumor cell stress resistance and promotes malignant progression through modulation of ER stress responses, cell death, and tumor microenvironment. Consequently, ERO1 has emerged as a promising therapeutic target for inhibitor development. This article comprehensively reviews recent advances in the structural-functional characteristics of ERO1 family members, their multifaceted roles in tumor progression, and mechanistic insights into ERO1-targeted antitumor strategies.
文章引用:姜东岳, 吴亮. ERO1在肿瘤生物学机制和治疗中的研究进展[J]. 世界肿瘤研究, 2025, 15(3): 132-139. https://doi.org/10.12677/wjcr.2025.153017

参考文献

[1] Urra, H., Dufey, E., Avril, T., Chevet, E. and Hetz, C. (2016) Endoplasmic Reticulum Stress and the Hallmarks of Cancer. Trends in Cancer, 2, 252-262. [Google Scholar] [CrossRef] [PubMed]
[2] Wang, W., Groenendyk, J. and Michalak, M. (2014) Endoplasmic Reticulum Stress Associated Responses in Cancer. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research, 1843, 2143-2149. [Google Scholar] [CrossRef] [PubMed]
[3] Zito, E., Guarrera, L. and Janssen-Heininger, Y.M.W. (2024) Fingerprint of the Oxido-Reductase ERO1: A Protein Disulfide Bond Producer and Supporter of Cancer. Biochimica et Biophysica Acta (BBA)-Reviews on Cancer, 1879, Article 189027. [Google Scholar] [CrossRef] [PubMed]
[4] Sevier, C.S. and Kaiser, C.A. (2008) Ero1 and Redox Homeostasis in the Endoplasmic Reticulum. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research, 1783, 549-556. [Google Scholar] [CrossRef] [PubMed]
[5] Chen, P., Sharma, A., Weiher, H. and Schmidt-Wolf, I.G.H. (2024) Biological Mechanisms and Clinical Significance of Endoplasmic Reticulum Oxidoreductase 1 Alpha (ERO1α) in Human Cancer. Journal of Experimental & Clinical Cancer Research, 43, Article No. 71. [Google Scholar] [CrossRef] [PubMed]
[6] Li, G., Mongillo, M., Chin, K., Harding, H., Ron, D., Marks, A.R., et al. (2009) Role of ERO1-Α-Mediated Stimulation of Inositol 1,4,5-Triphosphate Receptor Activity in Endoplasmic Reticulum Stress-Induced Apoptosis. Journal of Cell Biology, 186, 783-792. [Google Scholar] [CrossRef] [PubMed]
[7] Spina, A., Guidarelli, A., Fiorani, M., Varone, E., Catalani, A., Zito, E., et al. (2022) Crosstalk between ERO1α and Ryanodine Receptor in Arsenite-Dependent Mitochondrial ROS Formation. Biochemical Pharmacology, 198, Article 114973. [Google Scholar] [CrossRef] [PubMed]
[8] Liu, L., Wang, C., Li, S., Qu, Y., Xue, P., Ma, Z., et al. (2021) ERO1L Is a Novel and Potential Biomarker in Lung Adenocarcinoma and Shapes the Immune-Suppressive Tumor Microenvironment. Frontiers in Immunology, 12, Article 677169. [Google Scholar] [CrossRef] [PubMed]
[9] Pagani, M., Fabbri, M., Benedetti, C., Fassio, A., Pilati, S., Bulleid, N.J., et al. (2000) Endoplasmic Reticulum Oxidoreductin 1-Lβ (ERO1-Lβ), a Human Gene Induced in the Course of the Unfolded Protein Response. Journal of Biological Chemistry, 275, 23685-23692. [Google Scholar] [CrossRef] [PubMed]
[10] Inaba, K., Masui, S., Iida, H., Vavassori, S., Sitia, R. and Suzuki, M. (2010) Crystal Structures of Human Ero1α Reveal the Mechanisms of Regulated and Targeted Oxidation of PDI. The EMBO Journal, 29, 3330-3343. [Google Scholar] [CrossRef] [PubMed]
[11] Araki, K. and Inaba, K. (2012) Structure, Mechanism, and Evolution of Ero1 Family Enzymes. Antioxidants & Redox Signaling, 16, 790-799. [Google Scholar] [CrossRef] [PubMed]
[12] Benham, A.M. (2000) The CXXCXXC Motif Determines the Folding, Structure and Stability of Human Ero1-lα. The EMBO Journal, 19, 4493-4502. [Google Scholar] [CrossRef] [PubMed]
[13] Shergalis, A.G., Hu, S., Bankhead, A. and Neamati, N. (2020) Role of the ERO1-PDI Interaction in Oxidative Protein Folding and Disease. Pharmacology & Therapeutics, 210, Article 107525. [Google Scholar] [CrossRef] [PubMed]
[14] Puig, A. and Gilbert, H.F. (1994) Protein Disulfide Isomerase Exhibits Chaperone and Anti-Chaperone Activity in the Oxidative Refolding of Lysozyme. Journal of Biological Chemistry, 269, 7764-7771. [Google Scholar] [CrossRef] [PubMed]
[15] Malhotra, J.D. and Kaufman, R.J. (2007) Endoplasmic Reticulum Stress and Oxidative Stress: A Vicious Cycle or a Double-Edged Sword? Antioxidants & Redox Signaling, 9, 2277-2294. [Google Scholar] [CrossRef] [PubMed]
[16] Reth, M. (2002) Hydrogen Peroxide as Second Messenger in Lymphocyte Activation. Nature Immunology, 3, 1129-1134. [Google Scholar] [CrossRef] [PubMed]
[17] Bassot, A., Chen, J., Takahashi-Yamashiro, K., Yap, M.C., Gibhardt, C.S., Le, G.N.T., et al. (2023) The Endoplasmic Reticulum Kinase PERK Interacts with the Oxidoreductase ERO1 to Metabolically Adapt Mitochondria. Cell Reports, 42, Article 111899. [Google Scholar] [CrossRef] [PubMed]
[18] Dias-Gunasekara, S., Gubbens, J., van Lith, M., Dunne, C., Williams, J.A.G., Kataky, R., et al. (2005) Tissue-Specific Expression and Dimerization of the Endoplasmic Reticulum Oxidoreductase Ero1β. Journal of Biological Chemistry, 280, 33066-33075. [Google Scholar] [CrossRef] [PubMed]
[19] May, D., Itin, A., Gal, O., Kalinski, H., Feinstein, E. and Keshet, E. (2004) Ero1-lα Plays a Key Role in a HIF-1-Mediated Pathway to Improve Disulfide Bond Formation and VEGF Secretion under Hypoxia: Implication for Cancer. Oncogene, 24, 1011-1020. [Google Scholar] [CrossRef] [PubMed]
[20] Zhang, Y., Li, T., Zhang, L., Shangguan, F., Shi, G., Wu, X., et al. (2019) Targeting the Functional Interplay between Endoplasmic Reticulum Oxidoreductin-1α and Protein Disulfide Isomerase Suppresses the Progression of Cervical Cancer. EBioMedicine, 41, 408-419. [Google Scholar] [CrossRef] [PubMed]
[21] Kutomi, G., Tamura, Y., Tanaka, T., Kajiwara, T., Kukita, K., Ohmura, T., et al. (2013) Human Endoplasmic Reticulum Oxidoreductin 1‐α Is a Novel Predictor for Poor Prognosis of Breast Cancer. Cancer Science, 104, 1091-1096. [Google Scholar] [CrossRef] [PubMed]
[22] Seol, S., Kim, C., Lim, J.Y., Yoon, S.O., Hong, S.W., Kim, J.W., et al. (2016) Overexpression of Endoplasmic Reticulum Oxidoreductin 1-α (ERO1L) Is Associated with Poor Prognosis of Gastric Cancer. Cancer Research and Treatment, 48, 1196-1209. [Google Scholar] [CrossRef] [PubMed]
[23] Yang, S., Yang, C., Yu, F., Ding, W., Hu, Y., Cheng, F., et al. (2018) Endoplasmic Reticulum Resident Oxidase ERO1-Lalpha Promotes Hepatocellular Carcinoma Metastasis and Angiogenesis through the S1PR1/STAT3/VEGF-A Pathway. Cell Death & Disease, 9, Article No. 1105. [Google Scholar] [CrossRef] [PubMed]
[24] Zhang, J., Yang, J., Lin, C., Liu, W., Huo, Y., Yang, M., et al. (2020) Endoplasmic Reticulum Stress-Dependent Expression of ERO1L Promotes Aerobic Glycolysis in Pancreatic Cancer. Theranostics, 10, 8400-8414. [Google Scholar] [CrossRef] [PubMed]
[25] Wang, Z., Zong, H., Liu, W., Lin, W., Sun, A., Ding, Z., et al. (2024) Augmented ERO1α Upon mTORC1 Activation Induces Ferroptosis Resistance and Tumor Progression via Upregulation of SLC7A11. Journal of Experimental & Clinical Cancer Research, 43, Article No. 112. [Google Scholar] [CrossRef] [PubMed]
[26] Xie, J., Liao, G., Feng, Z., Liu, B., Li, X. and Qiu, M. (2022) ERO1L Promotes the Proliferation and Metastasis of Lung Adenocarcinoma via the Wnt2/β-Catenin Signaling Pathway. Molecular Carcinogenesis, 61, 897-909. [Google Scholar] [CrossRef] [PubMed]
[27] Wu, M., Li, R., Qin, J., Wang, Z., Guo, J., Lv, F., et al. (2023) ERO1α Promotes the Proliferation and Inhibits Apoptosis of Colorectal Cancer Cells by Regulating the PI3K/AKT Pathway. Journal of Molecular Histology, 54, 621-631. [Google Scholar] [CrossRef] [PubMed]
[28] Varone, E., Decio, A., Barbera, M.C., Bolis, M., Di Rito, L., Pisati, F., et al. (2022) Endoplasmic Reticulum Oxidoreductin 1-Alpha Deficiency and Activation of Protein Translation Synergistically Impair Breast Tumour Resilience. British Journal of Pharmacology, 179, 5180-5195. [Google Scholar] [CrossRef] [PubMed]
[29] Nishida, N., Yano, H., Nishida, T., Kamura, T. and Kojiro, M. (2006) Angiogenesis in Cancer. Vascular Health and Risk Management, 2, 213-219. [Google Scholar] [CrossRef] [PubMed]
[30] Zilli, F., Marques Ramos, P., Auf der Maur, P., Jehanno, C., Sethi, A., Coissieux, M., et al. (2021) The NFIB‐ERO1A Axis Promotes Breast Cancer Metastatic Colonization of Disseminated Tumour Cells. EMBO Molecular Medicine, 13, e13162. [Google Scholar] [CrossRef] [PubMed]
[31] Tanaka, T., Kutomi, G., Kajiwara, T., Kukita, K., Kochin, V., Kanaseki, T., et al. (2016) Cancer-Associated Oxidoreductase ERO1-α Drives the Production of VEGF via Oxidative Protein Folding and Regulating the mRNA Level. British Journal of Cancer, 114, 1227-1234. [Google Scholar] [CrossRef] [PubMed]
[32] Varone, E., Decio, A., Chernorudskiy, A., Minoli, L., Brunelli, L., Ioli, F., et al. (2021) The ER Stress Response Mediator ERO1 Triggers Cancer Metastasis by Favoring the Angiogenic Switch in Hypoxic Conditions. Oncogene, 40, 1721-1736. [Google Scholar] [CrossRef] [PubMed]
[33] Wang, Y., Alam, G.N., Ning, Y., Visioli, F., Dong, Z., Nör, J.E., et al. (2012) The Unfolded Protein Response Induces the Angiogenic Switch in Human Tumor Cells through the PERK/ATF4 Pathway. Cancer Research, 72, 5396-5406. [Google Scholar] [CrossRef] [PubMed]
[34] Waypa, G.B., Marks, J.D., Guzy, R., Mungai, P.T., Schriewer, J., Dokic, D., et al. (2010) Hypoxia Triggers Subcellular Compartmental Redox Signaling in Vascular Smooth Muscle Cells. Circulation Research, 106, 526-535. [Google Scholar] [CrossRef] [PubMed]
[35] Pitt, J.M., Marabelle, A., Eggermont, A., Soria, J.-., Kroemer, G. and Zitvogel, L. (2016) Targeting the Tumor Microenvironment: Removing Obstruction to Anticancer Immune Responses and Immunotherapy. Annals of Oncology, 27, 1482-1492. [Google Scholar] [CrossRef] [PubMed]
[36] Liu, L., Li, S., Qu, Y., Bai, H., Pan, X., Wang, J., et al. (2023) Ablation of ERO1A Induces Lethal Endoplasmic Reticulum Stress Responses and Immunogenic Cell Death to Activate Anti-Tumor Immunity. Cell Reports Medicine, 4, Article 101206. [Google Scholar] [CrossRef] [PubMed]
[37] Tanaka, T., Kajiwara, T., Torigoe, T., Okamoto, Y., Sato, N. and Tamura, Y. (2015) Cancer-Associated Oxidoreductase Ero1-α Drives the Production of Tumor-Promoting Myeloid-Derived Suppressor Cells via Oxidative Protein Folding. The Journal of Immunology, 194, 2004-2010. [Google Scholar] [CrossRef] [PubMed]
[38] Tay, A.H.M., Cinotti, R., Sze, N.S.K. and Lundqvist, A. (2023) Inhibition of Ero1a and IDO1 Improves Dendritic Cell Infiltration into Pancreatic Ductal Adenocarcinoma. Frontiers in Immunology, 14, Article 1264012. [Google Scholar] [CrossRef] [PubMed]
[39] Hurst, K.E., Lawrence, K.A., Essman, M.T., Walton, Z.J., Leddy, L.R. and Thaxton, J.E. (2019) Endoplasmic Reticulum Stress Contributes to Mitochondrial Exhaustion of CD8+ T Cells. Cancer Immunology Research, 7, 476-486. [Google Scholar] [CrossRef] [PubMed]
[40] Tanaka, T., Kutomi, G., Kajiwara, T., Kukita, K., Kochin, V., Kanaseki, T., et al. (2017) Cancer-Associated Oxidoreductase ERO1-α Promotes Immune Escape through Up-Regulation of PD-L1 in Human Breast Cancer. Oncotarget, 8, 24706-24718. [Google Scholar] [CrossRef] [PubMed]
[41] Liu, L., Li, S., Qu, Y., Wang, J., Fei, K., Wang, C., et al. (2022) Tumour ERO1A Instigates T Cell Dysfunction by Transmission of Endoplasmic Reticulum Stress. Journal of Clinical Oncology, 40, e14533-e14533. [Google Scholar] [CrossRef
[42] Wang, G., Han, J., Wang, G., Wu, X., Huang, Y., Wu, M., et al. (2021) ERO1α Mediates Endoplasmic Reticulum Stress-Induced Apoptosis via microRNA-101/EZH2 Axis in Colon Cancer RKO and HT-29 Cells. Human Cell, 34, 932-944. [Google Scholar] [CrossRef] [PubMed]
[43] Blais, J.D., Chin, K., Zito, E., Zhang, Y., Heldman, N., Harding, H.P., et al. (2010) A Small Molecule Inhibitor of Endoplasmic Reticulum Oxidation 1 (ERO1) with Selectively Reversible Thiol Reactivity. Journal of Biological Chemistry, 285, 20993-21003. [Google Scholar] [CrossRef] [PubMed]
[44] Johnson, B.D., Kaulagari, S.R., Chen, W., Hayes, K., Geldenhuys, W.J. and Hazlehurst, L.A. (2022) Identification of Natural Product Sulfuretin Derivatives as Inhibitors for the Endoplasmic Reticulum Redox Protein Ero1α. ACS Bio & Med Chem Au, 2, 161-170. [Google Scholar] [CrossRef] [PubMed]