起源识别复合体亚基1 (ORC1)在癌发生中的分子机制与治疗前景
Molecular Mechanism and Therapeutic Prospects of Origin Recognition Complex 1 (ORC1) in Carcinogenesis
摘要: 起源识别复合体亚基1 (ORC1)在调控DNA复制过程和维持细胞周期中发挥关键作用。此外，ORC1的表达在多种癌细胞中显著上调，并与癌症进展密切关联。进一步而言，ORC1在癌症中的功能紧密关联于细胞周期调控、细胞增殖、转移、免疫应答及DNA复制系统的维持。从机制上看，ORC1可能主要通过激活ERK/JNK信号通路促进癌变。因此，ORC1可作为重要的癌症生物标志物和潜在的治疗靶点。本文特别综述了ORC1在癌症进展中的作用机制及其治疗潜力的最新研究。对ORC1致癌功能的深入探索，有望为癌症诊断和治疗提供新策略。
Abstract: Origin Recognition Complex 1 (ORC1) plays a critical role in regulating the DNA replication process and maintaining the cell cycle. Additionally, ORC1 expression is significantly upregulated in various cancer cells and is closely associated with cancer progression. Furthermore, ORC1 functions in cancer are closely linked to regulating the cell cycle, cell proliferation, cell metastasis, immune responses, and maintaining the DNA replication system. Mechanistically, ORC1 may primarily promote carcinogenesis by activating the ERK/JNK signaling pathway. Therefore, ORC1 could serve as an important cancer biomarker and a potential therapeutic target. Specifically, this article summarizes the latest research on the mechanisms of ORC1 action in cancer progression and its potential therapeutic opportunities. Further investigations into the oncogenic functions of ORC1 may provide new approaches for cancer diagnosis and treatment.
文章引用：许珊, 赵廷宽. 起源识别复合体亚基1 (ORC1)在癌发生中的分子机制与治疗前景[J]. 临床医学进展, 2025, 15(10): 1112-1118. https://doi.org/10.12677/acm.2025.15102862

参考文献

[1] Vergara, Z., Gomez, M.S., Desvoyes, B., Sequeira-Mendes, J., Masoud, K., Costas, C., et al. (2023) Distinct Roles of Arabidopsis ORC1 Proteins in DNA Replication and Heterochromatic H3K27me1 Deposition. Nature Communications, 14, Article No. 1270. [Google Scholar] [CrossRef] [PubMed]
[2] Ortega, M.A., Nguyen, H. and Ward, W.S. (2015) ORC Proteins in the Mammalian Zygote. Cell and Tissue Research, 363, 195-200. [Google Scholar] [CrossRef] [PubMed]
[3] Kara, N., Hossain, M., Prasanth, S.G. and Stillman, B. (2015) Orc1 Binding to Mitotic Chromosomes Precedes Spatial Patterning during G1 Phase and Assembly of the Origin Recognition Complex in Human Cells. Journal of Biological Chemistry, 290, 12355-12369. [Google Scholar] [CrossRef] [PubMed]
[4] Amin, A., Wu, R., Cheung, M.H., Scott, J.F., Wang, Z., Zhou, Z., et al. (2020) An Essential and Cell-Cycle-Dependent ORC Dimerization Cycle Regulates Eukaryotic Chromosomal DNA Replication. Cell Reports, 30, 3323-3338.e6. [Google Scholar] [CrossRef] [PubMed]
[5] Coster, G., Frigola, J., Beuron, F., Morris, E.P. and Diffley, J.F.X. (2014) Origin Licensing Requires ATP Binding and Hydrolysis by the MCM Replicative Helicase. Molecular Cell, 55, 666-677. [Google Scholar] [CrossRef] [PubMed]
[6] Diaz-Trivino, S. (2005) The Genes Encoding Arabidopsis ORC Subunits Are E2F Targets and the Two ORC1 Genes Are Differently Expressed in Proliferating and Endoreplicating Cells. Nucleic Acids Research, 33, 5404-5414. [Google Scholar] [CrossRef] [PubMed]
[7] Xiong, W., Xie, C., Qiu, Y., Tu, Z. and Gong, Q. (2020) Origin Recognition Complex Subunit 1 Regulates Cell Growth and Metastasis in Glioma by Altering Activation of ERK and JNK Signaling Pathway. Molecular and Cellular Probes, 49, Article ID: 101496. [Google Scholar] [CrossRef] [PubMed]
[8] Wang, X., Wang, D., Ding, N., Mi, L., Yu, H., Wu, M., et al. (2021) The Synergistic Anti-Tumor Activity of EZH2 Inhibitor SHR2554 and HDAC Inhibitor Chidamide through ORC1 Reduction of DNA Replication Process in Diffuse Large B Cell Lymphoma. Cancers, 13, Article 4249. [Google Scholar] [CrossRef] [PubMed]
[9] Wu, L., Chen, H. and Yang, C. (2023) Origin Recognition Complex Subunit 1 (ORC1) Is a Potential Biomarker and Therapeutic Target in Cancer. BMC Medical Genomics, 16, Article No. 243. [Google Scholar] [CrossRef] [PubMed]
[10] Chen, Z., Zhou, L., Wang, L., Kazobinka, G., Zhang, X., Han, X., et al. (2017) HBO1 Promotes Cell Proliferation in Bladder Cancer via Activation of Wnt/β‐Catenin Signaling. Molecular Carcinogenesis, 57, 12-21. [Google Scholar] [CrossRef] [PubMed]
[11] Li, S., Zhu, A., Ren, K., Li, S. and Chen, L. (2020) DEFA1B Inhibits ZIKV Replication and Retards Cell Cycle Progression through Interaction with Orc1. Life Sciences, 263, Article ID: 118564. [Google Scholar] [CrossRef] [PubMed]
[12] Chen, X., Xiong, D., Ye, L., Wang, K., Huang, L., Mei, S., et al. (2019) Up-Regulated lncRNA XIST Contributes to Progression of Cervical Cancer via Regulating miR-140-5p and ORC1. Cancer Cell International, 19, Article No. 45. [Google Scholar] [CrossRef] [PubMed]
[13] Okano-Uchida, T., Kent, L.N., Ouseph, M.M., McCarty, B., Frank, J.J., Kladney, R., et al. (2018) Endoreduplication of the Mouse Genome in the Absence of ORC1. Genes & Development, 32, 978-990. [Google Scholar] [CrossRef] [PubMed]
[14] Li, J. and Cox, L.S. (2003) Characterisation of a Sexual Stage-Specific Gene Encoding ORC1 Homologue in the Human Malaria Parasite Plasmodium Falciparum. Parasitology International, 52, 41-52. [Google Scholar] [CrossRef] [PubMed]
[15] Noguchi, K., Vassilev, A., Ghosh, S., Yates, J.L. and DePamphilis, M.L. (2006) The BAH Domain Facilitates the Ability of Human Orc1 Protein to Activate Replication Origins in Vivo. The EMBO Journal, 25, 5372-5382. [Google Scholar] [CrossRef] [PubMed]
[16] Deshmukh, A.S., Srivastava, S., Herrmann, S., Gupta, A., Mitra, P., Gilberger, T.W., et al. (2012) The Role of N-Terminus of Plasmodium Falciparum ORC1 in Telomeric Localization and Var Gene Silencing. Nucleic Acids Research, 40, 5313-5331. [Google Scholar] [CrossRef] [PubMed]
[17] Duncker, B.P., Chesnokov, I.N. and McConkey, B.J. (2009) The Origin Recognition Complex Protein Family. Genome Biology, 10, Article No. 214. [Google Scholar] [CrossRef] [PubMed]
[18] Hossain, M., Bhalla, K. and Stillman, B. (2021) Multiple, Short Protein Binding Motifs in ORC1 and CDC6 Control the Initiation of DNA Replication. Molecular Cell, 81, 1951-1969.e6. [Google Scholar] [CrossRef] [PubMed]
[19] Wang, B. and Song, J. (2019) Structural Basis for the ORC1‐Cyclin A Association. Protein Science, 28, 1727-1733. [Google Scholar] [CrossRef] [PubMed]
[20] Emanuelsson, O., Nielsen, H., Brunak, S. and von Heijne, G. (2000) Predicting Subcellular Localization of Proteins Based on Their N-Terminal Amino Acid Sequence. Journal of Molecular Biology, 300, 1005-1016. [Google Scholar] [CrossRef] [PubMed]
[21] Kumar, D., Mukherji, A. and Saha, S. (2008) Expression and Subcellular Localization of ORC1 in Leishmania Major. Biochemical and Biophysical Research Communications, 375, 74-79. [Google Scholar] [CrossRef] [PubMed]
[22] Asano, M. and Wharton, R.P. (1999) E2F Mediates Developmental and Cell Cycle Regulation of ORC1 in Drosophila. The EMBO Journal, 18, 2435-2448. [Google Scholar] [CrossRef] [PubMed]
[23] Coffman, F.D., Reyes, M., Brown, M., Lambert, W.C. and Cohen, S. (2011) Localization of ORC1 during the Cell Cycle in Human Leukemia Cells. Analytical Cellular Pathology, 34, 355-361. [Google Scholar] [CrossRef] [PubMed]
[24] Dong, P., Xiong, Y., Yu, J., Chen, L., Tao, T., Yi, S., et al. (2018) Control of PD-L1 Expression by miR-140/142/340/383 and Oncogenic Activation of the OCT4-miR-18a Pathway in Cervical Cancer. Oncogene, 37, 5257-5268. [Google Scholar] [CrossRef] [PubMed]
[25] Zheng, R., Lin, S., Guan, L., Yuan, H., Liu, K., Liu, C., et al. (2018) Long Non-Coding RNA XIST Inhibited Breast Cancer Cell Growth, Migration, and Invasion via miR-155/CDX1 Axis. Biochemical and Biophysical Research Communications, 498, 1002-1008. [Google Scholar] [CrossRef] [PubMed]
[26] Wang, X., Wang, Q., Huang, J., Zhang, L., Zhou, X., Liu, J., et al. (2020) Novel Candidate Biomarkers of Origin Recognition Complex 1, 5 and 6 for Survival Surveillance in Patients with Hepatocellular Carcinoma. Journal of Cancer, 11, 1869-1882. [Google Scholar] [CrossRef] [PubMed]
[27] Lan, H., Tang, Z., Jin, H. and Sun, Y. (2016) Neddylation Inhibitor MLN4924 Suppresses Growth and Migration of Human Gastric Cancer Cells. Scientific Reports, 6, Article No. 24218. [Google Scholar] [CrossRef] [PubMed]
[28] Mendoza-Maldonado, R., Paolinelli, R., Galbiati, L., Giadrossi, S. and Giacca, M. (2010) Interaction of the Retinoblastoma Protein with ORC1 and Its Recruitment to Human Origins of DNA Replication. PLOS ONE, 5, e13720. [Google Scholar] [CrossRef] [PubMed]
[29] Young, A., Berry, R., Holloway, A.F., Blackburn, N.B., Dickinson, J.L., Skala, M., et al. (2014) RNA-Seq Profiling of a Radiation Resistant and Radiation Sensitive Prostate Cancer Cell Line Highlights Opposing Regulation of DNA Repair and Targets for Radiosensitization. BMC Cancer, 14, Article No. 808. [Google Scholar] [CrossRef] [PubMed]
[30] Wang, W., Liu, H., Wu, Y., Hong, Y., Yang, J., Liu, Y., et al. (2010) Estrogen Receptor α (ERα) Mediates 17β-Estradiol (E2)-Activated Expression of HBO1. Journal of Experimental & Clinical Cancer Research, 29, Article No. 140. [Google Scholar] [CrossRef] [PubMed]
[31] Bicknell, L.S., Walker, S., Klingseisen, A., Stiff, T., Leitch, A., Kerzendorfer, C., et al. (2011) Mutations in ORC1, Encoding the Largest Subunit of the Origin Recognition Complex, Cause Microcephalic Primordial Dwarfism Resembling Meier-Gorlin Syndrome. Nature Genetics, 43, 350-355. [Google Scholar] [CrossRef] [PubMed]
[32] Sun, M., Feng, X., Liu, Z., Han, W., Liang, Y.X. and She, Q. (2018) An ORC1/CDC6 Ortholog Functions as a Key Regulator in the DNA Damage Response in Archaea. Nucleic Acids Research, 46, 6697-6711. [Google Scholar] [CrossRef] [PubMed]
[33] Matsunuma, R., Niida, H., Ohhata, T., Kitagawa, K., Sakai, S., Uchida, C., et al. (2016) UV Damage-Induced Phosphorylation of HBO1 Triggers CRL4DDB2-Mediated Degradation to Regulate Cell Proliferation. Molecular and Cellular Biology, 36, 394-406. [Google Scholar] [CrossRef] [PubMed]
[34] Matsuoka, S., Ballif, B.A., Smogorzewska, A., McDonald, E.R., Hurov, K.E., Luo, J., et al. (2007) ATM and ATR Substrate Analysis Reveals Extensive Protein Networks Responsive to DNA Damage. Science, 316, 1160-1166. [Google Scholar] [CrossRef] [PubMed]
[35] Avvakumov, N., Lalonde, M., Saksouk, N., Paquet, E., Glass, K.C., Landry, A., et al. (2012) Conserved Molecular Interactions within the HBO1 Acetyltransferase Complexes Regulate Cell Proliferation. Molecular and Cellular Biology, 32, 689-703. [Google Scholar] [CrossRef] [PubMed]
[36] Ming, L., Han, Z., Ai, Z., Yang, X., Lin, F., Zhang, N., et al. (2024) Up-Regulated ORC1 Promotes Lung Adenocarcinoma by Inhibiting Ferroptosis via SLC7A11 Dependent Pathway. Heliyon, 10, e30506. [Google Scholar] [CrossRef] [PubMed]
[37] Shu, M., Qin, Y. and Jiang, M. (2008) RNA Interference Targeting ORC1 Gene Suppresses the Proliferation of Vascular Smooth Muscle Cells in Rats. Experimental and Molecular Pathology, 84, 206-212. [Google Scholar] [CrossRef] [PubMed]
[38] Jian, Y., Qiao, Q., Tang, J. and Qin, X. (2022) Origin Recognition Complex 1 Regulates Phospholipase Cδ1 to Inhibit Cell Proliferation, Migration and Epithelialmesenchymal Transition in Lung Adenocarcinoma. Oncology Letters, 24, Article No. 252. [Google Scholar] [CrossRef] [PubMed]
[39] Han, L. and Li, F. (2022) Origin Recognition Complex Subunit 1 (ORC1) Augments Malignant Behaviors of Lung Adenocarcinoma Cells via Targeting WNT Signaling. Bioengineered, 13, 13520-13533. [Google Scholar] [CrossRef] [PubMed]

为你推荐