m6A甲基化修饰在骨肉瘤中的作用与机制研究进展
The Role and Mechanism of m6A Methylation Modification in Osteosarcoma
DOI: 10.12677/acm.2025.1561746, PDF,   
作者: 潘艳齐：内蒙古医科大学研究生院，内蒙古 呼和浩特；冯 卫：内蒙古医科大学第二附属医院创伤外科，内蒙古 呼和浩特
关键词: 骨肉瘤；甲基化修饰；生物学功能；放化疗；分子机制；Osteosarcoma； Methylation Modification； Biological Function； Chemoradiotherapy； Molecular Mechanism
摘要: 骨肉瘤(osteosarcoma, OS)是儿童和青少年最常见的原发性骨恶性肿瘤，具有高度侵袭性和转移性，且预后不良，患者的5年生存率较低。N6-甲基腺苷(N6-methyladenosine, m6A)是真核细胞mRNA修饰中最常见的一种，在众多的生物学活动中都起到重要作用。最近研究发现，m6A甲基化修饰在RNA甲基化中扮演了关键角色，通过对“writer”，“eraser”和“reader”等分子的动态调节，参与mRNA的剪接、去核翻译、降解和稳定等生物学过程，对多种疾病产生重要影响，包括癌症。RNA的m6A甲基化与骨肉瘤密切相关，但机制尚未明确。本文就m6A修饰及其相关酶在骨肉瘤生物学功能中的调控机制，以及其在骨肉瘤发病机制、预后中的作用研究进展作一综述，可能为骨肉瘤的治疗提供新的思路与理论依据。
Abstract: Osteosarcoma (OS), the most prevalent primary malignant bone tumor in children and adolescents, exhibits high invasiveness, metastatic potential, and poor prognosis, with notably low 5-year survival rates. N6-methyladenosine (m6A), the predominant post-transcriptional modification in eukaryotic mRNA, plays crucial regulatory roles in diverse biological processes. Emerging evidence reveals that m6A methylation critically modulates RNA metabolism through dynamic coordination of “writer”, “eraser”, and “reader”, thereby governing mRNA splicing, nucleocytoplasmic transport, translation efficiency, degradation, and stability. This epigenetic mechanism significantly impacts various pathological processes, including carcinogenesis. Although RNA m6A methylation demonstrates close associations with osteosarcoma progression, its underlying mechanisms remain incompletely elucidated. This review systematically examines current advances in understanding the regulatory mechanisms of m6A modifications and associated enzymes in osteosarcoma biology, with emphasis on their pathophysiological roles in tumorigenesis, and prognostic evaluation. The synthesis of these findings may provide novel therapeutic strategies and theoretical foundations for improving clinical management of osteosarcoma.
文章引用：潘艳齐, 冯卫. m6A甲基化修饰在骨肉瘤中的作用与机制研究进展[J]. 临床医学进展, 2025, 15(6): 449-455. https://doi.org/10.12677/acm.2025.1561746

参考文献

[1] Chen, C., Shi, Q., Xu, J., Ren, T., Huang, Y. and Guo, W. (2022) Current Progress and Open Challenges for Applying Tyrosine Kinase Inhibitors in Osteosarcoma. Cell Death Discovery, 8, Article No. 488. [Google Scholar] [CrossRef] [PubMed]
[2] Cao, D., Ge, S. and Li, M. (2022) MiR-451a Promotes Cell Growth, Migration and EMT in Osteosarcoma by Regulating YTHDC1-Mediated M6a Methylation to Activate the AKT/mTOR Signaling Pathway. Journal of Bone Oncology, 33, Article ID: 100412. [Google Scholar] [CrossRef] [PubMed]
[3] Yang, Y., Zhou, Y., Wang, J., Zhou, Y., Watowich, S.S. and Kleinerman, E.S. (2024) CD103+ cDC1 Dendritic Cell Vaccine Therapy for Osteosarcoma Lung Metastases. Cancers, 16, Article 3251. [Google Scholar] [CrossRef] [PubMed]
[4] de Azevedo, J., Fernandes, T., Fernandes, J., de Azevedo, J., Lanza, D., Bezerra, C., et al. (2019) Biology and Pathogenesis of Human Osteosarcoma (Review). Oncology Letters, 19, 1099-1116. [Google Scholar] [CrossRef] [PubMed]
[5] Luo, Q., Yang, Z., Deng, R., Pang, X., Han, X., Liu, X., et al. (2023) Comprehensive Analysis of Prognosis of Patients with GBM Based on 4 m6A-Related LncRNAs and Immune Cell Infiltration. Heliyon, 9, e12838. [Google Scholar] [CrossRef] [PubMed]
[6] Shi, H., Chai, P., Jia, R. and Fan, X. (2020) Novel Insight into the Regulatory Roles of Diverse RNA Modifications: Re-Defining the Bridge between Transcription and Translation. Molecular Cancer, 19, Article No. 78. [Google Scholar] [CrossRef] [PubMed]
[7] Ling, Z., Chen, L. and Zhao, J. (2020) m6A-Dependent Up-Regulation of DRG1 by METTL3 and ELAVL1 Promotes Growth, Migration, and Colony Formation in Osteosarcoma. Bioscience Reports, 40, BSR20200282. [Google Scholar] [CrossRef] [PubMed]
[8] 王闻雪, 谭理, 汤博艺, 等. m6A甲基化修饰与骨肉瘤研究进展[J]. 中国骨与关节杂志, 2022, 11(5): 384-389.
[9] Wu, Q., Yin, X., Zhao, W., Xu, W. and Chen, L. (2022) Molecular Mechanism of m6A Methylation of Circdlc1 Mediated by RNA Methyltransferase METTL3 in the Malignant Proliferation of Glioma Cells. Cell Death Discovery, 8, Article No. 229. [Google Scholar] [CrossRef] [PubMed]
[10] Liu, Z., Liu, N., Huang, Z. and Wang, W. (2020) METTL14 Overexpression Promotes Osteosarcoma Cell Apoptosis and Slows Tumor Progression via Caspase 3 Activation. Cancer Management and Research, 12, 12759-12767. [Google Scholar] [CrossRef] [PubMed]
[11] Wu, H., Lai, G., Cheng, R., Huang, H., Wang, J., Liu, Z., et al. (2025) Discovery of Covalent and Cell‐Active ALKBH5 Inhibitors with Potent Antileukemia Effects in Vivo. Angewandte Chemie International Edition, 64, e202424928. [Google Scholar] [CrossRef] [PubMed]
[12] Lv, D., Ding, S., Zhong, L., Tu, J., Li, H., Yao, H., et al. (2022) M6A Demethylase FTO-Mediated Downregulation of DACT1 mRNA Stability Promotes Wnt Signaling to Facilitate Osteosarcoma Progression. Oncogene, 41, 1727-1741. [Google Scholar] [CrossRef] [PubMed]
[13] Mei, Z., Shen, Z., Pu, J., Liu, Q., Liu, G., He, X., et al. (2024) NAT10 Mediated ac4C Acetylation Driven m6A Modification via Involvement of YTHDC1-LDHA/PFKM Regulates Glycolysis and Promotes Osteosarcoma. Cell Communication and Signaling, 22, Article No. 51. [Google Scholar] [CrossRef] [PubMed]
[14] He, Q., Hao, P., He, G., Mai, H., Liu, W., Zhang, W., et al. (2022) IGF2BP1-Regulated Expression of Errα Is Involved in Metabolic Reprogramming of Chemotherapy Resistant Osteosarcoma Cells. Journal of Translational Medicine, 20, Article No. 348. [Google Scholar] [CrossRef] [PubMed]
[15] Liu, X., Yuan, L., Gao, Y., Zhou, L., Yang, J. and Pei, Z. (2020) Overexpression of METTL3 Associated with the Metabolic Status on 18F-FDG PET/CT in Patients with Esophageal Carcinoma. Journal of Cancer, 11, 4851-4860. [Google Scholar] [CrossRef] [PubMed]
[16] Yu, H., Yang, X., Tang, J., Si, S., Zhou, Z., Lu, J., et al. (2021) ALKBH5 Inhibited Cell Proliferation and Sensitized Bladder Cancer Cells to Cisplatin by m6A-CK2α-Mediated Glycolysis. Molecular Therapy—Nucleic Acids, 23, 27-41. [Google Scholar] [CrossRef] [PubMed]
[17] Quinn, J.M., Greenwade, M.M., Palisoul, M.L., Opara, G., Massad, K., Guo, L., et al. (2019) Therapeutic Inhibition of the Receptor Tyrosine Kinase AXL Improves Sensitivity to Platinum and Taxane in Ovarian Cancer. Molecular Cancer Therapeutics, 18, 389-398. [Google Scholar] [CrossRef] [PubMed]
[18] Huang, Z., Chen, P. and Liu, Y. (2024) WTAP‐Mediated m6A Modification of Circ_0032463 Promotes Osteosarcoma Progression by Sponging Mir‐145‐5p and Regulating GFRA1 Expression. Journal of Biochemical and Molecular Toxicology, 38, e23833. [Google Scholar] [CrossRef] [PubMed]
[19] Xu, J., Koch, J., Schmidt, C., Nientiedt, M., Neuberger, M., Erben, P., et al. (2025) Loss of YTHDC1 m6A Reading Function Promotes Invasiveness in Urothelial Carcinoma of the Bladder. Experimental & Molecular Medicine, 57, 118-130. [Google Scholar] [CrossRef] [PubMed]
[20] Tang, W., Kong, X., He, S., Deng, J., Mao, M., Peng, S., et al. (2024) WTAP Regulates SOX1 Expression to Affect the Tumorigenicity of Colorectal Cancer via an m6A-YTHDF2-Dependent Manner. Digestive Diseases and Sciences, 70, 598-611. [Google Scholar] [CrossRef] [PubMed]
[21] Zhao, X., Wu, Q., Gong, X., Liu, J. and Ma, Y. (2021) Osteosarcoma: A Review of Current and Future Therapeutic Approaches. BioMedical Engineering OnLine, 20, Article No. 24. [Google Scholar] [CrossRef] [PubMed]
[22] Tang, Q., Wang, L., Wang, Y., Gao, H. and Hou, Z. (2019) Efficacy of Methotrexate, Doxorubicin, and Cisplatin for Osteosarcoma: Study Protocol for a Systematic Review of Randomized Controlled Trial. Medicine, 98, e14442. [Google Scholar] [CrossRef] [PubMed]
[23] Qiu, Y.Q. and Chen, Y.L. (2020) Primary Meningeal Osteoblastic Osteosarcoma Containing Fibroblast Osteosarcoma: Clinicopathological Analysis and Literature Review. Osteoporosis International, 32, 1007-1012. [Google Scholar] [CrossRef] [PubMed]
[24] Pan, X., Hong, X., Li, S., Meng, P. and Xiao, F. (2021) METTL3 Promotes Adriamycin Resistance in MCF-7 Breast Cancer Cells by Accelerating Pri-MicroRNA-221-3p Maturation in a m6A-Dependent Manner. Experimental & Molecular Medicine, 53, 91-102. [Google Scholar] [CrossRef] [PubMed]
[25] Wang, C., Liang, W., Zhong, J., Liu, J., Zhou, C., Ma, C., et al. (2025) M6A-Mediated REGULATION of CPSF6 by METTL3 Promotes Oxaliplatin Resistance in Colorectal Cancer through Enhanced Glycolysis. Cellular Signalling, 130, Article ID: 111676. [Google Scholar] [CrossRef] [PubMed]
[26] Fan, X., Han, F., Wang, H., Shu, Z., Qiu, B., Zeng, F., et al. (2025) YTHDF2-Mediated m6A Modification of ONECUT2 Promotes Stemness and Oxaliplatin Resistance in Gastric Cancer through Transcriptionally Activating TFPI. Drug Resistance Updates, 79, Article ID: 101200. [Google Scholar] [CrossRef] [PubMed]
[27] Li, H., Li, Y., Zheng, X., Chen, F., Zhang, S., Xu, S., et al. (2024) RBM15 Facilitates Osimertinib Resistance of Lung Adenocarcinoma through m6A-Dependent Epigenetic Silencing of SPOCK1. Oncogene, 44, 307-321. [Google Scholar] [CrossRef] [PubMed]
[28] Zhang, Y., Shen, G., Zhang, D., Meng, T., Lv, Z., Chen, L., et al. (2025) N6‐Methyladenosine Modification Mediated by METTL3 Promotes DNA‐PKcs Expression to Induce Anlotinib Resistance in Osteosarcoma. Clinical and Translational Medicine, 15, e70228. [Google Scholar] [CrossRef] [PubMed]
[29] Zhou, L., Yang, C., Zhang, N., Zhang, X., Zhao, T. and Yu, J. (2020) Silencing METTL3 Inhibits the Proliferation and Invasion of Osteosarcoma by Regulating ATAD2. Biomedicine & Pharmacotherapy, 125, Article ID: 109964. [Google Scholar] [CrossRef] [PubMed]
[30] Jiang, R., Dai, Z., Wu, J., Ji, S., Sun, Y. and Yang, W. (2022) METTL3 Stabilizes HDAC5 mRNA in an m6A-Dependent Manner to Facilitate Malignant Proliferation of Osteosarcoma Cells. Cell Death Discovery, 8, Article No. 179. [Google Scholar] [CrossRef] [PubMed]
[31] Li, J., Rao, B., Yang, J., Liu, L., Huang, M., Liu, X., et al. (2020) Dysregulated m6A-Related Regulators Are Associated with Tumor Metastasis and Poor Prognosis in Osteosarcoma. Frontiers in Oncology, 10, Article 769. [Google Scholar] [CrossRef] [PubMed]
[32] Chen, S., Li, Y., Zhi, S., Ding, Z., Wang, W., Peng, Y., et al. (2020) WTAP Promotes Osteosarcoma Tumorigenesis by Repressing HMBOX1 Expression in an m6A-Dependent Manner. Cell Death & Disease, 11, Article No. 659. [Google Scholar] [CrossRef] [PubMed]
[33] Liu, H., Qin, G., Ji, Y., Wang, X., Bao, H., Guan, X., et al. (2021) Potential Role of m6A RNA Methylation Regulators in Osteosarcoma and Its Clinical Prognostic Value. Journal of Orthopaedic Surgery and Research, 16, Article No. 294. [Google Scholar] [CrossRef] [PubMed]
[34] Yuan, Y., Yan, G., He, M., Lei, H., Li, L., Wang, Y., et al. (2021) ALKBH5 Suppresses Tumor Progression via an m6A-Dependent Epigenetic Silencing of Pre-miR-181b-1/Yap Signaling Axis in Osteosarcoma. Cell Death & Disease, 12, Article No. 60. [Google Scholar] [CrossRef] [PubMed]
[35] Xu, M., Zhang, T., Xia, R., Wei, Y. and Wei, X. (2022) Targeting the Tumor Stroma for Cancer Therapy. Molecular Cancer, 21, Article No. 208. [Google Scholar] [CrossRef] [PubMed]
[36] Si, C., Chen, C., Guo, Y., Kang, Q. and Sun, Z. (2021) Effect, Mechanism, and Applications of Coding/Non-Coding RNA m6A Modification in Tumor Microenvironment. Frontiers in Cell and Developmental Biology, 9, Article 711815. [Google Scholar] [CrossRef] [PubMed]
[37] Wang, D., Han, Y., Peng, L., Huang, T., He, X., Wang, J., et al. (2023) Crosstalk between N6-Methyladenosine (m6A) Modification and Noncoding RNA in Tumor Microenvironment. International Journal of Biological Sciences, 19, 2198-2219. [Google Scholar] [CrossRef] [PubMed]
[38] Di, Z., Ling, Y., Zhun, W., et al. (2022) N6-Methyladenosine-Related lncRNAs Are Potential Prognostic Biomarkers and Correlated with Tumor Immune Microenvironment in Osteosarcoma. Frontiers in Genetics, 12, Article 805607.
[39] Chen, S., Zhou, L. and Wang, Y. (2020) ALKBH5-Mediated m6A Demethylation of LncRNA PVT1 Plays an Oncogenic Role in Osteosarcoma. Cancer Cell International, 20, Article No. 34. [Google Scholar] [CrossRef] [PubMed]
[40] Wang, Y., Lu, J., Wu, Q., Jin, Y., Wang, D., Chen, Y., et al. (2019) LncRNA LINRIS Stabilizes IGF2BP2 and Promotes the Aerobic Glycolysis in Colorectal Cancer. Molecular Cancer, 18, Article No. 174. [Google Scholar] [CrossRef] [PubMed]
[41] Bi, Y., Meng, D., Wan, M., Xu, N., Xu, Y., Yuan, K., et al. (2022) m6A-Related LncRNAs Predict Overall Survival of Patients and Regulate the Tumor Immune Microenvironment in Osteosarcoma. Computational Intelligence and Neuroscience, 2022, Article ID: 9315283. [Google Scholar] [CrossRef] [PubMed]
[42] Lai, Y., Liu, J., Hu, X., Zeng, X. and Gao, P. (2025) N6-Methyladenosine (m6A)-Forming Enzyme METTL3 Controls UAF1 Stability to Promote Inflammation in a Model of Colitis by Stimulating NLRP3. Scientific Reports, 15, Article No. 5876. [Google Scholar] [CrossRef] [PubMed]
[43] Jiang, Z., Zhang, C., Liu, R., Zhu, Z., Long, D., Wen, X., et al. (2025) M6A Demethyltransferase FTO Attenuates Meniscus Degeneration and Osteoarthritis via Orchestrating Autophagy and Energetic Metabolism. Advanced Science, 12, Article ID: 2412379. [Google Scholar] [CrossRef] [PubMed]
[44] Han, N., Yu, N. and Yu, L. (2025) The mRNA Stability of PIEZO1, Regulated by Methyltransferase-Like 3 via N6-Methylation of Adenosine Modification in a YT521-B Homology Domain Family 2-Dependent Manner, Facilitates the Progression of Diabetic Retinopathy. The American Journal of Pathology, 195, 265-280. [Google Scholar] [CrossRef] [PubMed]

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