线粒体microRNAs在肿瘤中的研究进展
Research Progress of Mitochondrial microRNAs in Tumorigenesi
DOI: 10.12677/acm.2025.151190, PDF,   
作者: 龙 胜:赣南医科大学第一临床医学院,江西 赣州;伍耿青*:赣南医科大学第一附属医院泌尿外科,江西 赣州
关键词: 线粒体microRNAs肿瘤分子机制Mitochondrial microRNA Tumor Molecular Control
摘要: microRNAs (miRNAs)是一类通常存在于细胞质中的短链非编码RNAs,通过与信使RNA (mRNA)的3'非翻译区(3'untranslated region, 3'UTR)结合,发挥调节转录后基因表达的功能。miRNAs在调控多种代谢过程和信号转导途径方面起着重要作用。线粒体是真核细胞中进行氧化代谢和ATP合成的关键场所,负责糖类、脂质和氨基酸等大分子的代谢。那些特异性定位于线粒体的miRNAs,以及在细胞质中直接或间接调节线粒体特定功能的miRNAs,被称为线粒体miRNAs (mitochondrial miRNAs, mitomiRs)。这些miRNAs能调控相关基因表达,并在关键线粒体代谢途径中发挥独特作用,从而促进肿瘤的发生与发展。本文重点探讨mitomiR在线粒体中的作用以及在肿瘤中的调控机制,旨在进一步阐明肿瘤发生发展的分子机制,开发潜在的癌症新疗法。
Abstract: microRNAs (miRNAs) are a class of short non-coding RNAs typically found in the cytoplasm. They function to regulate post-transcriptional gene expression by binding to the 3' untranslated region (3'UTR) of messenger RNA (mRNA). miRNAs play a crucial role in modulating various metabolic processes and signal transduction pathways. Mitochondria serve as the primary sites for oxidative metabolism and ATP synthesis in eukaryotic cells, and they are responsible for the metabolism of macromolecules, including sugars, lipids, and amino acids. Mitochondrial miRNAs (mitomiRs) are a subset of miRNAs localized specifically within mitochondria and modulate mitochondrial-specific functions, either directly or indirectly, within the cytoplasm. These mitomiRs can modulate gene expression and have a distinct role in pivotal mitochondrial metabolic pathways, thereby influencing the initiation and progression of tumors. This article concentrates on the role of mitomiRs in mitochondria and their regulatory mechanisms in tumorigenesis, with the goal of further elucidating the molecular underpinnings of tumorigenesis and development, and of identifying potential novel therapeutic targets for cancer.
文章引用:龙胜, 伍耿青. 线粒体microRNAs在肿瘤中的研究进展[J]. 临床医学进展, 2025, 15(1): 1420-1428. https://doi.org/10.12677/acm.2025.151190

参考文献

[1] Yuan, Z., Li, Y., Zhang, S., Wang, X., Dou, H., Yu, X., et al. (2023) Extracellular Matrix Remodeling in Tumor Progression and Immune Escape: From Mechanisms to Treatments. Molecular Cancer, 22, Article No. 48. [Google Scholar] [CrossRef] [PubMed]
[2] Wang, L., Wu, C., Rajasekaran, N. and Shin, Y.K. (2018) Loss of Tumor Suppressor Gene Function in Human Cancer: An Overview. Cellular Physiology and Biochemistry, 51, 2647-2693. [Google Scholar] [CrossRef] [PubMed]
[3] Bienertova-Vasku, J., Sana, J. and Slaby, O. (2013) The Role of MicroRNAs in Mitochondria in Cancer. Cancer Letters, 336, 1-7. [Google Scholar] [CrossRef] [PubMed]
[4] Rencelj, A., Gvozdenovic, N. and Cemazar, M. (2021) MitomiRs: Their Roles in Mitochondria and Importance in Cancer Cell Metabolism. Radiology and Oncology, 55, 379-392. [Google Scholar] [CrossRef] [PubMed]
[5] Loh, H., Norman, B.P., Lai, K., Rahman, N.M.A.N.A., Alitheen, N.B.M. and Osman, M.A. (2019) The Regulatory Role of Micrornas in Breast Cancer. International Journal of Molecular Sciences, 20, Article 4940. [Google Scholar] [CrossRef] [PubMed]
[6] Petrovic, N., Davidovic, R., Bajic, V., Obradovic, M. and Isenovic, R.E. (2017) MicroRNA in Breast Cancer: The Association with BRCA1/2. Cancer Biomarkers, 19, 119-128. [Google Scholar] [CrossRef] [PubMed]
[7] Zong, W., Rabinowitz, J.D. and White, E. (2016) Mitochondria and Cancer. Molecular Cell, 61, 667-676. [Google Scholar] [CrossRef] [PubMed]
[8] Mercer, T.R., Neph, S., Dinger, M.E., Crawford, J., Smith, M.A., Shearwood, A.J., et al. (2011) The Human Mitochondrial Transcriptome. Cell, 146, 645-658. [Google Scholar] [CrossRef] [PubMed]
[9] Nunnari, J. and Suomalainen, A. (2012) Mitochondria: In Sickness and in Health. Cell, 148, 1145-1159. [Google Scholar] [CrossRef] [PubMed]
[10] Jeong, S. and Seol, D. (2008) The Role of Mitochondria in Apoptosis. BMB Reports, 41, 11-22. [Google Scholar] [CrossRef] [PubMed]
[11] Adams, J.M. and Cory, S. (2007) The Bcl-2 Apoptotic Switch in Cancer Development and Therapy. Oncogene, 26, 1324-1337. [Google Scholar] [CrossRef] [PubMed]
[12] Geiger, J. and Dalgaard, L.T. (2016) Interplay of Mitochondrial Metabolism and MicroRNAs. Cellular and Molecular Life Sciences, 74, 631-646. [Google Scholar] [CrossRef] [PubMed]
[13] Ziemann, M., Lim, S.C., Kang, Y., Samuel, S., Sanchez, I.L., Gantier, M., et al. (2022) MicroRNA-101-3p Modulates Mitochondrial Metabolism via the Regulation of Complex II Assembly. Journal of Molecular Biology, 434, Article 167361. [Google Scholar] [CrossRef] [PubMed]
[14] Zheng, J. (2012) Energy Metabolism of Cancer: Glycolysis versus Oxidative Phosphorylation (Review). Oncology Letters, 4, 1151-1157. [Google Scholar] [CrossRef] [PubMed]
[15] Willers, I.M., Martínez-Reyes, I., Martínez-Diez, M. and Cuezva, J.M. (2012) miR-127-5p Targets the 3’UTR of Human β-F1-ATPase mRNA and Inhibits Its Translation. Biochimica et Biophysica Acta (BBA)-Bioenergetics, 1817, 838-848. [Google Scholar] [CrossRef] [PubMed]
[16] Carrer, M., Liu, N., Grueter, C.E., Williams, A.H., Frisard, M.I., Hulver, M.W., et al. (2012) Control of Mitochondrial Metabolism and Systemic Energy Homeostasis by MicroRNAs 378 and 378*. Proceedings of the National Academy of Sciences, 109, 15330-15335. [Google Scholar] [CrossRef] [PubMed]
[17] Bandiera, S., Rüberg, S., Girard, M., Cagnard, N., Hanein, S., Chrétien, D., et al. (2011) Nuclear Outsourcing of RNA Interference Components to Human Mitochondria. PLOS ONE, 6, e20746. [Google Scholar] [CrossRef] [PubMed]
[18] Das, S., Ferlito, M., Kent, O.A., Fox-Talbot, K., Wang, R., Liu, D., et al. (2012) Nuclear miRNA Regulates the Mitochondrial Genome in the Heart. Circulation Research, 110, 1596-1603. [Google Scholar] [CrossRef] [PubMed]
[19] Rayner, K.J., Esau, C.C., Hussain, F.N., McDaniel, A.L., Marshall, S.M., van Gils, J.M., et al. (2011) Inhibition of miR-33a/b in Non-Human Primates Raises Plasma HDL and Lowers VLDL Triglycerides. Nature, 478, 404-407. [Google Scholar] [CrossRef] [PubMed]
[20] Xu, Y., Fang, F., Zhang, J., Josson, S., St. Clair, W.H. and St. Clair, D.K. (2010) miR-17* Suppresses Tumorigenicity of Prostate Cancer by Inhibiting Mitochondrial Antioxidant Enzymes. PLOS ONE, 5, e14356. [Google Scholar] [CrossRef] [PubMed]
[21] Marwarha, G., Røsand, Ø., Slagsvold, K.H. and Høydal, M.A. (2022) GSK3β Inhibition Is the Molecular Pivot That Underlies the miR-210-Induced Attenuation of Intrinsic Apoptosis Cascade during Hypoxia. International Journal of Molecular Sciences, 23, Article 9375. [Google Scholar] [CrossRef] [PubMed]
[22] Fang, J., Song, X., Tian, J., Chen, H., Li, D., Wang, J., et al. (2011) Overexpression of MicroRNA-378 Attenuates Ischemia-Induced Apoptosis by Inhibiting Caspase-3 Expression in Cardiac Myocytes. Apoptosis, 17, 410-423. [Google Scholar] [CrossRef] [PubMed]
[23] Cheng, Y., Zhang, D., Zhu, M., Wang, Y., Guo, S., Xu, B., et al. (2018) Liver X Receptor Α Is Targeted by MicroRNA-1 to Inhibit Cardiomyocyte Apoptosis through a Ros-Mediated Mitochondrial Pathway. Biochemistry and Cell Biology, 96, 11-18. [Google Scholar] [CrossRef] [PubMed]
[24] Liu, L., Zhang, G., Liang, Z., Liu, X., Li, T., Fan, J., et al. (2013) MicroRNA-15b Enhances Hypoxia/Reoxygenation-Induced Apoptosis of Cardiomyocytes via a Mitochondrial Apoptotic Pathway. Apoptosis, 19, 19-29. [Google Scholar] [CrossRef] [PubMed]
[25] Pandey, A., Pain, J., Ghosh, A.K., Dancis, A. and Pain, D. (2015) Fe-S Cluster Biogenesis in Isolated Mammalian Mitochondria: Coordinated Use of Persulfide Sulfur and Iron and Requirements for GTP, NADH, and ATP. Journal of Biological Chemistry, 290, 640-657. [Google Scholar] [CrossRef] [PubMed]
[26] Gee, H.E., Ivan, C., Calin, G.A. and Ivan, M. (2014) HypoxamiRs and Cancer: From Biology to Targeted Therapy. Antioxidants & Redox Signaling, 21, 1220-1238. [Google Scholar] [CrossRef] [PubMed]
[27] Yoshioka, Y., Kosaka, N., Ochiya, T. and Kato, T. (2012) Micromanaging Iron Homeostasis: Hypoxia-Inducible Micro-RNA-210 Suppresses Iron Homeostasis-Related Proteins. Journal of Biological Chemistry, 287, 34110-34119. [Google Scholar] [CrossRef] [PubMed]
[28] Hale, A., Lee, C., Annis, S., Min, P., Pande, R., Creager, M.A., et al. (2014) An Argonaute 2 Switch Regulates Circulating miR-210 to Coordinate Hypoxic Adaptation across Cells. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research, 1843, 2528-2542. [Google Scholar] [CrossRef] [PubMed]
[29] Komatsu, S., Kitai, H. and Suzuki, H.I. (2023) Network Regulation of MicroRNA Biogenesis and Target Interaction. Cells, 12, Article 306. [Google Scholar] [CrossRef] [PubMed]
[30] Bandiera, S., Matégot, R., Girard, M., Demongeot, J. and Henrion-Caude, A. (2013) MitomiRs Delineating the Intracellular Localization of MicroRNAs at Mitochondria. Free Radical Biology and Medicine, 64, 12-19. [Google Scholar] [CrossRef] [PubMed]
[31] Kelly, T.J., Souza, A.L., Clish, C.B. and Puigserver, P. (2011) A Hypoxia-Induced Positive Feedback Loop Promotes Hypoxia-Inducible Factor 1α Stability through miR-210 Suppression of Glycerol-3-Phosphate Dehydrogenase 1-Like. Molecular and Cellular Biology, 31, 2696-2706. [Google Scholar] [CrossRef] [PubMed]
[32] Chan, S.Y., Zhang, Y., Hemann, C., Mahoney, C.E., Zweier, J.L. and Loscalzo, J. (2009) MicroRNA-210 Controls Mitochondrial Metabolism during Hypoxia by Repressing the Iron-Sulfur Cluster Assembly Proteins ISCU1/2. Cell Metabolism, 10, 273-284. [Google Scholar] [CrossRef] [PubMed]
[33] Chen, Z., Li, Y., Zhang, H., Huang, P. and Luthra, R. (2010) Hypoxia-Regulated MicroRNA-210 Modulates Mitochondrial Function and Decreases ISCU and COX10 Expression. Oncogene, 29, 4362-4368. [Google Scholar] [CrossRef] [PubMed]
[34] Krutilina, R., Sun, W., Sethuraman, A., Brown, M., Seagroves, T.N., Pfeffer, L.M., et al. (2014) MicroRNA-18a Inhibits Hypoxia-Inducible Factor 1α Activity and Lung Metastasis in Basal Breast Cancers. Breast Cancer Research, 16, Article No. R78. [Google Scholar] [CrossRef] [PubMed]
[35] Wang, Y., Dai, Y., Wang, S., Qiu, M., Quan, Z., Liu, Y., et al. (2017) MiR-199a-5p Inhibits Proliferation and Induces Apoptosis in Hemangioma Cells through Targeting HIF1A. International Journal of Immunopathology and Pharmacology, 31. [Google Scholar] [CrossRef] [PubMed]
[36] Wang, X., Ren, H., Zhao, T., Ma, W., Dong, J., Zhang, S., et al. (2016) Single Nucleotide Polymorphism in the MicroRNA-199a Binding Site of HIF1A Gene Is Associated with Pancreatic Ductal Adenocarcinoma Risk and Worse Clinical Outcomes. Oncotarget, 7, 13717-13729. [Google Scholar] [CrossRef] [PubMed]
[37] Sun, X., Charbonneau, C., Wei, L., Chen, Q. and Terek, R.M. (2015) MiR-181a Targets RGS16 to Promote Chondrosarcoma Growth, Angiogenesis, and Metastasis. Molecular Cancer Research, 13, 1347-1357. [Google Scholar] [CrossRef] [PubMed]
[38] Zhuang, X., Chen, Y., Wu, Z., Xu, Q., Chen, M., Shao, M., et al. (2019) Mitochondrial MiR-181a-5p Promotes Glucose Metabolism Reprogramming in Liver Cancer by Regulating the Electron Transport Chain. Carcinogenesis, 41, 972-983. [Google Scholar] [CrossRef] [PubMed]
[39] Liberti, M.V. and Locasale, J.W. (2016) The Warburg Effect: How Does It Benefit Cancer Cells? Trends in Biochemical Sciences, 41, 211-218. [Google Scholar] [CrossRef] [PubMed]
[40] Qu, C., Yan, C., Cao, W., Li, F., Qu, Y., Guan, K., et al. (2019) MiR‐128‐3p Contributes to Mitochondrial Dysfunction and Induces Apoptosis in Glioma Cells via Targeting Pyruvate Dehydrogenase Kinase 1. IUBMB Life, 72, 465-475. [Google Scholar] [CrossRef] [PubMed]
[41] Jiang, S., Zhang, L., Zhang, H., Hu, S., Lu, M., Liang, S., et al. (2012) A Novel miR-155/miR-143 Cascade Controls Glycolysis by Regulating Hexokinase 2 in Breast Cancer Cells. The EMBO Journal, 31, 1985-1998. [Google Scholar] [CrossRef] [PubMed]
[42] Sharma, P. and Kumar, S. (2018) Metformin Inhibits Human Breast Cancer Cell Growth by Promoting Apoptosis via a ROS-Independent Pathway Involving Mitochondrial Dysfunction: Pivotal Role of Superoxide Dismutase (SOD). Cellular Oncology, 41, 637-650. [Google Scholar] [CrossRef] [PubMed]
[43] Kardani, A., Yaghoobi, H., Alibakhshi, A. and Khatami, M. (2020) Inhibition of miR‐155 in MCF‐7 Breast Cancer Cell Line by Gold Nanoparticles Functionalized with Antagomir and AS1411 Aptamer. Journal of Cellular Physiology, 235, 6887-6895. [Google Scholar] [CrossRef] [PubMed]
[44] Ma, X., Li, C., Sun, L., Huang, D., Li, T., He, X., et al. (2014) Lin28/Let-7 Axis Regulates Aerobic Glycolysis and Cancer Progression via PDK1. Nature Communications, 5, Article No. 5212. [Google Scholar] [CrossRef] [PubMed]
[45] Zhao, L., Chen, X. and Cao, Y. (2011) New Role of MicroRNA: Carcinogenesis and Clinical Application in Cancer. Acta Biochimica et Biophysica Sinica, 43, 831-839. [Google Scholar] [CrossRef] [PubMed]
[46] Zhang, S., Liu, C. and Zhang, X. (2019) Mitochondrial Damage Mediated by miR-1 Overexpression in Cancer Stem Cells. Molecular Therapy-Nucleic Acids, 18, 938-953. [Google Scholar] [CrossRef] [PubMed]
[47] Wallace, L., Aikhionbare, K., Banerjee, S., Peagler, K., Pitts, M., Yao, X., et al. (2021) Differential Expression Profiles of Mitogenome Associated MicroRNAs among Colorectal Adenomatous Polyps. Cancer Research Journal, 9, 23-33. [Google Scholar] [CrossRef
[48] Castellani, G., Buccarelli, M., Lulli, V., Ilari, R., De Luca, G., Pedini, F., et al. (2022) MiR-378a-3p Acts as a Tumor Suppressor in Colorectal Cancer Stem-Like Cells and Affects the Expression of MALAT1 and NEAT1 LncRNAs. Frontiers in Oncology, 12, Article 867886. [Google Scholar] [CrossRef] [PubMed]
[49] Fan, S., Tian, T., Chen, W., Lv, X., Lei, X., Zhang, H., et al. (2019) Mitochondrial MiRNA Determines Chemoresistance by Reprogramming Metabolism and Regulating Mitochondrial Transcription. Cancer Research, 79, 1069-1084. [Google Scholar] [CrossRef] [PubMed]
[50] Mehla, K. and Singh, P.K. (2019) Metabolic Regulation of Macrophage Polarization in Cancer. Trends in Cancer, 5, 822-834. [Google Scholar] [CrossRef] [PubMed]
[51] Qing, J., Zhang, Z., Novák, P., Zhao, G. and Yin, K. (2020) Mitochondrial Metabolism in Regulating Macrophage Polarization: An Emerging Regulator of Metabolic Inflammatory Diseases. Acta Biochimica et Biophysica Sinica, 52, 917-926. [Google Scholar] [CrossRef] [PubMed]
[52] Duroux-Richard, I., Apparailly, F. and Khoury, M. (2021) Mitochondrial MicroRNAs Contribute to Macrophage Immune Functions Including Differentiation, Polarization, and Activation. Frontiers in Physiology, 12, Article 738140. [Google Scholar] [CrossRef] [PubMed]
[53] Zhang, S., He, K., Zhou, W., Cao, J. and Jin, Z. (2019) MiR-494-3p Regulates Lipopolysaccharide-Induced Inflammatory Responses in RAW264.7 Cells by Targeting PTEN. Molecular Medicine Reports, 19, 4288-4296. [Google Scholar] [CrossRef] [PubMed]
[54] Zhu, L., Wang, X., Wang, T., Zhu, W. and Zhou, X. (2018) MiR-494-3p Promotes the Progression of Endometrial Cancer by Regulating the PTEN/PI3K/AKT Pathway. Molecular Medicine Reports, 19, 581-588. [Google Scholar] [CrossRef] [PubMed]
[55] Yang, M., Li, C., Zhu, S., Cao, L., Kroemer, G., Zeh, H., et al. (2018) TFAM Is a Novel Mediator of Immunogenic Cancer Cell Death. OncoImmunology, 7, e1431086. [Google Scholar] [CrossRef] [PubMed]
[56] Yao, J., Zhou, E., Wang, Y., Xu, F., Zhang, D. and Zhong, D. (2014) MicroRNA-200a Inhibits Cell Proliferation by Targeting Mitochondrial Transcription Factor a in Breast Cancer. DNA and Cell Biology, 33, 291-300. [Google Scholar] [CrossRef] [PubMed]
[57] Fan, X., Zhou, S., Zheng, M., Deng, X., Yi, Y. and Huang, T. (2017) MiR-199a-3p Enhances Breast Cancer Cell Sensitivity to Cisplatin by Downregulating TFAM (TFAM). Biomedicine & Pharmacotherapy, 88, 507-514. [Google Scholar] [CrossRef] [PubMed]