Novel Detection and Clinical Utility of Serum-Derived Extracellular Vesicle in Angiosarcoma
DOI:
https://doi.org/10.2340/actadv.v105.40902Keywords:
Angiosarcoma, Serum, Extracellular vesicle, MicroRNA, BiomarkerAbstract
Cutaneous angiosarcoma is a rare and highly aggressive skin malignancy. The aim of this study is to explore the alteration of serum-derived extracellular vesicle (EV) in angiosarcoma patients and to evaluate its clinical utility as a novel circulating biomarker. In a microarray analysis to examine the differential expression of specific EV-associated microRNAs in sera between cutaneous angiosarcoma patients and healthy controls, 73 microRNAs with significant upregulation and 100 microRNAs with significant downregulation, respectively, were identified in patients with angio-sarcoma. Among them, quantitative PCR confirmed that miR-184, miR-3925-5p, miR-3926, and miR-5703 were upregulated in sera of cutaneous angiosarcoma patients compared with those of healthy controls and melanoma patients. Additionally, these 4 microRNAs were expressed more highly in angiosarcoma cell lines compared with normal human endothelial cell lines and were prone to elevate along with disease progression. Furthermore, a gene analysis predicted that the target gene set of microRNAs might affect the regulation of TP53 via the epigenetic regulation of MECP2. Taken together, these 4 extracellular vesicle-associated microRNAs in circulation serve as a promising liquid biomarker to identify angiosarcoma patients and trace disease progression.
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References
Breiteneder-Geleff S, Soleiman A, Kowalski H, Horvat R, Amann G, Kriehuber E, et al. Angiosarcomas express mixed endothelial phenotypes of blood and lymphatic capillaries. Am J Pathol 1999; 154: 385-394.
https://doi.org/10.1016/S0002-9440(10)65285-6 DOI: https://doi.org/10.1016/S0002-9440(10)65285-6
Bi S, Chen S, Wu B, Cen Y, Chen J. The effectiveness of different treatment modalities of cutaneous angiosarcoma: results from meta-analysis and observational data from SEER Database. Front Oncol 2021; 11: 627113.
https://doi.org/10.3389/fonc.2021.627113 DOI: https://doi.org/10.3389/fonc.2021.627113
Patel AM, Ryu JH. Angiosarcoma in the Lung. Chest 1993; 103: 1531-1535.
https://doi.org/10.1378/chest.103.5.1531 DOI: https://doi.org/10.1378/chest.103.5.1531
Zhang C, Xu G, Liu Z, Xu Y, Lin F, Baklaushev VP, et al. Epidemiology, tumor characteristics and survival in patients with angiosarcoma in the United States: a population-based study of 4537 cases. Jpn J Clin Oncol 2019; 49: 1092-1099.
https://doi.org/10.1093/jjco/hyz113 DOI: https://doi.org/10.1093/jjco/hyz113
Zhang L, Huang J, Yang N, Greshock J, Megraw MS, Giannakakis A, et al. microRNAs exhibit high frequency genomic alterations in human cancer. Proc Natl Acad Sci 2006; 103: 9136-9141.
https://doi.org/10.1073/pnas.0508889103 DOI: https://doi.org/10.1073/pnas.0508889103
Cortez MA, Bueso-Ramos C, Ferdin J, Lopez-Berestein G, Sood AK, Calin GA. MicroRNAs in body fluids-the mix of hormones and biomarkers. Nat Rev Clin Oncol 2011; 8: 467-77.
https://doi.org/10.1038/nrclinonc.2011.76 DOI: https://doi.org/10.1038/nrclinonc.2011.76
Lewis BP, Burge CB, Bartel DP. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 2005; 120: 15-20.
https://doi.org/10.1016/j.cell.2004.12.035 DOI: https://doi.org/10.1016/j.cell.2004.12.035
Friedman RC, Farh KK, Burge CB, Bartel DP. Most mammalian mRNAs are conserved targets of microRNAs. Genome Res 2009; 19: 92-105.
https://doi.org/10.1101/gr.082701.108 DOI: https://doi.org/10.1101/gr.082701.108
Miranda KC, Huynh T, Tay Y, Ang YS, Tam WL, Thomson AM, et al. A pattern-based method for the identification of MicroRNA binding sites and their corresponding heteroduplexes. Cell 2006; 126: 1203-1217.
https://doi.org/10.1016/j.cell.2006.07.031 DOI: https://doi.org/10.1016/j.cell.2006.07.031
Annese T, Tamma R, De Giorgis M, Ribatti D. microRNAs biogenesis, functions and role in tumor angiogenesis. Front Oncol 2020; 10: 581007
https://doi.org/10.3389/fonc.2020.581007 DOI: https://doi.org/10.3389/fonc.2020.581007
Yanaihara N, Caplen N, Bowman E, Seike M, Kumamoto K, Yi M, et al. Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell 2006; 9: 189-198.
https://doi.org/10.1016/j.ccr.2006.01.025 DOI: https://doi.org/10.1016/j.ccr.2006.01.025
Welsh JA, Goberdhan DCI, O'Driscoll L, Buzas EI, Blenkiron C, Bussolati B, et al. Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches [published correction appears in J Extracell Vesicles 2024; 13: e12451]. J Extracell Vesicles 2024; 13: e12404.
https://doi.org/10.1002/jev2.12451 DOI: https://doi.org/10.1002/jev2.12451
Li B, Cao Y, Sun M, Feng H. Expression, regulation, and function of exosome‐derived miRNAs in cancer progression and therapy. FASEB J 2021; 35: e21916.
https://doi.org/10.1096/fj.202100294RR DOI: https://doi.org/10.1096/fj.202100294RR
Urabe F, Kosaka N, Ito K, Kimura T, Egawa S, Ochiya T. Extracellular vesicles as biomarkers and therapeutic targets for cancer. Am J Physiol Cell Physiol 2020; 318: C29-C39.
https://doi.org/10.1152/ajpcell.00280.2019 DOI: https://doi.org/10.1152/ajpcell.00280.2019
Kohama I, Kosaka N, Chikuda H, Ochiya T. An insight into the roles of MicroRNAs and exosomes in sarcoma. Cancers 2019; 11: 428.
https://doi.org/10.3390/cancers11030428 DOI: https://doi.org/10.3390/cancers11030428
Chen Y, Kuang D, Zhao X, Chen D, Wang X, Yang Q, et al. miR-497-5p inhibits cell proliferation and invasion by targeting KCa3.1 in angiosarcoma. Oncotarget 2016; 7: 58148-58161.
https://doi.org/10.18632/oncotarget.11252 DOI: https://doi.org/10.18632/oncotarget.11252
Zhou Y, Zhou B, Pache L, Chang M, Khodabakhshi AH, Tanaseichuk O, et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat commun 2019; 10: 1523.
https://doi.org/10.1038/s41467-019-09234-6 DOI: https://doi.org/10.1038/s41467-019-09234-6
Wu G, Haw R. Functional interaction network construction and analysis for disease discovery. Methods Mol Biol 2017; 1558: 235-253.
https://doi.org/10.1007/978-1-4939-6783-4_11 DOI: https://doi.org/10.1007/978-1-4939-6783-4_11
Mendenhall WM, Mendenhall CM, Werning JW, Reith JD, Mendenhall NP. Cutaneous angiosarcoma. Am J Clin Oncol 2006; 29: 524-528.
https://doi.org/10.1097/01.coc.0000227544.01779.52 DOI: https://doi.org/10.1097/01.coc.0000227544.01779.52
Sun Z, Shi K, Yang S, Liu J, Zhou Q, Wang G, et al. Effect of exosomal miRNA on cancer biology and clinical applications. Mol Cancer 2018; 17: 147.
https://doi.org/10.1186/s12943-018-0897-7 DOI: https://doi.org/10.1186/s12943-018-0897-7
Masoudi MS, Mehrabian E, Mirzaei H. MiR‐21: A key player in glioblastoma pathogenesis. J Cell Biochem 2017; 119: 1285-1290.
https://doi.org/10.1002/jcb.26300 DOI: https://doi.org/10.1002/jcb.26300
Liu B, Shyr Y, Cai J, Liu Q. Interplay between miRNAs and host genes and their role in cancer. Brief Funct Genomics 2019; 18: 255-266.
https://doi.org/10.1093/bfgp/elz002 DOI: https://doi.org/10.1093/bfgp/elz002
Tengda L, Shuping L, Mingli G, Jie G, Yun L, Weiwei Z, et al. Serum exosomal microRNAs as potent circulating biomarkers for melanoma. Melanoma Res 2018; 28: 295-303.
https://doi.org/10.1097/CMR.0000000000000450 DOI: https://doi.org/10.1097/CMR.0000000000000450
Pfeffer SR, Grossmann KF, Cassidy PB, Yang CH, Fan M, Kopelovich L, et al. Detection of exosomal miRNAs in the plasma of melanoma patients. J Clin Med 2015; 4: 2012-2027.
https://doi.org/10.3390/jcm4121957 DOI: https://doi.org/10.3390/jcm4121957
Alegre E, Sanmamed MF, Rodriguez C, Carranza O, Martín-Algarra S, González A. Study of circulating microRNA-125b levels in serum exosomes in advanced melanoma. Arch Pathol Lab Med 2014; 138: 828-832.
https://doi.org/10.5858/arpa.2013-0134-OA DOI: https://doi.org/10.5858/arpa.2013-0134-OA
Xiao D, Barry S, Kmetz D, Egger M, Pan J, Rai SN, et al. Melanoma cell-derived exosomes promote epithelial-mesenchymal transition in primary melanocytes through paracrine/autocrine signaling in the tumor microenvironment. Cancer Lett 2016; 376: 318-327.
https://doi.org/10.1016/j.canlet.2016.03.050 DOI: https://doi.org/10.1016/j.canlet.2016.03.050
Li J, Chen J, Wang S, Li P, Zheng C, Zhou X, et al. Blockage of transferred exosome‐shuttled miR‐494 inhibits melanoma growth and metastasis. J Cell Physiol 2019; 234: 15763-15774.
https://doi.org/10.1002/jcp.28234 DOI: https://doi.org/10.1002/jcp.28234
Nejati-Koshki K, Roberts C-T, Babaei G, Rastegar M. The Epigenetic reader methyl-CpG-binding protein 2 (MeCP2) is an emerging oncogene in cancer biology. Cancers 2023; 15: 2683.
https://doi.org/10.3390/cancers15102683 DOI: https://doi.org/10.3390/cancers15102683
Basset-Séguin N, Molès JP, Mils V, Dereure O, Guilhou JJ. TP53 tumor suppressor gene and skin carcinogenesis. J Invest Dermatol 1994; 103: 102S-106S.
https://doi.org/10.1111/1523-1747.ep12399372 DOI: https://doi.org/10.1111/1523-1747.ep12399372
Pan W, Chai B, Li L, Lu Z, Ma Z. p53/MicroRNA-34 axis in cancer and beyond. Heliyon 2023; 9: e15155.
https://doi.org/10.1016/j.heliyon.2023.e15155 DOI: https://doi.org/10.1016/j.heliyon.2023.e15155
Lefort K, Brooks Y, Ostano P, Cario-André M, Calpini V, Guinea-Viniegra J, et al. A miR-34a-SIRT6 axis in the squamous cell differentiation network. EMBO J 2013; 32: 2248-2263.
https://doi.org/10.1038/emboj.2013.156 DOI: https://doi.org/10.1038/emboj.2013.156
Olivier M, Hollstein M, Hainaut P. TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb Perspect Biol 2010; 2: a001008.
https://doi.org/10.1101/cshperspect.a001008 DOI: https://doi.org/10.1101/cshperspect.a001008
Italiano A, Chen CL, Thomas R, Breen M, Bonnet F, Sevenet N, et al. Alterations of the p53 and PIK3CA/AKT/mTOR pathways in angiosarcomas: a pattern distinct from other sarcomas with complex genomics. Cancer 2012; 118: 5878-5887.
https://doi.org/10.1002/cncr.27614 DOI: https://doi.org/10.1002/cncr.27614
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