The DOI matches its Crossref record; 28 of the 29 references it cites were found in a registry or an index, and 1 are not checked yet.
Secretory Mechanisms and Intercellular Transfer of MicroRNAs in Living Cells
Open accessAbstract
The existence of circulating microRNAs (miRNAs) in the blood of cancer patients has raised the possibility that miRNAs may serve as a novel diagnostic marker. However, the secretory mechanism and biological function of extracellular miRNAs remain unclear. Here, we show that miRNAs are released through a ceramide-dependent secretory machinery and that the secretory miRNAs are transferable and functional in the recipient cells. Ceramide, whose biosynthesis is regulated by neutral sphingomyelinase 2 (nSMase2), triggers secretion of small membrane vesicles called exosomes. The decreased activity of nSMase2 with a chemical inhibitor, GW4869, and a specific small interfering RNA resulted in the reduced secretion of miRNAs. Complementarily, overexpression of nSMase2 increased extracellular amounts of miRNAs. We also revealed that the endosomal sorting complex required for transport system is unnecessary for the release of miRNAs. Furthermore, a tumor-suppressive miRNA secreted via this pathway was transported between cells and exerted gene silencing in the recipient cells, thereby leading to cell growth inhibition. Our findings shed a ray of light on the physiological relevance of secretory miRNAs.
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“CD9 and CD63 serve as the most commonly used identifiers of exosomes and have been targeted for selective isolation [37, 38].”
From Biogenesis of extracellular vesicles (EV): exosomes, microvesicles, retrovirus-like vesicles, and apoptotic bodies (2013) · cites this paper as [38]
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“Intriguingly, miRNAs can be released from cancer cells into body fluids via secreting exosomes particles [6,13].”
From Bioinformatic Interrogation of 5p-arm and 3p-arm Specific miRNA Expression Using TCGA Datasets (2015) · cites this paper as [13]
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“TSG101 and Alix are two other proteins sometimes used as exosome markers [38, 46, 47].”
From Biogenesis of extracellular vesicles (EV): exosomes, microvesicles, retrovirus-like vesicles, and apoptotic bodies (2013) · cites this paper as [38]
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1 retracted
RETRACTED: MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer
Taylor, D. D., & Gerçel-Taylor, Ç. (2008) · Gynecologic Oncology · doi:10.1016/j.ygyno.2008.04.033 · Cited by 2,333
RetractedValadi, H., Ekström, K., Bossios, A., Sjöstrand, M., Lee, J. J., & Lötvall, J. O. (2007) · Nature Cell Biology · doi:10.1038/ncb1596 · Cited by 12,834
Mantovani, A., Allavena, P., Sica, A., & Balkwill, F. (2008) · Nature · doi:10.1038/nature07205 · Cited by 11,399
Circulating microRNAs as stable blood-based markers for cancer detection
Mitchell, P. S., Parkin, R. K., Kroh, E. M., Fritz, B. R., Wyman, S. K., Pogosova-Agadjanyan, E. L., Peterson, A., Noteboom, J., O'Briant, K. C., Allen, A., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0804549105 · Cited by 7,969
A microRNA expression signature of human solid tumors defines cancer gene targets
Volinia, S., Calin, G. A., Liu, C.-G., Ambs, S., Cimmino, A., Petrocca, F., Visone, R., Iorio, M., Roldo, C., Ferracin, M., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0510565103 · Cited by 5,697
Skog, J., Würdinger, T., van Rijn, S., Meijer, D. H., Gainche, L., Curry, W. T., Carter, B. S., Krichevsky, A. M., & Breakefield, X. O. (2008) · Nature Cell Biology · doi:10.1038/ncb1800 · Cited by 5,001
Chen, X., Ba, Y., Ma, L., Cai, X., Yin, Y., Wang, K., Guo, J., Zhang, Y., Chen, J., Guo, X., et al. (2008) · Cell Research · doi:10.1038/cr.2008.282 · Cited by 4,560
Ceramide Triggers Budding of Exosome Vesicles into Multivesicular Endosomes
Trajković, K., Hsu, C., Chiantia, S., Rajendran, L., Wenzel, D., Wieland, F., Schwille, P., Brügger, B., & Simons, M. (2008) · Science · doi:10.1126/science.1153124 · Cited by 3,760
Causes and consequences of microRNA dysregulation in cancer
Croce, C. M. (2009) · Nature Reviews Genetics · doi:10.1038/nrg2634 · Cited by 3,039
Biogenesis of small RNAs in animals
Kim, V. N., Han, J., & Siomi, M. C. (2009) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2632 · Cited by 2,814
Research works printed but not linked: 1
- Fleischhacker, 2007, Biochim. Biophys. Acta, 1775, 181
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The regulation of exosome function in the CNS: implications for neurodegeneration
Properzi, F., Ferroni, E., Poleggi, A., & Vinci, R. (2015) · Swiss Medical Weekly · doi:10.4414/smw.2015.14204 · Cited by 62
Delaveris, C. S., Wang, C. L., Riley, N. M., Li, S., Kulkarni, R. U., & Bertozzi, C. R. (2023) · ACS Central Science · doi:10.1021/acscentsci.3c01066 · Cited by 25
Metadata
- Authors
- Kosaka, N., Iguchi, H., Yoshioka, Y., Takeshita, F., Matsuki, Y., & Ochiya, T.
- Affiliations
- National Cancer Center Research Institute (JP)
- Sumitomo Dainippon Pharma (Japan) (JP)
- Corresponding author
- Ochiya, Takahiro
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2010-06
- Volume
- 285
- Issue
- 23
- Pages
- 17442-17452
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2878508
- OpenAlex
- W2119043140
- Cited by
- 1,934
- References
- 29
- Citations by year
- 2026: 55 · 2025: 59 · 2024: 93 · 2023: 91 · 2022: 101 · 2021: 185 · 2020: 148 · 2019: 131 · 2018: 139 · 2017: 148 · 2016: 164 · 2015: 142 · 2014: 153 · 2013: 131 · 2012: 115
- FWCI
- 34.98
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology
- National Institute of Biomedical Innovation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- extracellular microRNAs, microRNA secretion, ceramide, neutral sphingomyelinase 2, exosomes, intercellular transfer, tumor suppressor microRNA, gene silencing, tumor cell growth inhibition, tumor markers, GW4869
- MeSH terms
- Aniline Compounds, Animals, Benzylidene Compounds, Biological Transport, Chlorocebus aethiops, Humans, Neoplasms, Sphingomyelin Phosphodiesterase, Biomarkers, Tumor, Culture Media, Conditioned, COS Cells, Gene Silencing, RNA Interference, RNA, Small Interfering, MicroRNAs, Exosomes
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