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.
“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]
The exosome-characterization passage (Fig. 2; page unavailable) identifies CD63 as an exosome marker, and its caption reports immunoprecipitating a CD63-positive exosome fraction with an anti-CD63 antibody. Our copy does not identify CD9 as an exosome marker or show its use for selective isolation, and it does not establish that CD9 and CD63 are the most commonly used identifiers. (LLM, conf=0.86)
Experimental — accuracy not yet measuredTSG101 and Alix are two proteins sometimes used as exosome markers.
“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]
The exosome-characterization passage (Figure 2; page unavailable) identifies CD63 as an exosome marker, not Alix or TSG101. The Alix passages (Figure 5; page unavailable) examine its role in miRNA secretion. Searches for TSG101 and for Alix as an exosome marker found no passage supporting the attributed claim. (LLM, conf=0.78)
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Self-citation
- 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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