Secretory Mechanisms and Intercellular Transfer of MicroRNAs in Living Cells*♦

By N. Kosaka, Haruhisa Iguchi, Y. Yoshioka, F. Takeshita, Yasushi Matsuki, T. Ochiya. Journal of Biological Chemistry, 2010

1,917 citations recorded by the source corpus.

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.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/37eaf47df0060772e22e4fbc17b5e18b381ddaff

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Citations in the corpus

Biogenesis and secretion of exosomes. (2014, positive): “Since this work, several labs have used neutral sphingomyelinase inhibition as a proof that their analysed EVs were indeed exosomes [46,47], although a potential effect of such treatments on release of PM-derived EVs, or on other cellular functions or secretions has never been actually ruled out.”
Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma (2011, background): “Extracellular miRNAs have been proposed as a means of intercellular communication (6, 14, 16), and exosome-mediated transfer of miRNA between cells has been reported in cell culture (15) and from plasma-derived microvesicles to endothelial cells in the experimental setting (17).”
Exosomes in Tumor Microenvironment Influence Cancer Progression and Metastasis (2013, background): “When lung cancer-bearing mice are treated with GW4869, Fabbri et al. [44] describe significantly lower number of lung metastases.”
Circulating microRNAs in exosomes indicate hepatocyte injury and inflammation in alcoholic, drug-induced and inflammatory liver diseases (2012, background): “Recent studies highlight the importance of extracellular miRNA in cell-to-cell communication and may also provide a mode of genetic information transfer.(34,35) Extracellular miRNA can be released from cells by way of different processes such as exosomes, microparticles, and proteins or unidentified”
Neutral Sphingomyelinase 2 (nSMase2)-dependent Exosomal Transfer of Angiogenic MicroRNAs Regulate Cancer Cell Metastasis (2013, methodology): “nSMase2 Regulates Cancer Cell Metastasis—In a previous study, we have described how miRNAs are released through ceramide-dependent secretory machinery via the exosome (10).”