Secretory Mechanisms and Intercellular Transfer of MicroRNAs in Living Cells
2010/03/30 by Nobuyoshi Kosaka, Haruhisa Iguchi, Yusuke Yoshioka +3 · 1,960 citations
Biochemistry, Genetics and Molecular Biology · #Apoptosis #Biochemistry #Biology #Cell biology #Ceramide #Endosome #Exocytosis #Exosome #Extracellular #Extracellular vesicle #Extracellular vesicles in disease #Gene #Gene silencing #Golgi apparatus #Intracellular #MicroRNA in disease regulation #Microvesicles #RNA #RNA interference #Secretion #Secretory Vesicle #Secretory pathway #Sphingolipid Metabolism and Signaling #microRNA
paper · pdf · doi:10.1074/jbc.m110.107821
published in Journal of Biological Chemistry 285(23), 17442-17452 (Elsevier BV)
openalex publication_date 2010/03/30 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/05
Abstract
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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