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Simple Summary  Extracellular vesicles (EVs) are heterogenous in size, cargo, and mechanism of biogenesis. While the mechanism of formation of small EVs, such as exosomes, has been widely investigated, little is known about the pathobiology of large EVs. We identify here a microRNA that alters cellular vesicologenesis increasing shedding of large EVs and slightly reducing shedding of small EVs. We also demonstrate that this microRNA, miR1227, targets SEC23A to promote this phenotype. Importantly, large EVs are released by cells undergoing a mesenchymal-amoeboid transition that functionally translates into a more metastatic phenotype.    Abstract  Cancer cells shed a heterogenous mixture of extracellular vesicles (EVs), differing in both size and composition, which likely influence physiological processes in different manners. However, how cells differentially control the shedding of these EV populations is poorly understood. Here, we show that miR-1227, which is enriched in prostate cancer EVs, compared to the cell of origin, but not in EVs derived from prostate benign epithelial cells, induces the shedding of large EVs (such as large oncosomes), while inhibiting the shedding of small EVs (such as exosomes). RNA sequencing from cells stably expressing miR-1227, a modified RISCTRAP assay that stabilizes and purifies mRNA-miR-1227 complexes for RNA sequencing, and in silico target prediction tools were used to identify miR-1227 targets that may mediate this alteration in EV shedding. The COPII vesicle protein SEC23A emerged and was validated by qPCR, WBlot, and luciferase assays as a direct target of miR-1227. The inhibition of SEC23A was sufficient to induce the shedding of large EVs. These results identify a novel mechanism of EV shedding, by which the inhibition of SEC23A by miR-1227 induces a shift in EV shedding, favoring the shedding of large EV over small EV.

miR-1227 Targets SEC23A to Regulate the Shedding of Large Extracellular Vesicles