Mutant KRAS colorectal cancer (CRC) cells release protein-laden exosomes that can alter the tumor microenvironment. To test whether exosomal RNAs also contribute to changes in gene expression in recipient cells, and whether mutant KRAS might regulate the composition of secreted miRNAs, we compared small RNAs of cells and matched exosomes from isogenic CRC cell lines differing only in KRAS status. We show that exosomal profiles are distinct from cellular profiles, and mutant exosomes cluster separately from wild type KRAS exosomes. miR-10b was selectively increased in wild type exosomes while miR-100 was increased in mutant exosomes. Neutral sphingomyelinase inhibition caused accumulation of miR-100 only in mutant cells, suggesting KRAS-dependent miRNA export. In Transwell co-culture experiments, mutant donor cells conferred miR-100-mediated target repression in wild type recipient cells. These findings suggest extracellular miRNAs can function in target cells and uncover a potential new mode of action for mutant KRAS in CRC.
- Phillip D Zamore, Howard Hughes Medical Institute, University of Massachusetts Medical School, United States
© 2015, Cha et al.
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