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Elife. 2015 Jul 1;4:e07197. doi: 10.7554/eLife.07197.

KRAS-dependent sorting of miRNA to exosomes.

Author information

1
Department of Biological Sciences, Vanderbilt University Medical Center, Nashville, United States.
2
Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, United States.
3
Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, United States.
4
Department of Medicine, Vanderbilt University Medical Center, Nashville, United States.
5
Department of Cardiology, Vanderbilt University Medical Center, Nashville, United States.
6
HudsonAlpha Institute for Biotechnology, Huntsville, United States.

Abstract

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 microRNAs (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 that extracellular miRNAs can function in target cells and uncover a potential new mode of action for mutant KRAS in CRC.

KEYWORDS:

KRAS; cancer; colorectal cancer; extracellular RNA; human; human biology; medicine; miRNA

PMID:
26132860
PMCID:
PMC4510696
DOI:
10.7554/eLife.07197
[Indexed for MEDLINE]
Free PMC Article

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