Diverse Long RNAs Are Differentially Sorted into Extracellular Vesicles Secreted by Colorectal Cancer Cells

The regulation and functional roles of secreted coding and long noncoding RNAs (lncRNAs; >200 nt) are largely unknown. We previously showed that mutant KRAS colorectal cancer (CRC) cells release extracellular vesicles (EVs) containing distinct proteomes, microRNAs (miRNAs), and circular RNAs. Her...

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Published in:	Cell reports (Cambridge) 2018-10, Vol.25 (3), p.715-725.e4
Main Authors:	Hinger, Scott A., Cha, Diana J., Franklin, Jeffrey L., Higginbotham, James N., Dou, Yongchao, Ping, Jie, Shu, Lihua, Prasad, Nripesh, Levy, Shawn, Zhang, Bing, Liu, Qi, Weaver, Alissa M., Coffey, Robert J., Patton, James G.
Format:	Article
Language:	eng
Subjects:	Biological Transport Cell Communication Cell Movement colorectal cancer Colorectal Neoplasms - genetics Colorectal Neoplasms - metabolism CRISPR display exosomes Exosomes - genetics Exosomes - metabolism extracellular RNA extracellular vesicles Extracellular Vesicles - metabolism Humans KRAS lncRNA Mutation Proto-Oncogene Proteins p21(ras) - genetics rab GTP-Binding Proteins - genetics rab GTP-Binding Proteins - metabolism Rab13 RNA, Long Noncoding - genetics RNA, Long Noncoding - metabolism RNA, Messenger - genetics RNA, Messenger - metabolism RNAseq Tumor Cells, Cultured
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Summary:	The regulation and functional roles of secreted coding and long noncoding RNAs (lncRNAs; >200 nt) are largely unknown. We previously showed that mutant KRAS colorectal cancer (CRC) cells release extracellular vesicles (EVs) containing distinct proteomes, microRNAs (miRNAs), and circular RNAs. Here, we comprehensively identify diverse classes of CRC extracellular long RNAs secreted in EVs and demonstrate differential export of specific RNAs. Distinct noncoding RNAs, including antisense transcripts and transcripts derived from pseudogenes, are enriched in EVs compared to cellular profiles. We detected strong enrichment of Rab13 in mutant KRAS EVs and demonstrate functional delivery of Rab13 mRNA to recipient cells. To assay functional transfer of lncRNAs, we implemented a CRISPR/Cas9-based RNA-tracking system to monitor delivery to recipient cells. We show that gRNAs containing export signals from secreted RNAs can be transferred from donor to recipient cells. Our data support the existence of cellular mechanisms to selectively export diverse classes of RNA. [Display omitted] •Differential enrichment of coding and noncoding RNAs in EVs suggests regulated export•The majority of mRNAs in EVs are not full length•Smaller mRNAs (∼1 kb) can be transferred from donor to recipient cells by EVs•lncRNAs can be transferred to recipient cells and trafficked to function in the nucleus Extracellular vesicles (EVs) contain protein and RNA cargo that can be transferred between cells. Hinger et al. identify distinct subsets of cellular coding and long noncoding RNAs that are enriched in EVs that can be functionally transferred between cells, supporting a regulated form of cell-cell communication.
ISSN:	2211-1247 2211-1247