Sources and Functions of Extracellular Small RNAs in Human Circulation

Fritz, Joëlle V.; Heintz‐Buschart, Anna; Ghosal, Anubrata; Wampach, Linda; Etheridge, Alton; Galas, David J.; Wilmes, Paul

doi:10.1146/annurev-nutr-071715-050711

Cited by 117 publications

(123 citation statements)

References 243 publications

(496 reference statements)

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“…Since original studies suggesting horizontal transfer of mRNAs and proteins (Ratajczak et al, 2006; Skog et al, 2008; Valadi et al, 2007), almost all known classes of RNA have been detected in extracellular fluids (Fritz et al, 2016). However, definitive studies demonstrating functional long coding and noncoding RNA transfer are limited (Ridder et al, 2014; Skog et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…However, the diversity of exRNA is extensive and microRNAs (miRNAs) are not the most abundant class of RNA found in EVs (Fritz et al, 2016; Mateescu et al, 2017). Analysis of cellular versus exRNA has repeatedly demonstrated selective biogenesis, export, and/or stability of specific RNAs (Cha et al, 2015; Dou et al, 2016; Kosaka et al, 2010; Santangelo et al, 2016; Skog et al, 2008; Squadrito et al, 2014; Valadi et al, 2007; Villarroya-Beltri et al, 2013; Wei et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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“…14 miRNAs and sRNAs secreted via EVs showed differences in abundance in various human pathological conditions and, therefore, have been put forth as novel biomarkers and diagnostic indicators for many diseases. [15][16][17] The disease-causing role of pathogens is only one of many host-pathogen interactions. Instead, microbes exist in the host without causing overt disease and constantly communicate each other.…”

Section: Introductionmentioning

confidence: 99%

Tiny RNAs and their voyage via extracellular vesicles: Secretion of bacterial small RNA and eukaryotic microRNA

Choi

Cho

et al. 2017

Exp Biol Med (Maywood)

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MicroRNAs are small non-coding RNAs that bind to the 3′-untranslated region of target mRNAs and have transcriptional or translational inhibitory function in eukaryotes. Before microRNAs were widely known, bacterial non-coding small RNAs around 50–200 nt in length were discovered whose mechanism of action resembled that of microRNAs. Recently, RNAs that are of similar size to or smaller than microRNAs have been discovered in bacteria and indeed, this class of small RNAs have been found throughout all domains of life. Moreover, recent findings suggest that these tiny RNAs can be released via extracellular vesicles (such as exosomes in eukaryotes and outer membrane vesicles in bacteria), which in turn heralds a new field of research, interkingdom communication. This review discusses two similar classes of small RNAs in evolutionarily distinct eukaryotes and bacteria. In addition to their biogenesis and regulation, we discuss small RNA vehicles and their secretion. Impact statement The possible endogenous functions of small RNAs such as regulatory small RNAs in bacteria and microRNAs in eukaryotes have been extensively studied since they were first discovered. However, their powerful functions should not be seen as limited to their cells of origin. Recently, several papers have demonstrated that small RNAs function as signaling molecules between cells. This is possible because small RNAs can be shuttled around after being incorporated into environmentally protective extracellular vesicles. It is now clearly plausible that secreted small RNAs can regulate other types of cells through biofluids. Given their “common molecule” status, the role of small RNAs in mediating bacteria-human crosstalk is an emerging and competitive area of genetic research. This review provides insight into the function of small RNAs in intercellular and even interkingdom communication.

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“…For example, macromolecule yield from different liquid biopsy isolation techniques can be influenced by freeze/thaw protocols, collection method, processing time, level of hemolysis, preservative agent exposure, and storage conditions [31]. In the case of EVs, the method of vesicle counting can also yield different results [32] and this variable should be accounted for in downstream analytics.…”

Section: Five-year Viewmentioning

confidence: 99%

Liquid biopsy for brain tumors

Shankar

Balaj

Stott

et al. 2017

Expert Review of Molecular Diagnostics

129

109

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Introduction Minimally invasive methods will augment the clinical approach for establishing the diagnosis or monitoring treatment response of central nervous system tumors. Liquid biopsy by blood or cerebrospinal fluid sampling holds promise in this regard. Areas covered In this literature review, the authors highlight recent studies describing the analysis of circulating tumor cells, cell free nucleic acids, and extracellular vesicles as strategies to accomplish liquid biopsy in glioblastoma and metastatic tumors. The authors then discuss the continued efforts to improve signal detection, standardize the liquid biopsy handling and preparation, develop platforms for clinical application, and establish a role for liquid biopsies in personalized medicine. Expert commentary As the technologies used to analyze these biomarkers continue to evolve, we propose that there is a future potential to precisely diagnose and monitor treatment response with liquid biopsies.

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Sources and Functions of Extracellular Small RNAs in Human Circulation

Cited by 117 publications

References 243 publications

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

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

Tiny RNAs and their voyage via extracellular vesicles: Secretion of bacterial small RNA and eukaryotic microRNA

Liquid biopsy for brain tumors

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