MicroRNAs in exosomes

​​​Research suggests that microRNAs travel around the body contained within exosomes. Find out about recent progress in this exciting field.

MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression. They exert their effects on the cells they are synthesized in, and are also released into the extracellular space and transported in body fluids such as blood and urine.

Recent research has uncovered evidence that miRNAs are transported in body fluids within exosomes; small cell-derived vesicles that function in intercellular communication processes. Once released into the extracellular fluid, exosomes fuse with other cells and transfer their cargo to the acceptor cell1.

Exosomal miRNAs may have important functions in cell-cell communication and have potential as biomarkers to detect and monitor disease. We review recent progress in this exciting research field.

miRNAs are actively sorted into vesicles

Understanding the origin of microsomal miRNAs may provide insights into their function. Are miRNAs randomly incorporated into exosomes, or does a more coordinated process occur?

Current evidence supports active miRNA sorting: researchers looked at the miRNA composition of exosomes and found that exosomal miRNA content differs significantly from that of the parent cell2. Another study identified a subset of miRNAs with a potential role in regulating endocytosis that were preferentially sorted into exosomes3.

Exosomal miRNA signatures also alter under specific conditions and diseases. Exosomal let-7f, miR-20b and miR-30e-3p levels were altered in the plasma of patients with small-cell lung cancer4. Similarly, miR-21 and miR-141 have been found to be altered in the presence of benign tumors and ovarian cancer5. These papers are just a small part of the increasing research effort to identify changes in exosomal miRNA under disease states and identify biomarkers for disease.

Exosomal miRNAs control gene expression in target cells

Exosomes play an important role in information exchange between cells. Once released, they travel throughout the body before releasing their contents into a recipient cell. As miRNAs regulate gene expression, this raises the possibility that miRNAs can control gene expression in target cells.

In the first paper to demonstrate transfer of exosome-derived miRNAs, it was found that small RNAs from mast cell exosomes could be transferred between mast cells and be potentially functional6. Subsequent research has also demonstrated the activity of exosome-derived miRNAs; miR-105 from breast cancer cells and miR-17-92 cluster miRNAs from leukemia cells were shown to have activity in recipient cells7,8.

A striking example of the control that exosomal miRNAs can have on a recipient cell gene expression has recently been uncovered in breast cancer exosomes. It was shown that cancer exosomes are able to rapidly silence certain mRNAs in recipient cells. These gene expression changes instigated non-tumorigenic epithelial cells to generate tumors, raising the possibility that exosomal miRNAs from cancer cells may have tumorigenic potential elsewhere9.

Making use of exosomal miRNAs: potential as biomarkers

The presence of exosomal miRNAs in disease opens up the possibility of using exosomal miRNAs as biomarkers. Exosomal miRNA profiling could be a non-invasive method to detect disease, or as a way to monitor progression or treatment efficacy.

Recent research has identified exosomal miRNA signatures for certain diseases. Exosomal biomarkers have recently been tested as biomarkers of cancers including acute myeloid leukemia10, colorectal cancer11,12 and hepatocellular carcinoma13. An exosomal biomarker signature has also recently been established to detect Alzheimer’s disease14,15.
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Are miRNAs a significant exosome component or not?

Although this research suggests that miRNAs are an important component of exosomes, the full picture might not be this clear cut, and other groups have argued that a significant quantity of miRNA is not present in exosomes16.

Clearly there are unanswered questions in the field of exosomal miRNAs that need to be addressed before we can really benefit from their potential. One thing is certain though: this will be an active area of research for the foreseeable future.
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The future of miRNA research

A huge amount of research is being carried out to find potential biomarkers for disease. To keep up with this fast paced area of research, tools are required for the profiling of exosomal miRNAs in a range of clinical samples. Our Multiplex miRNA Assays using FireflyTM technology can be used to detect miRNAs directly from crude biofluids with streamlined workflow and no need for RNA purification.

Multiplex miRNA profiling direct from biofluid


References

1. Simons M and Raposo G (2009). Exosomes - vesicular carriers for intercellular communication. Curr Opin Cell Biol 21, 575–581.

2. Zhang J, Li S, Li L, Li M, Guo C, Yao J, Mi S (2015). Exosome and exosomal microRNA: trafficking, sorting, and function. Genomics, Proteomics & Bioinformatics 13, 17–24.

3. Guduric-Fuchs J, O’Connor A, Camp B, O'Neill C, Medina RJ, Simpson DA (2012). Selective extracellular vesicle-mediated export of an overlapping set of microRNAs from multiple cell types. BMC Genomics 13, 357.

4. SilvaJ, García V, Zaballos Á, Provencio M, Lombardía L, Almonacid L, García JM, Domínuez G, Peña C, Diaz R, Herrera M, Varela A, Bonilla F (2011). Vesicle-related microRNAs in plasma of nonsmall cell lung cancer patients and correlation with survival. Eur Respir J 37, 617–623. 

5. Taylor DD, Gercel-Taylor C (2008). MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer. Gynecol Oncol 110, 13–21.

6. Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee J, Lötvall J (2007). Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 9, 654–659. 

7. Zhou W, Fong MY, Min Y, Somlo G, Liu L, Palomares MR, 3, Yu Y, 14, Chow A, O’Connor STF, Chin AR, Yen Y, Wang Y, Marcusson EG, Chu P, Wu J, Wu X, Li AX, Li Z, Gao H, Ren X, Boldin MP, Lin PC, Wang SE (2014). Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis. Cancer Cell 25, 501–515.

8. Umezu T, Ohyashiki K, Kuroda M, Ohyashiki JH (2013). Leukemia cell to endothelial cell communication via exosomal miRNAs. Oncogene 32, 2747–2755.

9. Melo SA, Sugimoto H, O’Connell JT, Kato N, Villanueva A, Vida A, Qiu L, Vitkin E, Perelman LT, Melo CA, Lucci A, Ivan C, Calin GA, Kalluri R (2014). Cancer exosomes perform cell-independent microRNA biogenesis and promote tumorigenesis. Cancer Cell 26, 707–721. 

10. Hornick NI, Huan J, Doron B, Goloviznina NA, Lapidus J, Chang BH, Kurre P (2015). Serum exosome microRNA as a minimally-invasive early biomarker of AML. Sci Rep 5, 11295. 

11. Matsumura T, Sugimachi K, Iinuma H, Takahashi Y, Kurashige J, Sawada G, Ueda M, Uchi R, Ueo H, Takano Y, Shinden Y, Eguchi H, Yamamoto H, Doki Y, Mori M, Ochiya T, Mimori K (2015). Exosomal microRNA in serum is a novel biomarker of recurrence in human colorectal cancer. Br J Cancer 113, 275–281. 

12. Ogata-Kawata H, Izumiya M, Kurioka D, Honma Y, Yamada Y, Furuta K, Gunji T, Ohta H, Okamoto H, Sonoda H, Watanabe M, Nakagama N, Yokota J, Kohno T, Tsuchiya N (2014).  Circulating exosomal microRNAs as biomarkers of colon cancer. PLOS One 9, e92921. 

13. Sugimachi K, Matsumura T, Hirata H, Uchi R, Ueda M, Ueo H, Shinden Y, Iguchi T, Eguchi H, Shirabe K, Ochiya T, Maehara Y, Mimori K (2015). Identification of a bona fide microRNA biomarker in serum exosomes that predicts hepatocellular carcinoma recurrence after liver transplantation. Br J Cancer 112, 532–538.

14. Cheng L, Doecke JD, Sharples RA, Villemagne VL, Fowler CJ, Rembach A, Martins RN, Rowe CC, Macaulay SL, Masters CL, Hill AF (2015). Prognostic serum miRNA biomarkers associated with Alzheimer’s disease shows concordance with neuropsychological and neuroimaging assessment. Mol Psychiatry 20, 1188–1196.

15. Lugli G, Cohen AM, Bennett DA, Shah RC, Fields CJ, Hernandez AG, Smalheiser NR (2015). Plasma Exosomal miRNAs in persons with and without Alzheimer disease: altered expression and prospects for biomarkers. PLOS One 10, e0139233. 

16. Chevillet JR, Kanga Q, Rufa IK, Briggsa HA, Vojtechc LN, Hughes SM, Chenga HH, Arroyoa JD, Mereditha EK, Gallichottea EN, Pogosova-Agadjanyane EL, Morrissey C, Stirewalte DL, Hladikc F, Yud EY, Higanod CS, Tewari M (2014). Quantitative and stoichiometric analysis of the microRNA content of exosomes. PNAS 111, 14888–14893.