Advertisement

Form and Function of Exosome-Associated Long Non-coding RNAs in Cancer

  • Chris Hewson
  • Kevin V. MorrisEmail author
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 394)

Abstract

The recent discovery that long non-coding RNAs (lncRNAs) are functional and are not merely “transcriptional noise” has spawned an entirely new arena of investigation. LncRNAs have been found to be functional in the regulation of a wide variety of genes, including those involved in cancer. Studies have identified that lncRNAs play a role in the development and regulation of cancer and can also act as prognostic markers. Meanwhile, exosomes , which are extracellular particles generated endogenously by cells, have been observed to act as transport vesicles for a variety of biological components, particularly proteins and RNAs. This transportation of biological components has been shown to impact a variety of biological processes including the development of cancer. Collectively, these observations, along with those of several recent studies, suggest that lncRNAs and exosomes may function together to disseminate cell signals that alter and/or control local cellular microenvironments. This review will identify the various roles that lncRNAs and exosomes play in cancer development, as well as the possibility that exosomes may transfer functional lncRNAs between cells as a means of cell-to-cell communication.

Keywords

Telomere Length Recipient Cell Transcriptional Noise miRNA Sponge Cancer Exosomes 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

The project was supported by NIAID PO1 AI099783-01, R01 AI111139-01, R01 DK104681-01 and Australian Research Council FT1300100572 to KVM.

References

  1. Åkerfelt M, Morimoto RI, Sistonen L (2010) Heat shock factors: integrators of cell stress, development and lifespan. Nat Rev Mol Cell Biol 11(8):545–555CrossRefPubMedPubMedCentralGoogle Scholar
  2. Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood MJA (2011) Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotech 29(4):341–345CrossRefGoogle Scholar
  3. Benetatos L, Vartholomatos G, Hatzimichael E (2011) MEG3 imprinted gene contribution in tumorigenesis. Int J Cancer 129(4):773–779CrossRefPubMedGoogle Scholar
  4. Bolhassani A, Rafati S (2008) Heat-shock proteins as powerful weapons in vaccine development. Expert Rev Vaccines 7(8):1185–1199CrossRefPubMedGoogle Scholar
  5. Brown CJ, Lafreniere RG, Powers VE, Sebastio G, Ballabio A, Pettigrew AL, Ledbetter DH, Levy E, Craig IW, Willard HF (1991) Localization of the X inactivation centre on the human X chromosome in Xq13. Nature 349(6304):82–84CrossRefPubMedGoogle Scholar
  6. Cai H, Reinisch K, Ferro-Novick S (2007) Coats, tethers, rabs, and SNAREs work together to mediate the intracellular destination of a transport vesicle. Develop Cell 12(5):671–682CrossRefGoogle Scholar
  7. Chen Z, Trotman LC, Shaffer D, Lin H-K, Dotan ZA, Niki M, Koutcher JA, Scher HI, Ludwig T, Gerald W, Cordon-Cardo C, Pandolfi PP (2005) Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 436(7051):725–730CrossRefPubMedPubMedCentralGoogle Scholar
  8. Chen WX, Liu XM, Lv MM, Chen L, Zhao JH, Zhong SL, Ji MH, Hu Q, Luo Z, Wu JZ, Tang JH (2014) Exosomes from drug-resistant breast cancer cells transmit chemoresistance by a horizontal transfer of microRNAs. PLoS ONE 9(4):e95240CrossRefPubMedPubMedCentralGoogle Scholar
  9. Cho J-A, Lee Y-S, Kim S-H, Ko J-K, Kim C-W (2009) MHC independent anti-tumor immune responses induced by Hsp70-enriched exosomes generate tumor regression in murine models. Cancer Lett 275(2):256–265CrossRefPubMedGoogle Scholar
  10. Clayton A, Turkes A, Navabi H, Mason MD, Tabi Z (2005) Induction of heat shock proteins in B-cell exosomes. J Cell Sci 118(16):3631–3638CrossRefPubMedGoogle Scholar
  11. Colombo M, Moita C, van Niel G, Kowal J, Vigneron J, Benaroch P, Manel N, Moita LF, Théry C, Raposo G (2013) Analysis of ESCRT functions in exosome biogenesis, composition and secretion highlights the heterogeneity of extracellular vesicles. J Cell Sci 126:5553CrossRefPubMedGoogle Scholar
  12. Demory Beckler M, Higginbotham JN, Franklin JL, Ham AJ, Halvey PJ, Imasuen IE, Whitwell C, Li M, Liebler DC, Coffey RJ (2013) Proteomic analysis of exosomes from mutant KRAS colon cancer cells identifies intercellular transfer of mutant KRAS. Mol Cell Proteomics 12(2):343–355CrossRefPubMedPubMedCentralGoogle Scholar
  13. Fabbri M, Paone A, Calore F, Galli R, Gaudio E, Santhanam R, Lovat F, Fadda P, Mao C, Nuovo GJ, Zanesi N, Crawford M, Ozer GH, Wernicke D, Alder H, Caligiuri MA, Nana-Sinkam P, Perrotti D, Croce CM (2012) MicroRNAs bind to toll-like receptors to induce prometastatic inflammatory response. Proc Natl Acad Sci USA 109(31):E2110–E2116CrossRefPubMedPubMedCentralGoogle Scholar
  14. Gezer U, Özgür E, Cetinkaya M, Isin M, Dalay N (2014) Long non-coding RNAs with low expression levels in cells are enriched in secreted exosomes. Cell Biol Int 38(9):1076–1079PubMedGoogle Scholar
  15. Gordon FE, Nutt CL, Cheunsuchon P, Nakayama Y, Provencher KA, Rice KA, Zhou Y, Zhang X, Klibanski A (2010) Increased expression of angiogenic genes in the brains of mouse meg3-null embryos. Endocrinology 151(6):2443–2452CrossRefPubMedPubMedCentralGoogle Scholar
  16. Guffanti A, Iacono M, Pelucchi P, Kim N, Solda G, Croft LJ, Taft RJ, Rizzi E, Askarian-Amiri M, Bonnal RJ, Callari M, Mignone F, Pesole G, Bertalot G, Bernardi LR, Albertini A, Lee C, Mattick JS, Zucchi I, De Bellis G (2009) A transcriptional sketch of a primary human breast cancer by 454 deep sequencing. BMC Genom 10:163CrossRefGoogle Scholar
  17. Guil S, Soler M, Portela A, Carrere J, Fonalleras E, Gomez A, Villanueva A, Esteller M (2012) Intronic RNAs mediate EZH2 regulation of epigenetic targets. Nat Struct Mol Biol 19(7):664–670CrossRefPubMedGoogle Scholar
  18. Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ, Tsai M-C, Hung T, Argani P, Rinn JL, Wang Y, Brzoska P, Kong B, Li R, West RB, van de Vijver MJ, Sukumar S, Chang HY (2010) Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature 464(7291):1071–1076CrossRefPubMedPubMedCentralGoogle Scholar
  19. Gutschner T, Hammerle M, Eissmann M, Hsu J, Kim Y, Hung G, Revenko A, Arun G, Stentrup M, Gross M, Zornig M, MacLeod AR, Spector DL, Diederichs S (2013) The noncoding RNA MALAT1 is a critical regulator of the metastasis phenotype of lung cancer cells. Cancer Res 73(3):1180–1189CrossRefPubMedPubMedCentralGoogle Scholar
  20. Henne William M, Buchkovich Nicholas J, Emr Scott D (2011) The ESCRT pathway. Develop Cell 21(1):77–91CrossRefGoogle Scholar
  21. Huber V, Fais S, Iero M, Lugini L, Canese P, Squarcina P, Zaccheddu A, Colone M, Arancia G, Gentile M, Seregni E, Valenti R, Ballabio G, Belli F, Leo E, Parmiani G, Rivoltini L (2005) Human colorectal cancer cells induce T-cell death through release of proapoptotic microvesicles: role in immune escape. Gastroenterology 128(7):1796–1804CrossRefPubMedGoogle Scholar
  22. Hung T, Wang Y, Lin MF, Koegel AK, Kotake Y, Grant GD, Horlings HM, Shah N, Umbricht C, Wang P, Wang Y, Kong B, Langerod A, Borresen-Dale AL, Kim SK, van de Vijver M, Sukumar S, Whitfield ML, Kellis M, Xiong Y, Wong DJ, Chang HY (2011) Extensive and coordinated transcription of noncoding RNAs within cell-cycle promoters. Nat Genet 43(7):621–629CrossRefPubMedPubMedCentralGoogle Scholar
  23. Johnsson P, Ackley A, Vidarsdottir L, Lui W-O, Corcoran M, Grandér D, Morris KV (2013) A pseudogene long-noncoding-RNA network regulates PTEN transcription and translation in human cells. Nat Struct Mol Biol 20(4):440–446CrossRefPubMedPubMedCentralGoogle Scholar
  24. Johnstone RM (2006) Exosomes biological significance: a concise review. Blood Cells Mol Dis 36(2):315–321CrossRefPubMedGoogle Scholar
  25. Johnstone RM, Adam M, Hammond JR, Orr L, Turbide C (1987) Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes). J Biol Chem 262(19):9412–9420PubMedGoogle Scholar
  26. Khan S, Aspe JR, Asumen MG, Almaguel F, Odumosu O, Acevedo-Martinez S, De Leon M, Langridge WHR, Wall NR (2009) Extracellular, cell-permeable survivin inhibits apoptosis while promoting proliferative and metastatic potential. Br J Cancer 100(7):1073–1086CrossRefPubMedPubMedCentralGoogle Scholar
  27. Kino T, Hurt DE, Ichijo T, Nader N, Chrousos GP (2010) Noncoding RNA GAS5 is a growth arrest—and starvation-associated repressor of the glucocorticoid receptorGoogle Scholar
  28. Klumperman J, Raposo G (2014) The complex ultrastructure of the endolysosomal system. Cold Spring Harb Perspect Biol 6(10):a016857CrossRefPubMedGoogle Scholar
  29. Knowling S, Morris KV (2011) Epigenetic regulation of gene expression in human cells by noncoding RNAs. Progress in molecular biology and translational science. G. Dirk. Academic Press. 102:1–10Google Scholar
  30. Kogure T, Yan IK, Lin W-L, Patel T (2013) Extracellular vesicle-mediated transfer of a novel long noncoding RNA TUC339: a mechanism of intercellular signaling in human hepatocellular cancer. Genes and Cancer 4(7–8):261–272CrossRefPubMedPubMedCentralGoogle Scholar
  31. Kranenburg O (2005) The KRAS oncogene: past, present, and future. Biochimica et Biophysica Acta (BBA)—Reviews on Cancer 1756(2):81–82CrossRefGoogle Scholar
  32. Kung JT, Colognori D, Lee JT (2013) Long noncoding RNAs: past, present, and future. Genetics 193(3):651–669CrossRefPubMedPubMedCentralGoogle Scholar
  33. Lee JT (2011) Gracefully ageing at 50, X-chromosome inactivation becomes a paradigm for RNA and chromatin control. Nat Rev Mol Cell Biol 12(12):815–826CrossRefPubMedGoogle Scholar
  34. Lee T, D’Asti E, Magnus N, Al-Nedawi K, Meehan B, Rak J (2011) Microvesicles as mediators of intercellular communication in cancer—the emerging science of cellular ‘debris’. Seminars in Immunopathology 33(5):455–467CrossRefPubMedGoogle Scholar
  35. Li XB, Zhang ZR, Schluesener HJ, Xu SQ (2006) Role of exosomes in immune regulation. J Cell Mol Med 10(2):364–375CrossRefPubMedPubMedCentralGoogle Scholar
  36. Lin R, Maeda S, Liu C, Karin M, Edgington TS (2006) A large noncoding RNA is a marker for murine hepatocellular carcinomas and a spectrum of human carcinomas. Oncogene 26(6):851–858CrossRefPubMedGoogle Scholar
  37. Lv L-H, Wan Y-L, Lin Y, Zhang W, Yang M, Li G-L, Lin H-M, Shang C-Z, Chen Y-J, Min J (2012) Anticancer drugs cause release of exosomes with heat shock proteins from human hepatocellular carcinoma cells that elicit effective natural killer cell antitumor responses in vitro. J Biol Chem 287(19):15874–15885CrossRefPubMedPubMedCentralGoogle Scholar
  38. Melo SA, Sugimoto H, O’Connell JT, Kato N, Villanueva A, Vidal 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(5):707–721CrossRefPubMedPubMedCentralGoogle Scholar
  39. Michalik KM, You X, Manavski Y, Doddaballapur A, Zornig M, Braun T, John D, Ponomareva Y, Chen W, Uchida S, Boon RA, Dimmeler S (2014) Long noncoding RNA MALAT1 regulates endothelial cell function and vessel growth. Circ Res 114(9):1389–1397CrossRefPubMedGoogle Scholar
  40. Morachis JM, Murawsky CM, Emerson BM (2010) Regulation of the p53 transcriptional response by structurally diverse core promoters. Genes Dev 24(2):135–147CrossRefPubMedPubMedCentralGoogle Scholar
  41. Morris KV, Mattick JS (2014) The rise of regulatory RNA. Nat Rev Genet 15:423–437CrossRefPubMedPubMedCentralGoogle Scholar
  42. Mourtada-Maarabouni M, Pickard MR, Hedge VL, Farzaneh F, Williams GT (2009) GAS5, a non-protein-coding RNA, controls apoptosis and is downregulated in breast cancer. Oncogene 28(2):195–208CrossRefPubMedGoogle Scholar
  43. Ostrowski M, Carmo NB, Krumeich S, Fanget I, Raposo G, Savina A, Moita CF, Schauer K, Hume AN, Freitas RP, Goud B, Benaroch P, Hacohen N, Fukuda M, Desnos C, Seabra MC, Darchen F, Amigorena S, Moita LF, Thery C (2010) Rab27a and Rab27b control different steps of the exosome secretion pathway. Nat Cell Biol 12(1):19–30 (sup pp 11–13)CrossRefPubMedGoogle Scholar
  44. Peinado H, Aleckovic M, Lavotshkin S, Matei I, Costa-Silva B, Moreno-Bueno G, Hergueta-Redondo M, Williams C, Garcia-Santos G, Ghajar CM, Nitadori-Hoshino A, Hoffman C, Badal K, Garcia BA, Callahan MK, Yuan J, Martins VR, Skog J, Kaplan RN, Brady MS, Wolchok JD, Chapman PB, Kang Y, Bromberg J, Lyden D (2012) Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med 18(6):883–891CrossRefPubMedPubMedCentralGoogle Scholar
  45. Pickard MR, Mourtada-Maarabouni M, Williams GT (2013) Long non-coding RNA GAS5 regulates apoptosis in prostate cancer cell lines. Biochimica et Biophysica Acta (BBA)—Molecular Basis of Disease 1832(10):1613–1623CrossRefGoogle Scholar
  46. Putz U, Howitt J, Doan A, Goh CP, Low LH, Silke J, Tan SS (2012) The tumor suppressor PTEN is exported in exosomes and has phosphatase activity in recipient cells. Sci Signal 5(243):ra70CrossRefPubMedGoogle Scholar
  47. Raiborg C, Stenmark H (2009) The ESCRT machinery in endosomal sorting of ubiquitylated membrane proteins. Nature 458(7237):445–452CrossRefPubMedGoogle Scholar
  48. Rani S, O’Brien K, Kelleher FC, Corcoran C, Germano S, Radomski MW, Crown J, O’Driscoll L (2011) Isolation of exosomes for subsequent mRNA, MicroRNA, and protein profiling. Methods Mol Biol 784:181–195CrossRefPubMedGoogle Scholar
  49. Raposo G, Marks MS, Cutler DF (2007) Lysosome-related organelles: driving post-Golgi compartments into specialisation. Curr Opin Cell Biol 19(4):394–401CrossRefPubMedPubMedCentralGoogle Scholar
  50. Record M, Carayon K, Poirot M, Silvente-Poirot S (2014) Exosomes as new vesicular lipid transporters involved in cell-cell communication and various pathophysiologies. Biochim Biophys Acta 1841(1):108–120CrossRefPubMedGoogle Scholar
  51. Redon S, Reichenbach P, Lingner J (2010) The non-coding RNA TERRA is a natural ligand and direct inhibitor of human telomerase. Nucleic Acids Res 38(17):5797–5806CrossRefPubMedPubMedCentralGoogle Scholar
  52. Schoeftner S, Blasco MA (2008) Developmentally regulated transcription of mammalian telomeres by DNA-dependent RNA polymerase II. Nat Cell Biol 10(2):228–236CrossRefPubMedGoogle Scholar
  53. Skog J, Würdinger T, van Rijn S, Meijer DH, Gainche L, Curry WT, Carter BS, Krichevsky AM, Breakefield XO (2008) Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol 10(12):1470–1476CrossRefPubMedPubMedCentralGoogle Scholar
  54. Spizzo R, Almeida MI, Colombatti A, Calin GA (2012) Long non-coding RNAs and cancer: a new frontier of translational research[quest]. Oncogene 31(43):4577–4587CrossRefPubMedPubMedCentralGoogle Scholar
  55. Struhl K (2007) Transcriptional noise and the fidelity of initiation by RNA polymerase II. Nat Struct Mol Biol 14(2):103–105CrossRefPubMedGoogle Scholar
  56. Takahashi K, Yan IK, Kogure T, Haga H, Patel T (2014) Extracellular vesicle-mediated transfer of long non-coding RNA ROR modulates chemosensitivity in human hepatocellular cancer. FEBS Open Bio 4:458–467CrossRefPubMedPubMedCentralGoogle Scholar
  57. Tano K, Mizuno R, Okada T, Rakwal R, Shibato J, Masuo Y, Ijiri K, Akimitsu N (2010) MALAT-1 enhances cell motility of lung adenocarcinoma cells by influencing the expression of motility-related genes. FEBS Lett 584(22):4575–4580CrossRefPubMedGoogle Scholar
  58. Thery C, Regnault A, Garin J, Wolfers J, Zitvogel L, Ricciardi-Castagnoli P, Raposo G, Amigorena S (1999) Molecular characterization of dendritic cell-derived exosomes. Selective accumulation of the heat shock protein hsc73. J Cell Biol 147(3):599–610CrossRefPubMedPubMedCentralGoogle Scholar
  59. Tripathi V, Ellis JD, Shen Z, Song DY, Pan Q, Watt AT, Freier SM, Bennett CF, Sharma A, Bubulya PA, Blencowe BJ, Prasanth SG, Prasanth KV (2010) The nuclear-retained noncoding RNA MALAT1 regulates alternative splicing by modulating SR splicing factor phosphorylation. Mol Cell 39(6):925–938CrossRefPubMedPubMedCentralGoogle Scholar
  60. Tsai M-C, Manor O, Wan Y, Mosammaparast N, Wang JK, Lan F, Shi Y, Segal E, Chang HY (2010) Long noncoding RNA as modular scaffold of histone modification complexes. Science 329(5992):689–693 (New York)CrossRefPubMedPubMedCentralGoogle Scholar
  61. Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO (2007) Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 9(6):654–659CrossRefPubMedGoogle Scholar
  62. Vanhaesebroeck B, Stephens L, Hawkins P (2012) PI3K signalling: the path to discovery and understanding. Nat Rev Mol Cell Biol 13(3):195–203CrossRefPubMedGoogle Scholar
  63. Zhang X, Rice K, Wang Y, Chen W, Zhong Y, Nakayama Y, Zhou Y, Klibanski A (2010) Maternally expressed gene 3 (MEG3) noncoding ribonucleic acid: isoform structure, expression, and functions. Endocrinology 151(3):939–947CrossRefPubMedPubMedCentralGoogle Scholar
  64. Zhao J, Ohsumi TK, Kung JT, Ogawa Y, Grau DJ, Sarma K, Song JJ, Kingston RE, Borowsky M, Lee JT (2010) Genome-wide identification of polycomb-associated RNAs by RIP-seq. Mol Cell 40(6):939–953CrossRefPubMedPubMedCentralGoogle Scholar
  65. Zhou Y, Zhong Y, Wang Y, Zhang X, Batista DL, Gejman R, Ansell PJ, Zhao J, Weng C, Klibanski A (2007) Activation of p53 by MEG3 non-coding RNA. J Biol Chem 282(34):24731–24742CrossRefPubMedGoogle Scholar
  66. Zitvogel L, Regnault A, Lozier A, Wolfers J, Flament C, Tenza D, Ricciardi-Castagnoli P, Raposo G, Amigorena S (1998) Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell derived exosomes. Nat Med 4(5):594–600CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Biotechnology and Biomedical SciencesThe University of New South WalesSydneyAustralia
  2. 2.Molecular and Experimental MedicineThe Scripps Research InstituteLa JollaUSA

Personalised recommendations