Lung cancer is one of the leading causes of cancer-related deaths. It is diagnosed mostly at the locally advanced or metastatic stage. Recently, micro RNAs (miRs) and their distribution in circulation have been implicated in physiological and pathological processes. In this study, miR-126 was evaluated in serum, exosome and exosome-free serum fractions in non-small cell lung cancer (NSCLC) patients at early and advanced stages, and compared with healthy controls. Down-regulation of miR-126 was found in serum of advanced stage NSCLC patients. In healthy controls, circulating miR-126 was equally distributed between exosomes and exosome-free serum fractions. Conversely, in both early and advanced stage NSCLC patients, miR-126 was mainly present in exosomes. Different fractions of miR-126 in circulation may reflect different conditions during tumour formation. Incubation of exosomes from early and advanced NSCLC patients induced blood vessel formation and malignant transformation in human bronchial epithelial cells. On the other hand, exosome-enriched miR-126 from normal endothelial cells inhibited cell growth and induces loss of malignancy of NSCLC cells. These findings suggest a role of exo-miRs in the modulation of the NSCLC microenvironmental niche. Exosome-delivered miRs thus hold a substantial promise as a diagnostics biomarker as well as a personalized therapeutic modality.

Department of Biomedical Sciences and Public Health Section of Anatomical Pathology Polytechnic University of Marche Via Tronto 10 a 60020 Ancona Italy

Department of Clinical and Molecular Sciences Section of Occupational Medicine Via Tronto 10 a 60020 Ancona Italy

Department of Clinical Sciences Section of Biochemistry Biology and Physics Via Tronto 10 a 60020 Ancona Italy

Institute of Biotechnology Czech Academy of Sciences Prague West 25242 Czech Republic

School of Medical Science Griffith University Southport Qld 4222 Australia

See more in PubMed

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J. Clin. 2016;66:7–30. doi: 10.3322/caac.21332. PubMed DOI

Chen Z, Fillmore CM, Hammerman PS, Kim CF, Wong KK. Non-small-cell lung cancers: a heterogeneous set of diseases. Nat. Rev. Cancer. 2014;14:535–546. doi: 10.1038/nrc3775. PubMed DOI PMC

Fu H, Yang H, Zhang X, Xu W. The emerging roles of exosomes in tumor-stroma interaction. J. Cancer Res. Clin. Oncol. 2016;142:1897–1907. doi: 10.1007/s00432-016-2145-0. PubMed DOI PMC

Falcone G, Felsani A, D’Agnano I. Signaling by exosomal microRNAs in cancer. J. Exp. Clin. Cancer Res. 2015;34:32. doi: 10.1186/s13046-015-0148-3. PubMed DOI PMC

Sato-Kuwabara Y, Melo S, Soares F, Calin G. The fusion of two worlds: Non-coding RNAs and extracellular vesicles - diagnostic and therapeutic implications. Int. J. Oncol. 2014;46:17–27. doi: 10.3892/ijo.2014.2712. PubMed DOI PMC

Falcone G, Felsani A, D’Agnano I. Signaling by exosomal microRNAs in cancer. J. Exp. Clin. Can. Res. 2015;34:32. doi: 10.1186/s13046-015-0148-3. PubMed DOI PMC

Ohshima K, et al. Let-7 MicroRNA family is selectively secreted into the extracellular environment via exosomes in a metastatic gastric cancer cell line. PLoS One. 2010;5:e13247–e13247. doi: 10.1371/journal.pone.0013247. PubMed DOI PMC

Kosaka N, et al. Neutral sphingomyelinase 2 (nSMase2)-dependent exosomal transfer of angiogenic microRNAs regulate cancer cell metastasis. J. Biol. Chem. 2013;288:10849–10859. doi: 10.1074/jbc.M112.446831. PubMed DOI PMC

Arroyo JD, et al. Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma. Proc. Natl. Acad. Sci. USA. 2011;108:5003–5008. doi: 10.1073/pnas.1019055108. PubMed DOI PMC

Koga Y, et al. Exosome can prevent RNase from degrading microRNA in feces. J. Gast. Oncol. 2011;2:215–222. PubMed PMC

Tomasetti M, Santarelli L, Neuzil J, Dong L. MicroRNA regulation of cancer metabolism: role in tumour suppression. Mitochondrion. 2014;19:29–38. doi: 10.1016/j.mito.2014.06.004. PubMed DOI

Tomasetti M, et al. Clinical significance of circulating miR-126 quantification in malignant mesothelioma patients. Clin. Biochem. 2012;45:575–581. doi: 10.1016/j.clinbiochem.2012.02.009. PubMed DOI

Tomasetti M, et al. MicroRNA-126 suppresses mesothelioma malignancy by targeting IRS1 and interfering with the mitochondrial function. Antiox. Redox Signal. 2014;21:2109–2125. doi: 10.1089/ars.2013.5215. PubMed DOI PMC

Ebrahimi F, Gopalan V, Smith RA, Lam A. K. miR-126 in human cancers: clinical roles and current perspectives. Exp. Mol. Pathol. 2014;96:98–107. doi: 10.1016/j.yexmp.2013.12.004. PubMed DOI

Krause BJ, et al. Micro-RNAs Let7e and 126 in plasma as markers of metabolic dysfunction in 10 to 12 years old children. PLoS One. 2015;10:e0128140. doi: 10.1371/journal.pone.0128140. PubMed DOI PMC

Huang TH, Chu TY. Repression of miR-126 and upregulation of adrenomedullin in the stromal endothelium by cancer-stromal cross talks confers angiogenesis of cervical cancer. Oncogene. 2014;33:3636–3647. doi: 10.1038/onc.2013.335. PubMed DOI

Lin Q, et al. A cluster of specified microRNAs in peripheral blood as biomarkers for metastatic non-small-cell lung cancer by stem-loop RT-PCR. J. Can. Res. Clin. Oncol. 2012;138:85–93. doi: 10.1007/s00432-011-1068-z. PubMed DOI PMC

Sun Y, et al. miR-126 inhibits non-small cell lung cancer cells proliferation by targeting EGFL7. Biochem. Biophys. Res. Commun. 2010;391:1483–1489. doi: 10.1016/j.bbrc.2009.12.098. PubMed DOI

Tao SC, et al. Chitosan Wound Dressings Incorporating Exosomes Derived from MicroRNA-126-Overexpressing Synovium Mesenchymal Stem Cells Provide Sustained Release of Exosomes and Heal Full-Thickness Skin Defects in a Diabetic Rat Model. Stem Cells Transl. Med. 2017;6:736–747. doi: 10.5966/sctm.2016-0275. PubMed DOI PMC

Takahashi A, et al. Exosomes maintain cellular homeostasis by excreting harmful DNA from cells. Nat. Commun. 2017;8:15287. doi: 10.1038/ncomms15287. PubMed DOI PMC

Van Balkom BW, Eisele AS, Pegtel DM, Bervoets S, Verhaar MC. Quantitative and qualitative analyses of small RNAs in human endothelial cells and exosomes provides insights into localized RNA processing, degradation and sorting. J. Extracell. Vesicles. 2015;4:26760. doi: 10.3402/jev.v4.26760. PubMed DOI PMC

Wang S, et al. The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis. Dev. Cell. 2008;15:261–271. doi: 10.1016/j.devcel.2008.07.002. PubMed DOI PMC

Boeri M, et al. MicroRNA signatures in tissues and plasma predict development and prognosis of computed tomography detected lung cancer. Proc. Natl. Acad. Sci. USA. 2011;108:3713–3718. doi: 10.1073/pnas.1100048108. PubMed DOI PMC

Bianchi F, et al. A serum circulating miRNA diagnostic test to identify asymptomatic high-risk individuals with early stage lung cancer. EMBO Mol. Med. 2011;3:495–503. doi: 10.1002/emmm.201100154. PubMed DOI PMC

Shen J, et al. Plasma microRNAs as potential biomarkers for non-small-cell lung cancer. Lab. Invest. 2011;91:579–587. doi: 10.1038/labinvest.2010.194. PubMed DOI PMC

Rodríguez M, et al. Different exosome cargo from plasma/bronchoalveolar lavage in non-small-cell lung cancer. Genes Chromosomes Cancer. 2014;53:713–24. PubMed

Skog J, et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat. Cell Biol. 2008;10:1470–1476. doi: 10.1038/ncb1800. PubMed DOI PMC

Cao WJ, et al. Therapeutic angiogenesis by ultrasound-mediated microRNA-126-3p delivery. Arterioscler. Thromb. Vasc. Biol. 2015;35:2401–2411. doi: 10.1161/ATVBAHA.115.306506. PubMed DOI

Ren G, Kang Y. A one-two punch of miR-126/126* against metastasis. Nat. Cell Biol. 2013;15:231–233. doi: 10.1038/ncb2703. PubMed DOI

Thind A, Wilson CJ. Exosomal miRNAs as cancer biomarkers and therapeutic targets. Extracell. Vesicles. 2016;5:31292. doi: 10.3402/jev.v5.31292. PubMed DOI PMC

Munagala R, Aqil F, Gupta RC. Exosomal miRNAs as biomarkers of recurrent lung cancer. Tumour Biol. 2016;37:10703–10714. doi: 10.1007/s13277-016-4939-8. PubMed DOI

Tanaka Y, et al. Clinical impact of serum exosomal microRNA-21 as a clinical biomarker in human esophageal squamous cell carcinoma. Cancer. 2013;119:1159–1167. doi: 10.1002/cncr.27895. PubMed DOI

Kosaka N, Yoshioka Y, Fujita Y, Ochiya T. Versatile roles of extracellular vesicles in cancer. J. Clin. Invest. 2016;126:1163–1172. doi: 10.1172/JCI81130. PubMed DOI PMC

Greening DW, et al. Secreted primary human malignant mesothelioma exosome signature reflects oncogenic cargo. Sci. Rep. 2016;6:32643. doi: 10.1038/srep32643. PubMed DOI PMC

Melo SA, et al. Cancer exosomes perform cell-independent microRNA biogenesis and promote tumorigenesis. Cancer Cell. 2014;26:707–721. doi: 10.1016/j.ccell.2014.09.005. PubMed DOI PMC

Ji JS, et al. Inhibition of microRNA-126 promotes the expression of Spred1 to inhibit angiogenesis in hepatocellular carcinoma after transcatheter arterial chemoembolization: in vivo study. Onco Targets Ther. 2016;9:4357–4367. doi: 10.2147/OTT.S110235. PubMed DOI PMC

Su SA, et al. Emerging role of exosome-mediated intercellular communication in vascular remodeling. Oncotarget. 2017;8:25700–25712. PubMed PMC

Jansen F, et al. Vascular endothelial microparticles-incorporated microRNAs are altered in patients with diabetes mellitus. Cardiovasc. Diabetol. 2016;15:49. doi: 10.1186/s12933-016-0367-8. PubMed DOI PMC

Garcia NA, Ontoria-Oviedo I, González-King H, Diez-Juan A, Sepúlveda P. Glucose starvation in cardiomyocytes enhances exosome secretion and promotes angiogenesis in endothelial cells. PLoS One. 2015;10:e0138849. doi: 10.1371/journal.pone.0138849. PubMed DOI PMC

Zhu N, et al. Endothelial-specific intron-derived miR-126 is down-regulated in human breast cancer and targets both VEGFA and PIK3R2. Mol. Cell Biochem. 2011;351:157–64. doi: 10.1007/s11010-011-0723-7. PubMed DOI

Desrochers LM, Antonyak MA, Cerione RA. Extracellular vesicles: Satellites of information transfer in cancer and stem cell biology. Dev. Cell. 2016;37:301–319. doi: 10.1016/j.devcel.2016.04.019. PubMed DOI PMC

Rooj AK, Mineo M, Godlewski J. MicroRNA and extracellular vesicles in glioblastoma: small but powerful. Brain Tumor Pathol. 2016;33:77–88. doi: 10.1007/s10014-016-0259-3. PubMed DOI PMC

Qin X, Xu H, Gong W, Deng W. The tumor cytosol miRNAs, fluid miRNAs, and exosome miRNAs in lung cancer. Front. Oncol. 2015;4:357. doi: 10.3389/fonc.2014.00357. PubMed DOI PMC

Katakowski M, et al. Exosomes from marrow stromal cells expressing miR-146b inhibit glioma growth. Cancer Lett. 2013;335:201–204. doi: 10.1016/j.canlet.2013.02.019. PubMed DOI PMC

Li J, et al. Exosomes-derived MiR-302b suppresses lung cancer cell proliferation and migration via TGFβRII inhibition. Cell Physiol. Biochem. 2016;38:1715–1726. doi: 10.1159/000443111. PubMed DOI

Dong LF, et al. Vitamin E analogues inhibit angiogenesis by selective induction of apoptosis in proliferating endothelial cells: the role of oxidative stress. Cancer Res. 2007;67:11906–11193. doi: 10.1158/0008-5472.CAN-07-3034. PubMed DOI

Non-Genomic Hallmarks of Aging-The Review

MiR-126 in intestinal-type sinonasal adenocarcinomas: exosomal transfer of MiR-126 promotes anti-tumour responses