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Medical Oncology
Published in: Medical Oncology 12/2014

01-12-2014 | Review Article

Cell-free microRNAs as cancer biomarkers: the odyssey of miRNAs through body fluids

Authors: Mohammad Amin Javidi, Amir Hossein Ahmadi, Babak Bakhshinejad, Nazila Nouraee, Sadegh Babashah, Majid Sadeghizadeh

Published in: Medical Oncology | Issue 12/2014

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Abstract

Cell-free microRNAs (cfmiRNAs), also known as extracellular or secretory microRNAs, are an emerging class of miRNAs that are released or secreted by cells. These miRNAs are transferred through various body fluids. A growing body of research has recently revealed that cancer cells also secrete their distinctive cfmiRNAs to the extracellular environment highlighting the contribution of cfmiRNAs to cancer progression. CfmiRNAs show high stability in the body fluids. Three pathways have been proposed for their entry into the body fluids: passive release from broken, injured and dead cells; active secretion through microvesicles; and active secretion via microvesicle-free protein-dependent route. Active pathways seem to play leading roles in the delivery of miRNAs. Detection of cfmiRNAs is of particular relevance to their translation into the clinic. Much effort has been devoted to the development of highly sensitive and efficient approaches for detection purposes. Nevertheless, some barriers such as finding a unique internal control for all cancer types remain to be bypassed. This review aims to provide an insight into the promises represented by cfmiRNAs as cancer biomarkers and describes advances made in the identification of numerous types of extracellular miRNAs that have potential for use in the diagnosis of a variety of cancers.
Literature
1.
Babashah S, Soleimani M. The oncogenic and tumour suppressive roles of microRNAs in cancer and apoptosis. Eur J Cancer. 2011;47:1127–37.PubMedCrossRef
2.
Babashah S, Sadeghizadeh M, Tavirani MR, Farivar S, Soleimani M. Aberrant microRNA expression and its implications in the pathogenesis of leukemias. Cell Oncol (Dordr). 2012;35:317–34.
3.
Babashah S. editor, MicroRNAs: key regulators of oncogenesis. Switzerland: Springer International Publishing; 2014. p. 3–28.
4.
Lynam-Lennon N, Maher SG, Reynolds JV. The roles of microRNA in cancer and apoptosis. Biol Rev Camb Philos Soc. 2009;84:55–71.PubMedCrossRef
5.
Chim SSC, Shing TKF, Hung ECW, et al. Detection and characterization of placental microRNAs in maternal plasma. Clin Chem. 2008;54:482–90.
6.
Mitchell PS, Parkin RK, Kroh EM, et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci. 2008;105:10513–8.
7.
Park NJ, Zhou H, Elashoff D, et al. Salivary microRNA: discovery, characterization, and clinical utility for oral cancer detection. Clin Cancer Res. 2009;15:5473–7.
8.
Chen X, Gao C, Li H, et al. Identification and characterization of microRNAs in raw milk during different periods of lactation, commercial fluid, and powdered milk products. Cell Res. 2010;20:1128–37.
9.
Kosaka N, Iguchi H, Yoshioka Y, Takeshita F, Matsuki Y, Ochiya T. Secretory mechanisms and intercellular transfer of microRNAs in living cells. J Biol Chem. 2010;285:17442–52.
10.
Kato, Y. An efficient fluorescent method for selective detection of mature miRNA species. In: Nucleic Acids Symposium Series. Oxford University Press; 2008. p. 71–72.
11.
Roy S, Soh JH, Gao Z. A microfluidic-assisted microarray for ultrasensitive detection of miRNA under an optical microscope. Lab Chip. 2011;11:1886–94.PubMedCrossRef
12.
Wang K, Zhang S, Weber J, Baxter D, Galas DJ. Export of microRNAs and microRNA-protective protein by mammalian cells. Nucleic Acids Res. 2010;38:7248–59.
13.
Zernecke A, Bidzhekov K, Noels H, et al. Delivery of microRNA-126 by apoptotic bodies induces CXCL12-dependent vascular protection. Sci Signal. 2009;2:ra81.
14.
Vickers KC, Palmisano BT, Shoucri BM, Shamburek RD, Remaley AT. MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins. Nat Cell Biol. 2011;13:423–33.
15.
Zhang J, Zhao H, Gao Y, Zhang W. Secretory miRNAs as novel cancer biomarkers. Biochim Biophys Acta. 2012;1826:32–43.
16.
Zhang Q, Xu J, Chen Q, Chen X, Zen K, Zhang C-Y. Selective secretion of microRNA in CNS system. Protein Cell. 2013;4:243–7.
17.
Turchinovich A, Weiz L, Burwinkel B. Extracellular miRNAs: the mystery of their origin and function. Trends Biochem Sci. 2012;37:460–5.
18.
Turchinovich A, et al. Characterization of extracellular circulating microRNA. Nucleic Acids Res. 2011;39:7223–33.
19.
Simons M, Raposo G. Exosomes–vesicular carriers for intercellular communication. Curr Opin Cell Biol. 2009;21:575–81.
20.
Cortez MA, Bueso-Ramos C, Ferdin J, Lopez-Berestein G, Sood AK, Calin GA. MicroRNAs in body fluids–the mix of hormones and biomarkers. Nat Rev Clin Oncol. 2011;8:467–77.
21.
Théry C, Zitvogel L, Amigorena S. Exosomes: composition, biogenesis and function. Nat Rev Immunol. 2002;2:569–79.PubMed
22.
Ronquist G, Brody I. The prostasome: its secretion and function in man. Biochim Biophys Acta. 1985;822:203–18.PubMedCrossRef
23.
Tetta C, Ghigo E, Silengo L, Deregibus MC, Camussi G. Extracellular vesicles as an emerging mechanism of cell-to-cell communication. Endocrine. 2013;44:11–9.
24.
Weber JA, Baxter DH, Zhang S, et al. The microRNA spectrum in 12 body fluids. Clin Chem. 2010;56:1733–41.
25.
Cocucci E, Racchetti G, Meldolesi J. Shedding microvesicles: artefacts no more. Trends Cell Biol. 2009;19:43–51.PubMedCrossRef
26.
Yuan A, Farber EL, Rapoport AL, et al. Transfer of microRNAs by embryonic stem cell microvesicles. PLoS One. 2009;4:e4722.
27.
Collino F, Deregibus MC, Bruno S, et al. Microvesicles derived from adult human bone marrow and tissue specific mesenchymal stem cells shuttle selected pattern of miRNAs. PLoS One. 2010;5:e11803.
28.
Zhang Y, Liu D, Chen X, et al. Secreted monocytic miR-150 enhances targeted endothelial cell migration. Mol Cell. 2010;39:133–44.
29.
Gibbings DJ, Ciaudo C, Erhardt M, Voinnet O. Multivesicular bodies associate with components of miRNA effector complexes and modulate miRNA activity. Nat Cell Biol. 2009;11:1143–9.
30.
Trajkovic K, Hsu C, Chiantia S, et al. Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science. 2008;319:1244–7.
31.
Fabbri M, Paone A, Calore F, et al. MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response. Proc Natl Acad Sci USA. 2012;109:E2110–6.
32.
Chen X, Liang H, Zhang J, Zen K, Zhang C-Y. Horizontal transfer of microRNAs: molecular mechanisms and clinical applications. Protein Cell. 2012;3:28–37.
33.
34.
Atay S, Gercel-Taylor C, Kesimer M, Taylor DD. Morphologic and proteomic characterization of exosomes released by cultured extravillous trophoblast cells. Exp Cell Res. 2011;317:1192–202.
35.
36.
Sahoo S, Losordo DW. Exosomes and cardiac repair after myocardial infarction. Circ Res. 2014;114:333–44.
37.
Bang C, Batkai S, Dangwal S, et al. Cardiac fibroblast-derived microRNA passenger strand-enriched exosomes mediate cardiomyocyte hypertrophy. J Clin Invest. 2014;124:2136–46.
38.
Ludwig JA, Weinstein JN. Biomarkers in cancer staging, prognosis and treatment selection. Nat Rev Cancer. 2005;5:845–56.PubMedCrossRef
39.
Mulrane L, Klinger R, McGee SF, Gallagher WM, O’Connor DP. microRNAs: a new class of breast cancer biomarkers. Expert Rev Mol Diagn. 2014;14:347–63.
40.
Etheridge A, Lee I, Hood L, Galas D, Wang K. Extracellular microRNA: a new source of biomarkers. Mutat Res. 2011;717:85–90.
41.
Schwarzenbach H, Nishida N, Calin GA, Pantel K. Clinical relevance of circulating cell-free microRNAs in cancer. Nat Rev Clin Oncol. 2014;11:145–56.
42.
Cortez MA, Bueso-Ramos C, Ferdin J, Lopez-Berestein G, Sood AK, Calin GA. MicroRNAs in body fluids–the mix of hormones and biomarkers. Nat Rev Clin Oncol. 2011;8:467–77.
43.
Lawrie CH, Gal S, Dunlop HM, et al. Detection of elevated levels of tumour-associated microRNAs in serum of patients with diffuse large B-cell lymphoma. Br J Haematol. 2008;141:672–5.
44.
Moussay E, Wang K, Cho J-H, et al. MicroRNA as biomarkers and regulators in B-cell chronic lymphocytic leukemia. Proc Natl Acad Sci. 2011;108:6573–8.
45.
Wu Q, Lu Z, Li H, Lu J, Guo L, Ge Q. Next-generation sequencing of microRNAs for breast cancer detection. J Biomed Biotechnol. 2011;2011:597145.
46.
Zhu W, Qin W, Atasoy U, Sauter ER. Circulating microRNAs in breast cancer and healthy subjects. BMC Res Notes. 2009;2:89.
47.
Ng EKO, Chong WWS, Jin H, et al. Differential expression of microRNAs in plasma of patients with colorectal cancer: a potential marker for colorectal cancer screening. Gut. 2009;58:1375–81.
48.
Tsujiura M, Ichikawa D, Komatsu S, et al. Circulating microRNAs in plasma of patients with gastric cancers. Br J Cancer. 2010;102:1174–9.
49.
Berindan-Neagoe I, Monroig Pdel C, Pasculli B, Calin GA. MicroRNAome genome: a treasure for cancer diagnosis and therapy. CA Cancer J Clin. 2014;64:311–36.
50.
de Planell-Saguer M, Rodicio MC. Analytical aspects of microRNA in diagnostics: a review. Anal Chim Acta. 2011;699:134–52.PubMedCrossRef
51.
Van Roosbroeck K, Pollet J, Calin GA. miRNAs and long noncoding RNAs as biomarkers in human diseases. Expert Rev Mol Diagn. 2013;13:183–204.
52.
53.
Pritchard CC, Cheng HH, Tewari M. MicroRNA profiling: approaches and considerations. Nat Rev Genet. 2012;13:358–69.PubMedCrossRef
54.
Love C, Dave S. MicroRNA expression profiling using microarrays. Methods Mol Biol. 2013;999:285–96.PubMedCrossRef
55.
Benes V, Castoldi M. Expression profiling of microRNA using real-time quantitative PCR, how to use it and what is available. Methods. 2010;50:244–9.PubMedCrossRef
56.
Qu KZ, Zhang K, Li H, Afdhal NH, Albitar M. Circulating microRNAs as biomarkers for hepatocellular carcinoma. J Clin Gastroenterol. 2011;45:355–60.
57.
Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ, Lötvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9:654–9.
58.
Heneghan HM, Miller N, Kelly R, Newell J, Kerin MJ. Systemic miRNA-195 differentiates breast cancer from other malignancies and is a potential biomarker for detecting noninvasive and early stage disease. Oncologist. 2010;15:673–82.
59.
Xie L, Chen X, Wang L, et al. Cell-free miRNAs may indicate diagnosis and docetaxel sensitivity of tumor cells in malignant effusions. BMC Cancer. 2010;10:591.
60.
Liu R, Zhang C, Hu Z, et al. A five-microRNA signature identified from genome-wide serum microRNA expression profiling serves as a fingerprint for gastric cancer diagnosis. Eur J Cancer. 2011;47:784–91.
61.
Huang Z, Huang D, Ni S, Peng Z, Sheng W, Du X. Plasma microRNAs are promising novel biomarkers for early detection of colorectal cancer. Int J Cancer. 2010;127:118–26.
62.
Cheng H, Zhang L, Cogdell DE, et al. Circulating plasma MiR-141 is a novel biomarker for metastatic colon cancer and predicts poor prognosis. PLoS One. 2011;6:e17745.
63.
Hu Z, Chen X, Zhao Y, et al. Serum microRNA signatures identified in a genome-wide serum microRNA expression profiling predict survival of non-small-cell lung cancer. J Clin Oncol. 2010;28:1721–6.
64.
Silva J, García V, Zaballos A, et al. Vesicle-related microRNAs in plasma of nonsmall cell lung cancer patients and correlation with survival. Eur Respir J. 2011;37:617–23.
65.
Liu X-G, Zhu W-Y, Huang Y-Y, et al. High expression of serum miR-21 and tumor miR-200c associated with poor prognosis in patients with lung cancer. Med Oncol. 2012;29:618–26.
66.
Wang ZX, Bian HB, Wang JR, Cheng ZX, Wang KM, De W. Prognostic significance of serum miRNA-21 expression in human non-small cell lung cancer. J Surg Oncol. 2011;104:847–51.
67.
Foss KM, Sima C, Ugolini D, Neri M, Allen KE, Weiss GJ. miR-1254 and miR-574-5p: serum-based microRNA biomarkers for early-stage non-small cell lung cancer. J Thorac Oncol. 2011;6:482–8.
68.
Shen J, Liu Z, Todd NW, et al. Diagnosis of lung cancer in individuals with solitary pulmonary nodules by plasma microRNA biomarkers. BMC Cancer. 2011;11:374.
69.
Shen J, Todd NW, Zhang H, et al. Plasma microRNAs as potential biomarkers for non-small-cell lung cancer. Lab Invest. 2011;91:579–87.
70.
Tanaka M, Oikawa K, Takanashi M, et al. Down-regulation of miR-92 in human plasma is a novel marker for acute leukemia patients. PLoS One. 2009;4:e5532.
71.
Guo H-Q, Huang G-L, Guo C-C, Pu X-X, Lin T-Y. Diagnostic and prognostic value of circulating miR-221 for extranodal natural killer/T-cell lymphoma. Dis Markers. 2010;29:251–8.
72.
Brase JC, Johannes M, Schlomm T, et al. Circulating miRNAs are correlated with tumor progression in prostate cancer. Int J Cancer. 2011;128:608–16.
73.
Yaman Agaoglu F, Kovancilar M, Dizdar Y, et al. Investigation of miR-21, miR-141, and miR-221 in blood circulation of patients with prostate cancer. Tumour Biol. 2011;32:583–8.
74.
Gui J, Tian Y, Wen X, et al. Serum microRNA characterization identifies miR-885-5p as a potential marker for detecting liver pathologies. Clin Sci (Lond). 2011;120:183–93.
75.
Li J, Wang Y, Yu W, Chen J, Luo J. Expression of serum miR-221 in human hepatocellular carcinoma and its prognostic significance. Biochem Biophys Res Commun. 2011;406:70–3.
76.
Xu J, Wu C, Che X, et al. Circulating microRNAs, miR-21, miR-122, and miR-223, in patients with hepatocellular carcinoma or chronic hepatitis. Mol Carcinog. 2011;50:136–42.
77.
Yamamoto Y, Kosaka N, Tanaka M, et al. MicroRNA-500 as a potential diagnostic marker for hepatocellular carcinoma. Biomarkers. 2009;14:529–38.
78.
Li L-M, Hu Z-B, Zhou Z-X, et al. Serum microRNA profiles serve as novel biomarkers for HBV infection and diagnosis of HBV-positive hepatocarcinoma. Cancer Res. 2010;70:9798–807.
79.
Wang J, Chen J, Chang P, et al. MicroRNAs in plasma of pancreatic ductal adenocarcinoma patients as novel blood-based biomarkers of disease. Cancer Prev Res (Phila). 2009;2:807–13.
80.
Resnick KE, Alder H, Hagan JP, Richardson DL, Croce CM, Cohn DE. The detection of differentially expressed microRNAs from the serum of ovarian cancer patients using a novel real-time PCR platform. Gynecol Oncol. 2009;112:55–9.
81.
Miyachi M, Tsuchiya K, Yoshida H, et al. Circulating muscle-specific microRNA, miR-206, as a potential diagnostic marker for rhabdomyosarcoma. Biochem Biophys Res Commun. 2010;400:89–93.
82.
Wong TS, Liu XB, Wong BY, Ng RW, Yuen AP, Wei WI. Mature miR-184 as Potential Oncogenic microRNA of Squamous Cell Carcinoma of Tongue. Clin Cancer Res. 2008;14:2588–92.
83.
Liu CJ, Kao SY, Tu HF, Tsai MM, Chang KW, Lin SC. Increase of microRNA miR-31 level in plasma could be a potential marker of oral cancer. Oral Dis. 2010;16:360–4.
84.
Momen-Heravi F, Trachtenberg AJ, Kuo WP, Cheng YS. Genomewide study of salivary MicroRNAs for detection of oral cancer. J Dent Res. 2014;93:86S–93S.
85.
Wu W, Hou W, Wu Z, Wang Y, Yi Y, Lin W. [miRNA-144 in the saliva is a genetic marker for early diagnosis of esophageal cancer]. Nan Fang Yi Ke Da Xue Xue Bao. 2013;33:1783–6.
86.
Liu CJ, Lin SC, Yang CC, Cheng HW, Chang KW. Exploiting salivary miR-31 as a clinical biomarker of oral squamous cell carcinoma. Head Neck. 2012;34:219–24.
87.
Hanke M, Hoefig K, Merz H, et al. A robust methodology to study urine microRNA as tumor marker: microRNA-126 and microRNA-182 are related to urinary bladder cancer. Urol Oncol. 2010;28:655–61.
88.
Abdalla MA, Haj-Ahmad Y. Promising candidate urinary MicroRNA biomarkers for the early detection of hepatocellular carcinoma among high-risk Hepatitis C virus Egyptian patients. J Cancer. 2012;3:19–31.PubMedCentralPubMedCrossRef
89.
Srivastava A, Goldberger H, Dimtchev A, et al. MicroRNA profiling in prostate cancer–the diagnostic potential of urinary miR-205 and miR-214. PLoS One. 2013;8:e76994.
90.
Bryant RJ, Pawlowski T, Catto JW, et al. Changes in circulating microRNA levels associated with prostate cancer. Br J Cancer. 2012;106:768–74.
91.
Corcoran C, Rani S, O’Driscoll L. miR-34a is an intracellular and exosomal predictive biomarker for response to docetaxel with clinical relevance to prostate cancer progression. Prostate. 2014;74:1320–34.
92.
Zhang DZ, Lau KM, Chan ES, et al. Cell-free urinary microRNA-99a and microRNA-125b are diagnostic markers for the non-invasive screening of bladder cancer. PLoS One. 2014;9:e100793.
Metadata
Title
Cell-free microRNAs as cancer biomarkers: the odyssey of miRNAs through body fluids
Authors
Mohammad Amin Javidi
Amir Hossein Ahmadi
Babak Bakhshinejad
Nazila Nouraee
Sadegh Babashah
Majid Sadeghizadeh
Publication date
01-12-2014
Publisher
Springer US
Published in
Medical Oncology / Issue 12/2014
Print ISSN: 1357-0560
Electronic ISSN: 1559-131X
DOI
https://doi.org/10.1007/s12032-014-0295-y

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