Skip to main content

Advertisement

Log in

Recent progress toward the use of circulating microRNAs as clinical biomarkers

  • Review Article
  • Published:
Archives of Toxicology Aims and scope Submit manuscript

Abstract

MicroRNAs (miRNAs) have been shown to be critical mediators of many cellular and developmental processes and have been implicated in different human diseases. Since the observation of extracellular miRNAs present in various biofluids, much attention and excitement have been garnered toward understanding the functional roles of these circulating extracellular miRNAs and establishing their potential use as noninvasive diagnostic biomarkers. Here, we will review the current state of miRNA biomarkers for many human diseases, including their emerging use in toxicological applications, and discuss the current challenges in the field, with an emphasis on technical issues that often hinder discovery-based miRNA biomarker studies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Abue M, Yokoyama M, Shibuya R, Tamai K, Yamaguchi K, Sato I, Tanaka N, Hamada S, Shimosegawa T, Sugamura K et al (2015) Circulating miR-483-3p and miR-21 is highly expressed in plasma of pancreatic cancer. Int J Oncol 46:539–547

    CAS  PubMed  Google Scholar 

  • Akat KM, Moore-McGriff D, Morozov P, Brown M, Gogakos T, Correa Da Rosa J, Mihailovic A, Sauer M, Ji R, Ramarathnam A et al (2014) Comparative RNA-sequencing analysis of myocardial and circulating small RNAs in human heart failure and their utility as biomarkers. Proc Natl Acad Sci USA 111:11151–11156

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Alemar B, Izetti P, Gregório C, Macedo GS, Castro MAA, Osvaldt AB, Matte U, Ashton-Prolla P (2016) miRNA-21 and miRNA-34a are potential minimally invasive biomarkers for the diagnosis of pancreatic ductal adenocarcinoma. Pancreas 45:84–92

    Article  CAS  PubMed  Google Scholar 

  • Argyropoulos C, Wang K, McClarty S, Huang D, Bernardo J, Ellis D, Orchard T, Galas D, Johnson J (2013) Urinary microRNA profiling in the nephropathy of type 1 diabetes. PLoS ONE 8:e54662

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Argyropoulos C, Wang K, Bernardo J, Ellis D, Orchard T, Galas D, Johnson JP (2015) Urinary microRNA profiling predicts the development of microalbuminuria in patients with type 1 diabetes. J Clin Med 4:1498–1517

    Article  PubMed  PubMed Central  Google Scholar 

  • Arroyo JD, Chevillet JR, Kroh EM, Ruf IK, Pritchard CC, Gibson DF, Mitchell PS, Bennett CF, Pogosova-Agadjanyan EL, Stirewalt DL et al (2011) Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma. Proc Natl Acad Sci USA 108:5003–5008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Axtell MJ, Westholm JO, Lai EC (2011) Vive la différence: biogenesis and evolution of microRNAs in plants and animals. Genome Biol 12:221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ayala W, Moore LV, Hess EL (1951) The purple color reaction given by diphenylamine reagent. I. With normal and rheumatic fever sera. J Clin Invest 30:781–785

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Badrnya S, Baumgartner R, Assinger A (2014) Smoking alters circulating plasma microvesicle pattern and microRNA signatures. Thromb Haemost 112(1):128–136

    Article  CAS  PubMed  Google Scholar 

  • Balasubramanyam M, Aravind S, Gokulakrishnan K, Prabu P, Sathishkumar C, Ranjani H, Mohan V (2011) Impaired miR-146a expression links subclinical inflammation and insulin resistance in Type 2 diabetes. Mol Cell Biochem 351:197–205

    Article  CAS  PubMed  Google Scholar 

  • Bianchi F, Nicassio F, Marzi M, Belloni E, Dall’Olio V, Bernard L, Pelosi G, Maisonneuve P, Veronesi G, Di Fiore PP (2011) A serum circulating miRNA diagnostic test to identify asymptomatic high-risk individuals with early stage lung cancer: serum miRNAs to diagnose asymptomatic NSCLC. EMBO Mol Med 3:495–503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Boeri M, Verri C, Conte D, Roz L, Modena P, Facchinetti F, Calabrò E, Croce CM, Pastorino U, Sozzi G (2011) MicroRNA signatures in tissues and plasma predict development and prognosis of computed tomography detected lung cancer. Proc Natl Acad Sci USA 108:3713–3718

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bollati V, Angelici L, Rizzo G, Pergoli L, Rota F, Hoxha M, Nordio F, Bonzini M, Tarantini L, Cantone L et al (2015) Microvesicle-associated microRNA expression is altered upon particulate matter exposure in healthy workers and in A549 cells. J Appl Toxicol JAT 35:59–67

    Article  CAS  PubMed  Google Scholar 

  • Cha DJ, Franklin JL, Dou Y, Liu Q, Higginbotham JN, DemoryBeckler M, Weaver AM, Vickers K, Prasad N, Levy S et al (2015) KRAS-dependent sorting of miRNA to exosomes. eLife 4:e07197

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Chen X, Ba Y, Ma L, Cai X, Yin Y, Wang K, Guo J, Zhang Y, Chen J, Guo X et al (2008) Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res 18:997–1006

    Article  CAS  PubMed  Google Scholar 

  • Chen W, Cai F, Zhang B, Barekati Z, Zhong XY (2013) The level of circulating miRNA-10b and miRNA-373 in detecting lymph node metastasis of breast cancer: potential biomarkers. Tumour Biol J Int Soc Oncodev Biol Med 34:455–462

    Article  CAS  Google Scholar 

  • Chen H, Lan H-Y, Roukos DH, Cho WC (2014a) Application of microRNAs in diabetes mellitus. J Endocrinol 222:R1–R10

    Article  CAS  PubMed  Google Scholar 

  • Chen Q, Yang L, Xiao Y, Zhu J, Li Z (2014b) Circulating microRNA-182 in plasma and its potential diagnostic and prognostic value for pancreatic cancer. Med Oncol Northwood Lond Engl 31:225

    Article  CAS  Google Scholar 

  • Cheng H, Zhang L, Cogdell DE, Zheng H, Schetter AJ, Nykter M, Harris CC, Chen K, Hamilton SR, Zhang W (2011) Circulating plasma MiR-141 is a novel biomarker for metastatic colon cancer and predicts poor prognosis. PLoS ONE 6:e17745

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Corsten MF, Dennert R, Jochems S, Kuznetsova T, Devaux Y, Hofstra L, Wagner DR, Staessen JA, Heymans S, Schroen B (2010) Circulating microRNA-208b and microRNA-499 reflect myocardial damage in cardiovascular disease. Circ Cardiovasc Genet 3:499–506

    Article  PubMed  Google Scholar 

  • Cote GA, Gore AJ, McElyea SD, Heathers LE, Xu H, Sherman S, Korc M (2014) A pilot study to develop a diagnostic test for pancreatic ductal adenocarcinoma based on differential expression of select miRNA in plasma and bile. Am J Gastroenterol 109:1942–1952

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cuk K, Zucknick M, Heil J, Madhavan D, Schott S, Turchinovich A, Arlt D, Rath M, Sohn C, Benner A et al (2013) Circulating microRNAs in plasma as early detection markers for breast cancer. Int J Cancer 132:1602–1612

    Article  CAS  PubMed  Google Scholar 

  • D’Alessandra Y, Devanna P, Limana F, Straino S, Di Carlo A, Brambilla PG, Rubino M, Carena MC, Spazzafumo L, De Simone M et al (2010) Circulating microRNAs are new and sensitive biomarkers of myocardial infarction. Eur Heart J 31:2765–2773

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • De Rosa S, Fichtlscherer S, Lehmann R, Assmus B, Dimmeler S, Zeiher AM (2011) Transcoronary concentration gradients of circulating microRNAs. Circulation 124:1936–1944

    Article  PubMed  CAS  Google Scholar 

  • Delić D, Eisele C, Schmid R, Baum P, Wiech F, Gerl M, Zimdahl H, Pullen SS, Urquhart R (2016) Urinary Exosomal miRNA Signature in Type II Diabetic Nephropathy Patients. PLoS ONE 11:e0150154

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Demory Beckler M, Higginbotham JN, Franklin JL, Ham A-J, 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 Proteom MCP 12:343–355

    Article  CAS  Google Scholar 

  • Denzer K, Kleijmeer MJ, Heijnen HF, Stoorvogel W, Geuze HJ (2000) Exosome: from internal vesicle of the multivesicular body to intercellular signaling device. J Cell Sci 113(Pt 19):3365–3374

    CAS  PubMed  Google Scholar 

  • Devaux Y, Vausort M, Goretti E, Nazarov PV, Azuaje F, Gilson G, Corsten MF, Schroen B, Lair M-L, Heymans S et al (2012) Use of circulating microRNAs to diagnose acute myocardial infarction. Clin Chem 58:559–567

    Article  CAS  PubMed  Google Scholar 

  • El-Khoury V, Pierson S, Kaoma T, Bernardin F, Berchem G (2016) Assessing cellular and circulating miRNA recovery: the impact of the RNA isolation method and the quantity of input material. Sci Rep 6:19529

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ellis KL, Cameron VA, Troughton RW, Frampton CM, Ellmers LJ, Richards AM (2013) Circulating microRNAs as candidate markers to distinguish heart failure in breathless patients. Eur J Heart Fail 15:1138–1147

    Article  CAS  PubMed  Google Scholar 

  • Erson AE, Petty EM (2008) MicroRNAs in development and disease. Clin Genet 74:296–306

    Article  CAS  PubMed  Google Scholar 

  • Fabian MR, Sonenberg N, Filipowicz W (2010) Regulation of mRNA translation and stability by microRNAs. Annu Rev Biochem 79:351–379

    Article  CAS  PubMed  Google Scholar 

  • Feng X, Wang Z, Fillmore R, Xi Y (2014) MiR-200, a new star miRNA in human cancer. Cancer Lett 344:166–173

    Article  CAS  PubMed  Google Scholar 

  • Fish JE, Santoro MM, Morton SU, Yu S, Yeh R-F, Wythe JD, Ivey KN, Bruneau BG, Stainier DYR, Srivastava D (2008) miR-126 regulates angiogenic signaling and vascular integrity. Dev Cell 15:272–284

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gao W, Yu Y, Cao H, Shen H, Li X, Pan S, Shu Y (2010) Deregulated expression of miR-21, miR-143 and miR-181a in non small cell lung cancer is related to clinicopathologic characteristics or patient prognosis. Biomed Pharmacother Bioméd Pharmacothérapie 64:399–408

    Article  CAS  Google Scholar 

  • Gidlöf O, Smith JG, Miyazu K, Gilje P, Spencer A, Blomquist S, Erlinge D (2013) Circulating cardio-enriched microRNAs are associated with long-term prognosis following myocardial infarction. BMC Cardiovasc Disord 13:12

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Goonetilleke KS, Siriwardena AK (2007) Systematic review of carbohydrate antigen (CA 19-9) as a biochemical marker in the diagnosis of pancreatic cancer. Eur J Surg Oncol J Eur Soc Surg Oncol Br Assoc Surg Oncol 33:266–270

    CAS  Google Scholar 

  • Goren Y, Kushnir M, Zafrir B, Tabak S, Lewis BS, Amir O (2012) Serum levels of microRNAs in patients with heart failure. Eur J Heart Fail 14:147–154

    Article  CAS  PubMed  Google Scholar 

  • Guay C, Regazzi R (2013) Circulating microRNAs as novel biomarkers for diabetes mellitus. Nat Rev Endocrinol 9:513–521

    Article  CAS  PubMed  Google Scholar 

  • Ha M, Kim VN (2014) Regulation of microRNA biogenesis. Nat Rev Mol Cell Biol 15:509–524

    Article  CAS  PubMed  Google Scholar 

  • Hansen TF, Carlsen AL, Heegaard NHH, Sørensen FB, Jakobsen A (2015) Changes in circulating microRNA-126 during treatment with chemotherapy and bevacizumab predicts treatment response in patients with metastatic colorectal cancer. Br J Cancer 112:624–629

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • He Y, Lin J, Kong D, Huang M, Xu C, Kim T-K, Etheridge A, Luo Y, Ding Y, Wang K (2015) Current state of circulating microRNAs as cancer biomarkers. Clin Chem 61:1138–1155

    Article  CAS  PubMed  Google Scholar 

  • Hergenreider E, Heydt S, Tréguer K, Boettger T, Horrevoets AJG, Zeiher AM, Scheffer MP, Frangakis AS, Yin X, Mayr M et al (2012) Atheroprotective communication between endothelial cells and smooth muscle cells through miRNAs. Nat Cell Biol 14:249–256

    Article  CAS  PubMed  Google Scholar 

  • Ho AS, Huang X, Cao H, Christman-Skieller C, Bennewith K, Le Q-T, Koong AC (2010) Circulating miR-210 as a novel hypoxia marker in pancreatic cancer. Transl Oncol 3:109–113

    Article  PubMed  PubMed Central  Google Scholar 

  • Hu Z, Chen X, Zhao Y, Tian T, Jin G, Shu Y, Chen Y, Xu L, Zen K, Zhang C et al (2010) Serum microRNA signatures identified in a genome-wide serum microRNA expression profiling predict survival of non-small-cell lung cancer. J Clin Oncol Off J Am Soc Clin Oncol 28:1721–1726

    Article  Google Scholar 

  • Huang Z, Huang D, Ni S, Peng Z, Sheng W, Du X (2010) Plasma microRNAs are promising novel biomarkers for early detection of colorectal cancer. Int J Cancer 127:118–126

    Article  CAS  PubMed  Google Scholar 

  • Huang Y, Shen XJ, Zou Q, Wang SP, Tang SM, Zhang GZ (2011) Biological functions of microRNAs: a review. J Physiol Biochem 67:129–139

    Article  CAS  PubMed  Google Scholar 

  • Huang S, Chen M, Li L, He MA, Hu D, Zhang X, Li J, Tanguay RM, Feng J, Cheng L et al (2014) Circulating microRNAs and the occurrence of acute myocardial infarction in Chinese populations. Circ Cardiovasc Genet 7:189–198

    Article  CAS  PubMed  Google Scholar 

  • Jansen F, Yang X, Hoelscher M, Cattelan A, Schmitz T, Proebsting S, Wenzel D, Vosen S, Franklin BS, Fleischmann BK et al (2013) Endothelial microparticle-mediated transfer of microRNA-126 promotes vascular endothelial cell repair via SPRED1 and is abrogated in glucose-damaged endothelial microparticles. Circulation 128:2026–2038

    Article  CAS  PubMed  Google Scholar 

  • Jansen F, Wang H, Przybilla D, Franklin BS, Dolf A, Pfeifer P, Schmitz T, Flender A, Endl E, Nickenig G, Werner N (2016) Vascular endothelial microparticles-incorporated microRNAs are altered in patients with diabetes mellitus. Cardiovasc Diabetol 15:49. doi:10.1186/s12933-016-0367-8

    Article  PubMed  PubMed Central  Google Scholar 

  • Ji X, Takahashi R, Hiura Y, Hirokawa G, Fukushima Y, Iwai N (2009) Plasma miR-208 as a biomarker of myocardial injury. Clin Chem 55:1944–1949

    Article  CAS  PubMed  Google Scholar 

  • Kanki M, Moriguchi A, Sasaki D, Mitori H, Yamada A, Unami A, Miyamae Y (2014) Identification of urinary miRNA biomarkers for detecting cisplatin-induced proximal tubular injury in rats. Toxicology 324:158–168

    Article  CAS  PubMed  Google Scholar 

  • Kong L, Zhu J, Han W, Jiang X, Xu M, Zhao Y, Dong Q, Pang Z, Guan Q, Gao L et al (2011a) Significance of serum microRNAs in pre-diabetes and newly diagnosed type 2 diabetes: a clinical study. Acta Diabetol 48:61–69

    Article  CAS  PubMed  Google Scholar 

  • Kong X, Du Y, Wang G, Gao J, Gong Y, Li L, Zhang Z, Zhu J, Jing Q, Qin Y et al (2011b) Detection of differentially expressed microRNAs in serum of pancreatic ductal adenocarcinoma patients: miR-196a could be a potential marker for poor prognosis. Dig Dis Sci 56:602–609

    Article  CAS  PubMed  Google Scholar 

  • Koppers-Lalic D, Hackenberg M, Bijnsdorp IV, van Eijndhoven MAJ, Sadek P, Sie D, Zini N, Middeldorp JM, Ylstra B, de Menezes RX et al (2014) Nontemplated nucleotide additions distinguish the small RNA composition in cells from exosomes. Cell Rep 8:1649–1658

    Article  CAS  PubMed  Google Scholar 

  • Kosaka N, Iguchi H, Yoshioka Y, Takeshita F, Matsuki Y, Ochiya T (2010) Secretory mechanisms and intercellular transfer of microRNAs in living cells. J Biol Chem 285:17442–17452

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kozakowska M, Ciesla M, Stefanska A, Skrzypek K, Was H, Jazwa A, Grochot-Przeczek A, Kotlinowski J, Szymula A, Bartelik A et al (2012) Heme oxygenase-1 inhibits myoblast differentiation by targeting myomirs. Antioxid Redox Signal 16:113–127

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kozomara A, Griffiths-Jones S (2014) miRBase: annotating high confidence microRNAs using deep sequencing data. Nucl Acids Res 42:D68–D73

    Article  CAS  PubMed  Google Scholar 

  • Krichevsky AM, Gabriely G (2009) miR-21: a small multi-faceted RNA. J Cell Mol Med 13:39–53

    Article  CAS  PubMed  Google Scholar 

  • Lee RC, Feinbaum RL, Ambros V (1993) The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75:843–854

    Article  CAS  PubMed  Google Scholar 

  • Leroyer AS, Tedgui A, Boulanger CM (2008) Microparticles and type 2 diabetes. Diabetes Metab 34(Suppl 1):S27–32

    Article  CAS  PubMed  Google Scholar 

  • Liu L-Z, Li C, Chen Q, Jing Y, Carpenter R, Jiang Y, Kung H-F, Lai L, Jiang B-H (2011) MiR-21 induced angiogenesis through AKT and ERK activation and HIF-1α expression. PLoS ONE 6:e19139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu R, Chen X, Du Y, Yao W, Shen L, Wang C, Hu Z, Zhuang R, Ning G, Zhang C et al (2012a) Serum microRNA expression profile as a biomarker in the diagnosis and prognosis of pancreatic cancer. Clin Chem 58:610–618

    Article  CAS  PubMed  Google Scholar 

  • Liu X-G, Zhu W-Y, Huang Y-Y, Ma L-N, Zhou S-Q, Wang Y-K, Zeng F, Zhou J-H, Zhang Y-K (2012b) High expression of serum miR-21 and tumor miR-200c associated with poor prognosis in patients with lung cancer. Med Oncol Northwood Lond Engl 29:618–626

    Article  CAS  Google Scholar 

  • Liu Y, Gao G, Yang C, Zhou K, Shen B, Liang H, Jiang X (2014) The role of circulating microRNA-126 (miR-126): a novel biomarker for screening prediabetes and newly diagnosed type 2 diabetes mellitus. Int J Mol Sci 15:10567–10577

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Long G, Wang F, Duan Q, Yang S, Chen F, Gong W, Yang X, Wang Y, Chen C, Wang DW (2012) Circulating miR-30a, miR-195 and let-7b associated with acute myocardial infarction. PLoS ONE 7:e50926

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ma L, Reinhardt F, Pan E, Soutschek J, Bhat B, Marcusson EG, Teruya-Feldstein J, Bell GW, Weinberg RA (2010) Therapeutic silencing of miR-10b inhibits metastasis in a mouse mammary tumor model. Nat Biotechnol 28:341–347

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Madhavan D, Peng C, Wallwiener M, Zucknick M, Nees J, Schott S, Rudolph A, Riethdorf S, Trumpp A, Pantel K et al (2016) Circulating miRNAs with prognostic value in metastatic breast cancer and for early detection of metastasis. Carcinogenesis 37:461

    Article  CAS  PubMed  Google Scholar 

  • Maegdefessel L (2014) The emerging role of microRNAs in cardiovascular disease. J Intern Med 276(6):633–644

    Article  CAS  Google Scholar 

  • Mandel P, Metais P (1948) Comptes rendus séances société. Biol Ses Fil 142:241–243

    CAS  Google Scholar 

  • Mar-Aguilar F, Mendoza-Ramírez JA, Malagón-Santiago I, Espino-Silva PK, Santuario-Facio SK, Ruiz-Flores P, Rodríguez-Padilla C, Reséndez-Pérez D (2013) Serum circulating microRNA profiling for identification of potential breast cancer biomarkers. Dis Markers 34:163–169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Matamala N, Vargas MT, González-Cámpora R, Miñambres R, Arias JI, Menéndez P, Andrés-León E, Gómez-López G, Yanowsky K, Calvete-Candenas J et al (2015) Tumor microRNA expression profiling identifies circulating microRNAs for early breast cancer detection. Clin Chem 61:1098–1106

    Article  CAS  PubMed  Google Scholar 

  • Melman YF, Shah R, Danielson K, Xiao J, Simonson B, Barth A, Chakir K, Lewis GD, Lavender Z, Truong QA et al (2015) Circulating microRNA-30d is associated with response to cardiac resynchronization therapy in heart failure and regulates cardiomyocyte Apoptosis A translational pilot study. Circulation 131:2202–2216

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Meng X, Müller V, Milde-Langosch K, Trillsch F, Pantel K, Schwarzenbach H (2016) Diagnostic and prognostic relevance of circulating exosomal miR-373, miR-200a, miR-200b and miR-200c in patients with epithelial ovarian cancer. Oncotarget 7:16923

    PubMed  PubMed Central  Google Scholar 

  • Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, Pogosova-Agadjanyan EL, Peterson A, Noteboom J, O’Briant KC, Allen A et al (2008) Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci USA 105:10513–10518

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Morimura R, Komatsu S, Ichikawa D, Takeshita H, Tsujiura M, Nagata H, Konishi H, Shiozaki A, Ikoma H, Okamoto K et al (2011) Novel diagnostic value of circulating miR-18a in plasma of patients with pancreatic cancer. Br J Cancer 105:1733–1740

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Motta V, Angelici L, Nordio F, Bollati V, Fossati S, Frascati F, Tinaglia V, Bertazzi PA, Battaglia C, Baccarelli AA (2013) Integrative analysis of miRNA and inflammatory gene expression after acute particulate matter exposure. Toxicol Sci Off J Soc Toxicol 132:307–316

    Article  CAS  Google Scholar 

  • Nassirpour R, Mathur S, Gosink MM, Li Y, Shoieb AM, Wood J, O’Neil SP, Homer BL, Whiteley LO (2014) Identification of tubular injury microRNA biomarkers in urine: comparison of next-generation sequencing and qPCR-based profiling platforms. BMC Genom 15:485

    Article  CAS  Google Scholar 

  • Nielsen LB, Wang C, Sørensen K, Bang-Berthelsen CH, Hansen L, Andersen M-LM, Hougaard P, Juul A, Zhang C-Y et al (2012) Circulating levels of microRNA from children with newly diagnosed type 1 diabetes and healthy controls: evidence that miR-25 associates to residual beta-cell function and glycaemic control during disease progression. J Diabetes Res 2012:e896362

    Google Scholar 

  • Ng EKO, Chong WWS, Jin H, Lam EKY, Shin VY, Yu J, Poon TCW, Ng SSM, Sung JJY (2009) Differential expression of microRNAs in plasma of patients with colorectal cancer: a potential marker for colorectal cancer screening. Gut 58:1375–1381

    Article  CAS  PubMed  Google Scholar 

  • Ng EKO, Li R, Shin VY, Jin HC, Leung CPH, Ma ESK, Pang R, Chua D, Chu K-M, Law WL et al (2013) Circulating microRNAs as specific biomarkers for breast cancer detection. PLoS ONE 8:e53141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nishimura Y, Kondo C, Morikawa Y, Tonomura Y, Torii M, Yamate J, Uehara T (2015) Plasma miR-208 as a useful biomarker for drug-induced cardiotoxicity in rats. J Appl Toxicol JAT 35:173–180

    Article  CAS  PubMed  Google Scholar 

  • Ogata-Kawata H, Izumiya M, Kurioka D, Honma Y, Yamada Y, Furuta K, Gunji T, Ohta H, Okamoto H, Sonoda H et al (2014) Circulating exosomal microRNAs as biomarkers of colon cancer. PLoS ONE 9:e92921

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Olivieri F, Antonicelli R, Lorenzi M, D’Alessandra Y, Lazzarini R, Santini G, Spazzafumo L, Lisa R, La Sala L, Galeazzi R et al (2013) Diagnostic potential of circulating miR-499-5p in elderly patients with acute non ST-elevation myocardial infarction. Int J Cardiol 167:531–536

    Article  PubMed  Google Scholar 

  • Ortega FJ, Mercader JM, Catalán V, Moreno-Navarrete JM, Pueyo N, Sabater M, Gómez-Ambrosi J, Anglada R, Fernández-Formoso JA, Ricart W et al (2013) Targeting the circulating microRNA signature of obesity. Clin Chem 59:781–792

    Article  CAS  PubMed  Google Scholar 

  • Ortega FJ, Mercader JM, Moreno-Navarrete JM, Rovira O, Guerra E, Esteve E, Xifra G, Martínez C, Ricart W, Rieusset J et al (2014) Profiling of circulating microRNAs reveals common microRNAs linked to type 2 diabetes that change with insulin sensitization. Diabet Care 37:1375–1383

    Article  CAS  Google Scholar 

  • Osipova J, Fischer D-C, Dangwal S, Volkmann I, Widera C, Schwarz K, Lorenzen JM, Schreiver C, Jacoby U, Heimhalt M et al (2014) Diabetes-associated microRNAs in pediatric patients with type 1 diabetes mellitus: a cross-sectional cohort study. J Clin Endocrinol Metab 99:E1661–1665

    Article  CAS  PubMed  Google Scholar 

  • Pavkovic M, Riefke B, Ellinger-Ziegelbauer H (2014) Urinary microRNA profiling for identification of biomarkers after cisplatin-induced kidney injury. Toxicology 324:147–157

    Article  CAS  PubMed  Google Scholar 

  • Pavkovic M, Riefke B, Frisk A-L, Gröticke I, Ellinger-Ziegelbauer H (2015) Glomerulonephritis-induced changes in urinary and kidney microRNA profiles in rats. Toxicol Sci Off J Soc Toxicol 145:348–359

    Article  CAS  Google Scholar 

  • Pavkovic M, Robinson-Cohen C, Chua AS, Nicoara O, Cárdenas-González M, Bijol V, Ramachandran K, Hampson L, Pirmohamed M, Antoine DJ et al (2016) Detection of drug-induced acute kidney injury in humans using urinary KIM-1, miR-21, -200c, and -423. Toxicol Sci Off J Soc Toxicol 152:205–213

    Article  CAS  Google Scholar 

  • Pescador N, Pérez-Barba M, Ibarra JM, Corbatón A, Martínez-Larrad MT, Serrano-Ríos M (2013) Serum circulating microRNA profiling for identification of potential type 2 diabetes and obesity biomarkers. PLoS ONE 8:e77251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Petriella D, De Summa S, Lacalamita R, Galetta D, Catino A, Logroscino AF, Palumbo O, Carella M, Zito FA, Simone G et al (2015) miRNA profiling in serum and tissue samples to assess noninvasive biomarkers for NSCLC clinical outcome. Tumour Biol J Int Soc Oncodev Biol, Med

    Google Scholar 

  • Pezzolesi MG, Satake E, McDonnell KP, Major M, Smiles AM, Krolewski AS (2015) Circulating TGF-β1-regulated miRNAs and the risk of rapid progression to ESRD in type 1 diabetes. Diabetes 64:3285–3293

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pillai RS (2005) MicroRNA function: Multiple mechanisms for a tiny RNA? RNA 11:1753–1761

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Qing S, Yuan S, Yun C, Hui H, Mao P, Wen F, Ding Y, Liu Q (2014) Serum MiRNA biomarkers serve as a fingerprint for proliferative diabetic retinopathy. Cell Physiol Biochem 34(5):1733–1740

    Article  CAS  PubMed  Google Scholar 

  • Romaine SP, Tomaszewski M, Condorelli G, Samani NJ (2015) MicroRNAs in cardiovascular disease: an introduction for clinicians. Heart 101(12):921–928

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rong Y, Bao W, Shan Z, Liu J, Yu X, Xia S, Gao H, Wang X, Yao P, Hu FB et al (2013) Increased microRNA-146a levels in plasma of patients with newly diagnosed type 2 diabetes mellitus. PLoS ONE 8:e73272

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Salas-Pérez F, Codner E, Valencia E, Pizarro C, Carrasco E, Pérez-Bravo F (2013) MicroRNAs miR-21a and miR-93 are down regulated in peripheral blood mononuclear cells (PBMCs) from patients with type 1 diabetes. Immunobiology 218:733–737

    Article  PubMed  CAS  Google Scholar 

  • Schultz NA, Dehlendorff C, Jensen BV et al (2014) MicroRNA biomarkers in whole blood for detection of pancreatic cancer. JAMA 311:392–404

    Article  CAS  PubMed  Google Scholar 

  • Shan L, Ji Q, Cheng G, Xia J, Liu D, Wu C, Zhu B, Ding Y (2015) Diagnostic value of circulating miR-21 for colorectal cancer: a meta-analysis. Cancer Biomark Sect Dis Markers 15:47–56

    CAS  Google Scholar 

  • Shen J, Todd NW, Zhang H, Yu L, Lingxiao X, Mei Y, Guarnera M, Liao J, Chou A, Lu CL et al (2011) Plasma microRNAs as potential biomarkers for non-small-cell lung cancer. Lab Investig J Tech Methods Pathol 91:579–587

    Article  CAS  Google Scholar 

  • Shifeng H, Danni W, Pu C, Ping Y, Ju C, Liping Z (2013) Circulating liver-specific miR-122 as a novel potential biomarker for diagnosis of cholestatic liver injury. PLoS ONE 8:73133

    Article  CAS  Google Scholar 

  • Starkey Lewis PJ, Dear J, Platt V, Simpson KJ, Craig DGN, Antoine DJ, French NS, Dhaun N, Webb DJ, Costello EM et al (2011) Circulating microRNAs as potential markers of human drug-induced liver injury. Hepatol Baltim Md 54:1767–1776

    Article  CAS  Google Scholar 

  • Takahashi K, Yokota S-I, Tatsumi N, Fukami T, Yokoi T, Nakajima M (2013) Cigarette smoking substantially alters plasma microRNA profiles in healthy subjects. Toxicol Appl Pharmacol 272:154–160

    Article  CAS  PubMed  Google Scholar 

  • Théry C, Amigorena S, Raposo G, Clayton A (2006) Isolation and characterization of exosomes from cell culture supernatants and biological fluids. In: Board Juan Bonifacino Al (ed) Curr Protoc Cell Biol Chapter 3, Unit 3.22

  • Turchinovich A, Weiz L, Langheinz A, Burwinkel B (2011) Characterization of extracellular circulating microRNA. Nucl Acids Res 39:7223–7233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tushuizen ME, Nieuwland R, Rustemeijer C, Hensgens BE, Sturk A, Heine RJ, Diamant M (2007) Elevated endothelial microparticles following consecutive meals are associated with vascular endothelial dysfunction in type 2 diabetes. Diabet Care 30:728–730

    Article  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • van Schooneveld E, Wouters MC, Van der Auwera I, Peeters DJ, Wildiers H, Van Dam PA, Vergote I, Vermeulen PB, Dirix LY, Van Laere SJ (2012) Expression profiling of cancerous and normal breast tissues identifies microRNAs that are differentially expressed in serum from patients with (metastatic) breast cancer and healthy volunteers. Breast Cancer Res BCR 14:R34

    Article  PubMed  CAS  Google Scholar 

  • Vickers KC, Palmisano BT, Shoucri BM, Shamburek RD, Remaley AT (2011) MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins. Nat Cell Biol 13:423–433

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Villarroya-Beltri C, Gutiérrez-Vázquez C, Sánchez-Cabo F, Pérez-Hernández D, Vázquez J, Martin-Cofreces N, Martinez-Herrera DJ, Pascual-Montano A, Mittelbrunn M, Sánchez-Madrid F (2013) Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs. Nat Commun 4:2980

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Vliegenthart ADB, Shaffer JM, Clarke JI, Peeters LEJ, Caporali A, Bateman DN, Wood DM, Dargan PI, Craig DG, Moore JK et al (2015) Comprehensive microRNA profiling in acetaminophen toxicity identifies novel circulating biomarkers for human liver and kidney injury. Sci Rep 5:15501

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wagner J, Riwanto M, Besler C, Knau A, Fichtlscherer S, Röxe T, Zeiher AM, Landmesser U, Dimmeler S (2013) Characterization of levels and cellular transfer of circulating lipoprotein-bound microRNAs. Arterioscler Thromb Vasc Biol 33:1392–1400

    Article  CAS  PubMed  Google Scholar 

  • Wang L-G, Gu J (2012) Serum microRNA-29a is a promising novel marker for early detection of colorectal liver metastasis. Cancer Epidemiol 36:e61–67

    Article  CAS  PubMed  Google Scholar 

  • Wang J, Chen J, Chang P, LeBlanc A, Li D, Abbruzzesse JL, Frazier ML, Killary AM, Sen S (2009) MicroRNAs in plasma of pancreatic ductal adenocarcinoma patients as novel blood-based biomarkers of disease. Cancer Prev Res Phila Pa 2:807–813

    Article  CAS  Google Scholar 

  • Wang G-K, Zhu J-Q, Zhang J-T, Li Q, Li Y, He J, Qin Y-W, Jing Q (2010a) Circulating microRNA: a novel potential biomarker for early diagnosis of acute myocardial infarction in humans. Eur Heart J 31:659–666

    Article  PubMed  CAS  Google Scholar 

  • Wang K, Zhang S, Weber J, Baxter D, Galas DJ (2010b) Export of microRNAs and microRNA-protective protein by mammalian cells. Nucl Acids Res 38:7248–7259

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang Z-X, Bian H-B, Wang J-R, Cheng Z-X, Wang K-M, De W (2011) Prognostic significance of serum miRNA-21 expression in human non-small cell lung cancer. J Surg Oncol 104:847–851

    Article  CAS  PubMed  Google Scholar 

  • Wang J, Zhang Y, Zhang W, Jin Y, Dai J (2012) Association of perfluorooctanoic acid with HDL cholesterol and circulating miR-26b and miR-199-3p in workers of a fluorochemical plant and nearby residents. Environ Sci Technol 46:9274–9281

    Article  CAS  PubMed  Google Scholar 

  • Wang J, Raimondo M, Guha S, Chen J, Diao L, Dong X, Wallace MB, Killary AM, Frazier ML, Woodward TA et al (2014) Circulating microRNAs in pancreatic juice as candidate biomarkers of pancreatic cancer. J Cancer 5:696–705

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wang C, Wan S, Yang T, Niu D, Zhang A, Yang C, Cai J, Wu J, Song J, Zhang C-Y, et al. (2016) Increased serum microRNAs are closely associated with the presence of microvascular complications in type 2 diabetes mellitus. Sci Rep 6:20032. doi:10.1038/srep20032

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Witwer KW, Buzás EI, Bemis LT, Bora A, Lässer C, Lötvall J, Nolte-’t Hoen EN, Piper MG, Sivaraman S, Skog J, et al. (2013) Standardization of sample collection, isolation and analysis methods in extracellular vesicle research. J Extracell Vesicles 2. doi:10.3402/jev.v2i0.20360

  • Wozniak MB, Scelo G, Muller DC, Mukeria A, Zaridze D, Brennan P (2015) Circulating microRNAs as non-invasive biomarkers for early detection of non-small-cell lung cancer. PLoS ONE 10:e0125026

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wu J, Yang T, Li X, Yang Q, Liu R, Huang J, Li Y, Yang C, Jiang Y (2013) Alteration of serum miR-206 and miR-133b is associated with lung carcinogenesis induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Toxicol Appl Pharmacol 267:238–246

    Article  CAS  PubMed  Google Scholar 

  • Xie Y, Todd NW, Liu Z, Zhan M, Fang H, Peng H, Alattar M, Deepak J, Stass SA, Jiang F (2010) Altered miRNA expression in sputum for diagnosis of non-small cell lung cancer. Lung Cancer Amst Neth 67:170–176

    Article  Google Scholar 

  • Xin H, Li Y, Buller B, Katakowski M, Zhang Y, Wang X, Shang X, Zhang ZG, Chopp M (2012) Exosome-mediated transfer of miR-133b from multipotent mesenchymal stromal cells to neural cells contributes to neurite outgrowth. Stem Cells Dayt Ohio 30:1556–1564

    Article  CAS  Google Scholar 

  • Yang M, Chen J, Su F, Yu B, Su F, Lin L, Liu Y, Huang J-D, Song E (2011) Microvesicles secreted by macrophages shuttle invasion-potentiating microRNAs into breast cancer cells. Mol Cancer 10:117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu S-L, Chen H-Y, Chang G-C, Chen C-Y, Chen H-W, Singh S, Cheng C-L, Yu C-J, Lee Y-C, Chen H-S et al (2008) MicroRNA signature predicts survival and relapse in lung cancer. Cancer Cell 13:48–57

    Article  CAS  PubMed  Google Scholar 

  • Yuan T, Huang X, Woodcock M, Du M, Dittmar R, Wang Y, Tsai S, Kohli M, Boardman L, Patel T et al (2016) Plasma extracellular RNA profiles in healthy and cancer patients. Sci Rep 6:19413

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yuchuan H, Ya D, Jie Z, Jingqiu C, Yanrong L, Dongliang L, Changguo W, Kuoyan M, Guangneng L, Fang X et al (2014) Circulating miRNAs might be promising biomarkers to reflect the dynamic pathological changes in smoking-related interstitial fibrosis. Toxicol Ind Health 30:182–191

    Article  PubMed  CAS  Google Scholar 

  • Zampetaki A, Kiechl S, Drozdov I, Willeit P, Mayr U, Prokopi M, Mayr A, Weger S, Oberhollenzer F, Bonora E et al (2010) Plasma microRNA profiling reveals loss of endothelial miR-126 and other microRNAs in type 2 diabetes. Circ Res 107:810–817

    Article  CAS  PubMed  Google Scholar 

  • Zampetaki A, Willeit P, Burr S, Yin X, Langley SR, Kiechl S, Klein R, Rossing P, Chaturvedi N, Mayr M (2016) Angiogenic microRNAs linked to incidence and progression of diabetic retinopathy in type 1 diabetes. Diabetes 65:216–227

    CAS  PubMed  Google Scholar 

  • Zhang Y, Jia Y, Zheng R, Guo Y, Wang Y, Guo H, Fei M, Sun S (2010) Plasma microRNA-122 as a biomarker for viral-, alcohol-, and chemical-related hepatic diseases. Clin Chem 56:1830–1838

    Article  CAS  PubMed  Google Scholar 

  • Zhao F-L, Hu G-D, Wang X-F, Zhang X-H, Zhang Y-K, Yu Z-S (2012) Serum overexpression of microRNA-10b in patients with bone metastatic primary breast cancer. J Int Med Res 40(3):859–866

    Article  CAS  PubMed  Google Scholar 

  • Zhao Z, He J, Zhang J, Liu M, Yang S, Li N, Li X (2014) Dysregulated miR1254 and miR579 for cardiotoxicity in patients treated with bevacizumab in colorectal cancer. Tumour Biol J Int Soc Oncodev Biol Med 35:5227–5235

    Article  CAS  Google Scholar 

  • Zhong J, He Y, Chen W, Shui X, Chen C, Lei W (2014) Circulating microRNA-19a as a potential novel biomarker for diagnosis of acute myocardial infarction. Int J Mol Sci 15:20355–20364

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported by research contracts from DOD W911NF-10-2-0111 and DTRA HDTRA1-13-C-0055.

Author contributions

Vikas Ghai and Kai Wang wrote the manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Kai Wang.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ghai, V., Wang, K. Recent progress toward the use of circulating microRNAs as clinical biomarkers. Arch Toxicol 90, 2959–2978 (2016). https://doi.org/10.1007/s00204-016-1828-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00204-016-1828-2

Keywords

Navigation