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Circulating MicroRNAs as Novel Biomarkers of Drug-Induced Liver Injury in Humans

  • Julian KrauskopfEmail author
  • Jos C. Kleinjans
  • Theo M. de Kok
Protocol
Part of the Methods in Pharmacology and Toxicology book series (MIPT)

Abstract

MicroRNAs have become a promising candidate for responding to the need for more specific and sensitive biomarkers for drug-induced liver injury (DILI). These small noncoding RNA molecules exert a regulatory function on biological processes by fine tuning gene expression levels. MicroRNAs are the most abundant and stable class of small RNAs in the cell and they are expressed in a cell type- and organ-specific manner. The expression of miRNAs changes with disease state and cells are actively and/or passively secreting miRNAs into the peripheral circulation. These extracellular, circulating miRNAs have been found to reflect the condition of distant organs. Numerous studies have shown elevated serum levels of miR-122, a liver-enriched miRNA, upon drug-induced hepatotoxicity and as a consequence of other liver injuries. These studies demonstrate the potential use of blood samples as minimally invasive, miRNA based “liquid biopsies,” able to interrogate hepatotoxic mechanisms and liver pathology. The purpose of this review is to summarize the recent advances on miRNA-based biomarker research for drug-induced liver injury.

Key words

Drug-induced liver injury microRNAs Acetaminophen Biomarker 

References

  1. 1.
    Regev A (2014) Drug-induced liver injury and drug development: industry perspective. Semin Liver Dis 34(2):227–239. https://doi.org/10.1055/s-0034-1375962 CrossRefGoogle Scholar
  2. 2.
    Pettersson J, Hindorf U, Persson P, Bengtsson T, Malmqvist U, Werkstrom V, Ekelund M (2008) Muscular exercise can cause highly pathological liver function tests in healthy men. Br J Clin Pharmacol 65(2):253–259. https://doi.org/10.1111/j.1365-2125.2007.03001.x CrossRefPubMedGoogle Scholar
  3. 3.
    West J, Brousil J, Gazis A, Jackson L, Mansell P, Bennett A, Aithal GP (2006) Elevated serum alanine transaminase in patients with type 1 or type 2 diabetes mellitus. QJM 99(12):871–876. https://doi.org/10.1093/qjmed/hcl116 CrossRefPubMedGoogle Scholar
  4. 4.
    Amacher DE, Schomaker SJ, Aubrecht J (2013) Development of blood biomarkers for drug-induced liver injury: an evaluation of their potential for risk assessment and diagnostics. Mol Diagn Ther 17(6):343–354. https://doi.org/10.1007/s40291-013-0049-0 CrossRefPubMedGoogle Scholar
  5. 5.
    Szabo G, Bala S (2013) MicroRNAs in liver disease. Nat Rev Gastroenterol Hepatol 10(9):542–552. https://doi.org/10.1038/nrgastro.2013.87 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136(2):215–233. https://doi.org/10.1016/j.cell.2009.01.002 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Jopling CL, Yi M, Lancaster AM, Lemon SM, Sarnow P (2005) Modulation of hepatitis C virus RNA abundance by a liver-specific MicroRNA. Science 309(5740):1577–1581. https://doi.org/10.1126/science.1113329 CrossRefPubMedGoogle Scholar
  8. 8.
    Wang K, Zhang S, Marzolf B, Troisch P, Brightman A, Hu Z, Hood LE, Galas DJ (2009) Circulating microRNAs, potential biomarkers for drug-induced liver injury. Proc Natl Acad Sci U S A 106(11):4402–4407. https://doi.org/10.1073/pnas.0813371106 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Hou J, Lin L, Zhou W, Wang Z, Ding G, Dong Q, Qin L, Wu X, Zheng Y, Yang Y, Tian W, Zhang Q, Wang C, Zhang Q, Zhuang SM, Zheng L, Liang A, Tao W, Cao X (2011) Identification of miRNomes in human liver and hepatocellular carcinoma reveals miR-199a/b-3p as therapeutic target for hepatocellular carcinoma. Cancer Cell 19(2):232–243. https://doi.org/10.1016/j.ccr.2011.01.001 CrossRefPubMedGoogle Scholar
  10. 10.
    Falcon-Perez JM, Royo F (2015) Circulating RNA: looking at the liver through a frosted glass. Biomarkers 20(6-7):339–354. https://doi.org/10.3109/1354750X.2015.1101785 CrossRefPubMedGoogle Scholar
  11. 11.
    Schwarzenbach H, Nishida N, Calin GA, Pantel K (2014) Clinical relevance of circulating cell-free microRNAs in cancer. Nat Rev Clin Oncol 11(3):145–156. https://doi.org/10.1038/nrclinonc.2014.5 CrossRefPubMedGoogle Scholar
  12. 12.
    Diaz LA Jr, Bardelli A (2014) Liquid biopsies: genotyping circulating tumor DNA. J Clin Oncol 32(6):579–586. https://doi.org/10.1200/JCO.2012.45.2011 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    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(5):843–854CrossRefGoogle Scholar
  14. 14.
    Griffiths-Jones S (2006) miRBase: the microRNA sequence database. Methods Mol Biol 342:129–138. https://doi.org/10.1385/1-59745-123-1:129 CrossRefPubMedGoogle Scholar
  15. 15.
    Ha M, Kim VN (2014) Regulation of microRNA biogenesis. Nat Rev Mol Cell Biol 15(8):509–524. https://doi.org/10.1038/nrm3838 CrossRefGoogle Scholar
  16. 16.
    Krauskopf J, Caiment F, Claessen SM, Johnson KJ, Warner RL, Schomaker SJ, Burt DA, Aubrecht J, Kleinjans JC (2015) Application of high-throughput sequencing to circulating microRNAs reveals novel biomarkers for drug-induced liver injury. Toxicol Sci 143(2):268–276. https://doi.org/10.1093/toxsci/kfu232 CrossRefPubMedGoogle Scholar
  17. 17.
    Williams Z, Ben-Dov IZ, Elias R, Mihailovic A, Brown M, Rosenwaks Z, Tuschl T (2013) Comprehensive profiling of circulating microRNA via small RNA sequencing of cDNA libraries reveals biomarker potential and limitations. Proc Natl Acad Sci U S A 110(11):4255–4260. https://doi.org/10.1073/pnas.1214046110 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Ameres SL, Zamore PD (2013) Diversifying microRNA sequence and function. Nat Rev Mol Cell Biol 14(8):475–488. https://doi.org/10.1038/nrm3611 CrossRefPubMedGoogle Scholar
  19. 19.
    Yokoi T, Nakajima M (2013) microRNAs as mediators of drug toxicity. Annu Rev Pharmacol Toxicol 53:377–400. https://doi.org/10.1146/annurev-pharmtox-011112-140250 CrossRefPubMedGoogle Scholar
  20. 20.
    Tsuchiya Y, Nakajima M, Takagi S, Taniya T, Yokoi T (2006) MicroRNA regulates the expression of human cytochrome P450 1B1. Cancer Res 66(18):9090–9098. https://doi.org/10.1158/0008-5472.CAN-06-1403 CrossRefPubMedGoogle Scholar
  21. 21.
    Shimada T, Yamazaki H, Mimura M, Inui Y, Guengerich FP (1994) Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther 270(1):414–423PubMedGoogle Scholar
  22. 22.
    Mohri T, Nakajima M, Fukami T, Takamiya M, Aoki Y, Yokoi T (2010) Human CYP2E1 is regulated by miR-378. Biochem Pharmacol 79(7):1045–1052. https://doi.org/10.1016/j.bcp.2009.11.015 CrossRefPubMedGoogle Scholar
  23. 23.
    Shukla U, Tumma N, Gratsch T, Dombkowski A, Novak RF (2013) Insights into insulin-mediated regulation of CYP2E1: miR-132/-212 targeting of CYP2E1 and role of phosphatidylinositol 3-kinase, Akt (protein kinase B), mammalian target of rapamycin signaling in regulating miR-132/-212 and miR-122/-181a expression in primary cultured rat hepatocytes. Drug Metab Dispos 41(10):1769–1777. https://doi.org/10.1124/dmd.113.052860 CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Takagi S, Nakajima M, Kida K, Yamaura Y, Fukami T, Yokoi T (2010) MicroRNAs regulate human hepatocyte nuclear factor 4alpha, modulating the expression of metabolic enzymes and cell cycle. J Biol Chem 285(7):4415–4422. https://doi.org/10.1074/jbc.M109.085431 CrossRefPubMedGoogle Scholar
  25. 25.
    Takagi S, Nakajima M, Mohri T, Yokoi T (2008) Post-transcriptional regulation of human pregnane X receptor by micro-RNA affects the expression of cytochrome P450 3A4. J Biol Chem 283(15):9674–9680. https://doi.org/10.1074/jbc.M709382200 CrossRefPubMedGoogle Scholar
  26. 26.
    Court MH, Duan SX, Von Moltke LL, Greenblatt DJ, Patten CJ, Miners JO, Mackenzie PI (2001) Interindividual variability in acetaminophen glucuronidation by human liver microsomes: identification of relevant acetaminophen UDP-glucuronosyltransferase isoforms. J Pharmacol Exp Ther 299(3):998–1006PubMedGoogle Scholar
  27. 27.
    Dluzen DF, Sun DX, Salzberg AC, Jones N, Bushey RT, Robertson GP, Lazarus P (2014) Regulation of UDP-glucuronosyltransferase 1A1 expression and activity by microRNA 491-3p. J Pharmacol Exp Ther 348(3):465–477. https://doi.org/10.1124/jpet.113.210658 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Dluzen DF, Sutliff AK, Chen G, Watson CJW, Ishmael FT, Lazarus P (2016) Regulation of UGT2B expression and activity by miR-216b-5p in liver cancer cell lines. J Pharmacol Exp Ther 359(1):182–193. https://doi.org/10.1124/jpet.116.235044 CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Li X, Pan YZ, Seigel GM, Hu ZH, Huang M, Yu AM (2011) Breast cancer resistance protein BCRP/ABCG2 regulatory microRNAs (hsa-miR-328, -519c and -520h) and their differential expression in stem-like ABCG2+ cancer cells. Biochem Pharmacol 81(6):783–792. https://doi.org/10.1016/j.bcp.2010.12.018 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, Pogosova-Agadjanyan EL, Peterson A, Noteboom J, O'Briant KC, Allen A, Lin DW, Urban N, Drescher CW, Knudsen BS, Stirewalt DL, Gentleman R, Vessella RL, Nelson PS, Martin DB, Tewari M (2008) Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci U S A 105(30):10513–10518. https://doi.org/10.1073/pnas.0804549105 CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Chen X, Ba Y, Ma L, Cai X, Yin Y, Wang K, Guo J, Zhang Y, Chen J, Guo X, Li Q, Li X, Wang W, Zhang Y, Wang J, Jiang X, Xiang Y, Xu C, Zheng P, Zhang J, Li R, Zhang H, Shang X, Gong T, Ning G, Wang J, Zen K, Zhang J, Zhang CY (2008) Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res 18(10):997–1006. https://doi.org/10.1038/cr.2008.282 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Skog J, Wurdinger T, van Rijn S, Meijer DH, Gainche L, Sena-Esteves M, Curry WT Jr, 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):1470–1476. https://doi.org/10.1038/ncb1800 CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Zhang YJ, Liu DQ, Chen X, Li J, Li LM, Bian Z, Sun F, JW L, Yin YA, Cai X, Sun Q, Wang KH, Ba Y, Wang QA, Wang DJ, Yang JW, Liu PS, Xu T, Yan QA, Zhang JF, Zen K, Zhang CY (2010) Secreted monocytic miR-150 enhances targeted endothelial cell migration. Mol Cell 39(1):133–144. https://doi.org/10.1016/j.molcel.2010.06.010 CrossRefPubMedGoogle Scholar
  34. 34.
    Arroyo JD, Chevillet JR, Kroh EM, Ruf IK, Pritchard CC, Gibson DF, Mitchell PS, Bennett CF, Pogosova-Agadjanyan EL, Stirewalt DL, Tait JF, Tewari M (2011) Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma. Proc Natl Acad Sci U S A 108(12):5003–5008. https://doi.org/10.1073/pnas.1019055108 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Starkey-Lewis PJ, Dear J, Platt V, Simpson KJ, Craig DG, Antoine DJ, French NS, Dhaun N, Webb DJ, Costello EM, Neoptolemos JP, Moggs J, Goldring CE, Park BK (2011) Circulating microRNAs as potential markers of human drug-induced liver injury. Hepatology 54(5):1767–1776. https://doi.org/10.1002/hep.24538 CrossRefPubMedGoogle Scholar
  36. 36.
    Thulin P, Nordahl G, Gry M, Yimer G, Aklillu E, Makonnen E, Aderaye G, Lindquist L, Mattsson CM, Ekblom B, Antoine DJ, Park BK, Linder S, Harrill AH, Watkins PB, Glinghammar B, Schuppe-Koistinen I (2014) Keratin-18 and microRNA-122 complement alanine aminotransferase as novel safety biomarkers for drug-induced liver injury in two human cohorts. Liver Int 34(3):367–378. https://doi.org/10.1111/liv.12322 CrossRefPubMedGoogle Scholar
  37. 37.
    Cermelli S, Ruggieri A, Marrero JA, Ioannou GN, Beretta L (2011) Circulating microRNAs in patients with chronic hepatitis C and non-alcoholic fatty liver disease. PLoS One 6(8):e23937. https://doi.org/10.1371/journal.pone.0023937 CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Ji F, Yang B, Peng X, Ding H, You H, Tien P (2011) Circulating microRNAs in hepatitis B virus-infected patients. J Viral Hepat 18(7):e242–e251. https://doi.org/10.1111/j.1365-2893.2011.01443.x CrossRefPubMedGoogle Scholar
  39. 39.
    Qu KZ, Zhang K, Li H, Afdhal NH, Albitar M (2011) Circulating microRNAs as biomarkers for hepatocellular carcinoma. J Clin Gastroenterol 45(4):355–360. https://doi.org/10.1097/MCG.0b013e3181f18ac2 CrossRefPubMedGoogle Scholar
  40. 40.
    Bandiera S, Baumert TF, Zeisel MB (2016) Circulating microRNAs for early detection of hepatitis B-related hepatocellular carcinoma. Hepatobiliary Surg Nutr 5(3):198–200. 10.21037/hbsn.2016.03.08 CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Tryndyak VP, Latendresse JR, Montgomery B, Ross SA, Beland FA, Rusyn I, Pogribny IP (2012) Plasma microRNAs are sensitive indicators of inter-strain differences in the severity of liver injury induced in mice by a choline- and folate-deficient diet. Toxicol Appl Pharmacol 262(1):52–59. https://doi.org/10.1016/j.taap.2012.04.018 CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Pirola CJ, Fernandez Gianotti T, Castano GO, Mallardi P, San Martino J, Mora Gonzalez Lopez Ledesma M, Flichman D, Mirshahi F, Sanyal AJ, Sookoian S (2015) Circulating microRNA signature in non-alcoholic fatty liver disease: from serum non-coding RNAs to liver histology and disease pathogenesis. Gut 64(5):800–812. https://doi.org/10.1136/gutjnl-2014-306996 CrossRefGoogle Scholar
  43. 43.
    Ward J, Kanchagar C, Veksler-Lublinsky I, Lee RC, McGill MR, Jaeschke H, Curry SC, Ambros VR (2014) Circulating microRNA profiles in human patients with acetaminophen hepatotoxicity or ischemic hepatitis. Proc Natl Acad Sci U S A 111(33):12169–12174. https://doi.org/10.1073/pnas.1412608111 CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Vliegenthart AD, Shaffer JM, Clarke JI, Peeters LE, Caporali A, Bateman DN, Wood DM, Dargan PI, Craig DG, Moore JK, Thompson AI, Henderson NC, Webb DJ, Sharkey J, Antoine DJ, Park BK, Bailey MA, Lader E, Simpson KJ, Dear JW (2015) Comprehensive microRNA profiling in acetaminophen toxicity identifies novel circulating biomarkers for human liver and kidney injury. Sci Rep 5:15501. https://doi.org/10.1038/srep15501 CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Krauskopf J, Caiment F, De Kok TM, Johnson KJ, Warner RL, Schomaker SJ, Chandler P, Aubrecht J, Kleinjans JC (2016) High-throughput sequencing of circulating miRNAs in human reveals novel biomarkers for drug-induced liver injury, hepatitis B, liver cirrhosis and type 2 diabetes. Toxicol Lett 258(Supplement):S79. https://doi.org/10.1016/j.toxlet.2016.06.1364 CrossRefGoogle Scholar
  46. 46.
    Royo F, Falcon-Perez JM (2012) Liver extracellular vesicles in health and disease. J Extracell Vesicles 1. https://doi.org/10.3402/jev.v1i0.18825
  47. 47.
    Yang X, Weng Z, Mendrick DL, Shi Q (2014) Circulating extracellular vesicles as a potential source of new biomarkers of drug-induced liver injury. Toxicol Lett 225(3):401–406. https://doi.org/10.1016/j.toxlet.2014.01.013 CrossRefPubMedGoogle Scholar
  48. 48.
    Momen-Heravi F, Saha B, Kodys K, Catalano D, Satishchandran A, Szabo G (2015) Increased number of circulating exosomes and their microRNA cargos are potential novel biomarkers in alcoholic hepatitis. J Transl Med 13:261. https://doi.org/10.1186/s12967-015-0623-9 CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Bala S, Petrasek J, Mundkur S, Catalano D, Levin I, Ward J, Alao H, Kodys K, Szabo G (2012) Circulating microRNAs in exosomes indicate hepatocyte injury and inflammation in alcoholic, drug-induced, and inflammatory liver diseases. Hepatology 56(5):1946–1957. https://doi.org/10.1002/hep.25873 CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Wang K, Yuan Y, Li H, Cho JH, Huang D, Gray L, Qin S, Galas DJ (2013) The spectrum of circulating RNA: a window into systems toxicology. Toxicol Sci 132(2):478–492. https://doi.org/10.1093/toxsci/kft014 CrossRefPubMedGoogle Scholar
  51. 51.
    Weber JA, Baxter DH, Zhang S, Huang DY, Huang KH, Lee MJ, Galas DJ, Wang K (2010) The microRNA spectrum in 12 body fluids. Clin Chem 56(11):1733–1741. https://doi.org/10.1373/clinchem.2010.147405 CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Yang X, Salminen WF, Shi Q, Greenhaw J, Gill PS, Bhattacharyya S, Beger RD, Mendrick DL, Mattes WB, James LP (2015) Potential of extracellular microRNAs as biomarkers of acetaminophen toxicity in children. Toxicol Appl Pharmacol 284(2):180–187. https://doi.org/10.1016/j.taap.2015.02.013 CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Su YW, Chen X, Jiang ZZ, Wang T, Wang C, Zhang Y, Wen J, Xue M, Zhu D, Zhang Y, Su YJ, Xing TY, Zhang CY, Zhang LY (2012) A panel of serum MicroRNAs as specific biomarkers for diagnosis of compound- and herb-induced liver injury in rats. PLos One 7(5):e37395. https://doi.org/10.1371/journal.pone.0037395 CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Yan S, Wang J, Zhang W, Dai J (2014) Circulating microRNA profiles altered in mice after 28 d exposure to perfluorooctanoic acid. Toxicol Lett 224(1):24–31CrossRefGoogle Scholar
  55. 55.
    Yang X, Greenhaw J, Shi Q, ZQ S, Qian F, Davis K, Mendrick DL, Salminen WF (2012) Identification of urinary microRNA profiles in rats that may diagnose hepatotoxicity. Toxicol Sci 125(2):335–344. https://doi.org/10.1093/toxsci/kfr321 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Julian Krauskopf
    • 1
    • 2
    Email author
  • Jos C. Kleinjans
    • 1
  • Theo M. de Kok
    • 1
  1. 1.Department of ToxicogenomicsMaastricht UniversityMaastrichtThe Netherlands
  2. 2.Department of Toxicogenomics, GROW School for Oncology and Developmental BiologyMaastricht UniversityMaastrichtThe Netherlands

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