Skip to content
naulon
Get started

No retraction, correction or concern found when last checked on Oct 20, 2026.

miR-21: a non‐specific biomarker of all maladies

Ana E. Jenike, Marc K. Halushka

Biomarker Research · 2021 · Review · CC BY

doi:10.1186/s40364-021-00272-1

Abstract

miRNA-21 is among the most abundant and highly conserved microRNAs (miRNAs) recognized. It is expressed in essentially all cells where it performs vital regulatory roles in health and disease. It is also frequently claimed to be a biomarker of diseases such as cancer and heart disease in bodily-fluid based miRNA studies. Here we dissociate its contributions to cellular physiology and pathology from its potential as a biomarker. We show how it has been claimed as a specific predictive or prognostic biomarker by at least 29 diseases. Thus, it has no specificity to any one disease. As a result, it should not be considered a viable candidate to be a biomarker, despite its continued evaluation as such. This theme of multiple assignments of a miRNA as a biomarker is shared with other common, ubiquitous miRNAs and should be concerning for them as well.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 20, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

MicroRNAs (miRNAs) are a class of small regulatory RNA. They have important functions in health, disease, and development. miRNAs have a fairly consistent numerical naming convention and hundreds to thousands of highly-conserved miRNAs are known across most species. Because miRNAs are stable in bodily fluids, they have been considered as potential biomarkers of disease. Scores of papers have assigned a litany of miRNA biomarkers to a plethora of different disease states. Amongst miRNAs, miR-21-5p (miR-21) is one of the most highly-expressed and highly-studied.

miR-21 was among the first identified microRNAs and is located within the Vacuole Membrane Protein 1 (VMP1) locus on chromosome 17. It has been implicated in both neoplastic and non-neoplastic pathologies through many of its gene targets. Three of the main targets of miR-21 are Phosphatase and Tensin Homolog (PTEN), Tropomyosin 1 (TPM1), and Programmed Cell Death 4 (PDCD4). The regulation of miR-21 is more complex than most miRNAs. It is transcribed from both a ~ 3.5 kb and a ~ 4.3 kb pri-miR-21, from within the VMP1 locus. The transcription of miR-21 is regulated by hypoxia and cytokines, such as interferon. Further post-translational regulation occurs through transforming growth factor beta (TGFβ) mediated events.

Functionally, miR-21 has been assigned a variety of activities. In both neoplastic and non-neoplastic disease, the down regulation of miR-21 increased the rate of cell death, the exact target of this is unknown, though possibilities are HIF-1α, PTEN, and PDCD4. miR-21 increases cell migration through TPM1 and PDCD4 in neoplastic disease. The upregulation by cytokines indicates a role in inflammation. In cardiovascular disease, miR-21 increases fibrosis and cardiac hypertrophy. Due to these important functional activities, miR-21 has been targeted for therapeutic intervention in neoplastic and other diseases. Outside of its role as a biomarker, we refer the reader to these excellent reviews of miR-21 function.

miR-21: a biomarker across a spectrum of diseases

Not only is miR-21 highly-expressed, it is also ubiquitous across most cell types. However, its common abundant expression is not consistent cell to cell. It has the highest reported levels of expression in macrophages, monocytes and dendritic cells based on cell-specific surveys. From the University of California, Santa Clara (UCSC) Genome Browser Human cellular microRNAome barCharts, the median reads per million (RPM) of miR-21 amongst 75 combined macrophage, monocyte and dendritic cells was 137,021 RPM whereas it was only 38,281 RPM amongst 470 other cells of a combined 75 cell types (Fig. 1). Because of the abundance of miR-21, it is easily measured from bodily fluids such as plasma, serum, urine, peripheral blood mononuclear cells (PBMCs), and other spaces. Across thousands of studies of miRNAs as biomarkers, it frequently appears as having altered expression.

Table 1 lists a subset of studies and diseases in which miR-21 has been implicated as a nonneoplastic biomarker and Table 2 lists cancer biomarker studies. As one can see from the data, miR-21 is implicated as a biomarker in no less than 29 diseases or processes. As far back as 2014, it had already been implicated in 10 non-neoplastic diseases and multiple cancers. Of note, miR-21 is elevated in each of these disease states ranging from cardiovascular disease to cancer. These 45 publications span from 2008 to 2020 and have over 5,000 collective citations (median 68) indicating they are well-known studies and that miR-21 is continued to be pursued as a biomarker.

What do all of these biomarker studies tell us?

If miR-21 is a marker of at least 29 diseases, then it cannot be a specific biomarker for any disease. Another way to think about this is as follows: If one did a study with 200 subjects and 100 of them had high miR-21 levels and 100 had low miR-21 levels, what disease does the group with the high miR-21 predict? Lung cancer? Myocardial infarction? Lupus? Because that can’t be known, how can one believe that miR-21 can be a predictive marker for any disease in a general population? The only way miR-21 can be associated with a disease is if the patient’s diagnoses are known a priori, as is the construct of biomarker studies. How about miR-21 serving as a biomarker for a prognostic change between low grade and advancing disease? Based on all of the potential reasons that a miR-21 level can be elevated, how much confidence can an elevated miR-21 level in a patient (and elevated relative to what?) be specific to the disease of inquiry versus any other potential health change? Again, there are too many reasons why miR-21 levels may change to be comfortably assigned to the disease of interest.

Another use of miR-21, as seen from the tables, is as one of multiple miRNAs that collectively serve as a biomarker of disease. These sorts of studies tend to find the optimal area under the curve (AUC) based on 2–6 miRNAs. While this approach likely brings more power to the study than a solitary miR-21 approach, it is still difficult to appreciate that miR-21 adds anything to that collection other than to indicate a cell stressor or perhaps a change in the inflammatory cell milieu. As well, miR-21 levels are frequently used in conjunction with other common miRNAs such as miR-155, miR-92a, and miR-122, which also decreases specificity towards a particular disease (Table 1).

One important point about all of these studies is that there is ample evidence that miR-21 expression really is altered in many disease states. That is likely telling us something very fundamental about the expression and function of this highly conserved miRNA. It would seem to suggest that miR-21 is commonly upregulated in a stress environment. Another possibility is macrophages/dendritic cells/circulating monocytes are increased in disease states as part of a global inflammatory response. As the percentage of these cells increase, the levels of miR-21 will increase in tandem in the same bodily fluids. If this is true, then miR-21 may have a very narrow value as a biomarker, where it can be used in conjunction with other cell-specific miRNAs to address the extent of inflammation, if that was a diagnostic factor for a particular disease.

Although we have focused the discussion on miR-21 as a biomarker, all ubiquitous miRNAs should be viewed with caution as potential prognostic biomarkers for any disease. Unfortunately, many miRNAs, such as the let-7 family, miR-10a, miR-22, and others are also both commonly identified as disease biomarkers and common to many different cell types. Each of these three miRNAs are also implicated in a range of neoplastic and non-neoplastic disorders.

Need to separate the functional importance of a miRNA from its value as a biomarker

miR-21 is clearly involved in key regulatory pathways. Modulating its expression in in vivo and in vitro studies show clear and important phenotype changes. We may ultimately find that a miR-21 pathway can be successfully targeted for therapeutic intervention. In fact, at least two clinical trials, one in Alport Syndrome (NCT03373786), and another in diabetic wound healing (NCT02581098) are attempting exactly that and may indicate the usefulness in modulating miR-21 levels for efficacy. However, this important role in disease does not make it a useful biomarker to predict these diseases.

Conclusions

Sadly, miR-21 cannot be considered a specific biomarker for any disease if it is a biomarker of many diseases. While its levels may genuinely vary across bodily fluids in disease states, these variations have no specificity. The miRNA community should stop trying to develop miRNA biomarker studies around miR-21 or other miRNAs with the same characteristics. Future miRNA biomarker researchers should be cognizant of other claims on their miRNA of interest and move toward miRNAs that are more unique.

The best miRNA biomarkers will be those that indicate injury or perturbation to a specific cell type. Already one such miRNA, miR-371a-3p has shown promise as a biomarker for testicular cancer. Whether it will make it into clinical practice is unknown. Other cell specific miRNAs, such as miR-122, a hepatocyte-specific miRNA, is useful in identifying liver injury, while the myomiRs, miR-133, miR-206, miR-208, miR-499 have shown some promise for their ability to identify cardiac injury.

In conclusion, miR-21 is a critically important miRNA in health, development, and disease, but based on a significant body of work, is not a useful fluid-based biomarker. Research into this role should not be pursued.

References 82

  1. 1.

    Mendell JT, Olson EN. MicroRNAs in stress signaling and human disease. Cell. 2012;148(6):1172-87.

    Not in our library10.1016/j.cell.2012.02.005

  2. 2.

    Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116(2):281-97.

    Not in our library10.1016/s0092-8674(04)00045-5

  3. 3.
    miRBase: annotating high confidence microRNAs using deep sequencing data · 2013
    No notice
  4. 4.

    Fromm B, Domanska D, Hoye E, Ovchinnikov V, Kang W, Aparicio-Puerta E, Johansen M, Flatmark K, Mathelier A, Hovig E, et al. MirGeneDB 2.0: the metazoan microRNA complement. Nucleic Acids Res. 2020;48(D1):D132-41.

    Not in our library10.1093/nar/gkz885

  5. 5.

    Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, Pogosova-Agadjanyan EL, Peterson A, Noteboom J, O’Briant KC, Allen A, et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci U S A. 2008;105(30):10513-8.

    Not in our library10.1073/pnas.0804549105

  6. 6.

    Chen X, Ba Y, Ma L, Cai X, Yin Y, Wang K, Guo J, Zhang Y, Chen J, Guo X, et al. Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res. 2008;18(10):997-1006.

    Not in our library10.1038/cr.2008.282

  7. 7.

    Xie QY, Almudevar A, Whitney-Miller CL, Barry CT, McCall MN. A microRNA biomarker of hepatocellular carcinoma recurrence following liver transplantation accounting for within-patient heterogeneity. BMC Med Genomics. 2016;9:18.

    Not in our library10.1186/s12920-016-0179-4

  8. 8.

    Allen-Rhoades W, Kurenbekova L, Satterfield L, Parikh N, Fuja D, Shuck RL, Rainusso N, Trucco M, Barkauskas DA, Jo E, et al. Cross-species identification of a plasma microRNA signature for detection, therapeutic monitoring, and prognosis in osteosarcoma. Cancer medicine. 2015;4(7):977-88.

    Not in our library10.1002/cam4.438

  9. 9.

    Zampetaki A, Kiechl S, Drozdov I, Willeit P, Mayr U, Prokopi M, Mayr A, Weger S, Oberhollenzer F, Bonora E, et al. Plasma microRNA profiling reveals loss of endothelial miR-126 and other microRNAs in type 2 diabetes. Circ Res. 2010;107(6):810-7.

    Not in our library10.1161/circresaha.110.226357

  10. 10.

    Lagos-Quintana M, Rauhut R, Lendeckel W, Tuschl T. Identification of novel genes coding for small expressed RNAs. Science. 2001;294(5543):853-8.

    Not in our library10.1126/science.1064921

  11. 11.

    Meng F, Henson R, Wehbe-Janek H, Ghoshal K, Jacob ST, Patel T. MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology. 2007;133(2):647-58.

    Not in our library10.1053/j.gastro.2007.05.022

  12. 12.

    Zhu Q, Wang Z, Hu Y, Li J, Li X, Zhou L, Huang Y. miR-21 promotes migration and invasion by the miR-21-PDCD4-AP-1 feedback loop in human hepatocellular carcinoma. Oncol Rep. 2012;27(5):1660-8.

    Not in our library10.3892/or.2012.1682

  13. 13.

    Zhang JG, Wang JJ, Zhao F, Liu Q, Jiang K, Yang GH. MicroRNA-21 (miR-21) represses tumor suppressor PTEN and promotes growth and invasion in non-small cell lung cancer (NSCLC). Clin Chim Acta. 2010;411(11–12):846-52.

    Not in our library10.1016/j.cca.2010.02.074

  14. 14.

    Zhu S, Si ML, Wu H, Mo YY. MicroRNA-21 targets the tumor suppressor gene tropomyosin 1 (TPM1). J Biol Chem. 2007;282(19):14328-36.

    Not in our library10.1074/jbc.m611393200

  15. 15.

    da Costa Martins PA, De Windt LJ. miR-21: a miRaculous Socratic paradox. Cardiovasc Res. 2010;87(3):397-400.

    Not in our library10.1093/cvr/cvq196

  16. 16.

    Yang CH, Yue J, Fan M, Pfeffer LM. IFN induces miR-21 through a signal transducer and activator of transcription 3-dependent pathway as a suppressive negative feedback on IFN-induced apoptosis. Cancer Res. 2010;70(20):8108-16.

    Not in our library10.1158/0008-5472.can-10-2579

  17. 17.

    Davis BN, Hilyard AC, Lagna G, Hata A. SMAD proteins control DROSHA-mediated microRNA maturation. Nature. 2008;454(7200):56-61.

    Not in our library10.1038/nature07086

  18. 18.

    Liu Y, Nie H, Zhang K, Ma D, Yang G, Zheng Z, Liu K, Yu B, Zhai C, Yang S. A feedback regulatory loop between HIF-1alpha and miR-21 in response to hypoxia in cardiomyocytes. FEBS Lett. 2014;588(17):3137-46.

    Not in our library10.1016/j.febslet.2014.05.067

  19. 19.

    Si ML, Zhu S, Wu H, Lu Z, Wu F, Mo YY. miR-21-mediated tumor growth. Oncogene. 2007;26(19):2799-803.

    Not in our library10.1038/sj.onc.1210083

  20. 20.

    Liu G, Friggeri A, Yang Y, Milosevic J, Ding Q, Thannickal VJ, Kaminski N, Abraham E. miR-21 mediates fibrogenic activation of pulmonary fibroblasts and lung fibrosis. The Journal of experimental medicine. 2010;207(8):1589-97.

    Not in our library10.1084/jem.20100035

  21. 21.

    Tatsuguchi M, Seok HY, Callis TE, Thomson JM, Chen JF, Newman M, Rojas M, Hammond SM, Wang DZ. Expression of microRNAs is dynamically regulated during cardiomyocyte hypertrophy. J Mol Cell Cardiol. 2007;42(6):1137-41.

    Not in our library10.1016/j.yjmcc.2007.04.004

  22. 22.
    Engineered exosomes for targeted co-delivery of miR-21 inhibitor and chemotherapeutics to reverse drug resistance in colon cancer · 2020
    No notice
  23. 23.

    Chan JK, Blansit K, Kiet T, Sherman A, Wong G, Earle C, Bourguignon LY. The inhibition of miR-21 promotes apoptosis and chemosensitivity in ovarian cancer. Gynecol Oncol. 2014;132(3):739-44.

    Not in our library10.1016/j.ygyno.2014.01.034

  24. 24.

    Li T, Li RS, Li YH, Zhong S, Chen YY, Zhang CM, Hu MM, Shen ZJ. miR-21 as an independent biochemical recurrence predictor and potential therapeutic target for prostate cancer. J Urol. 2012;187(4):1466-72.

    Not in our library10.1016/j.juro.2011.11.082

  25. 25.
    Turning 21: Induction of miR-21 as a Key Switch in the Inflammatory Response · 2015
    No notice
  26. 26.

    Pfeffer SR, Yang CH, Pfeffer LM. The Role of miR-21 in Cancer. Drug development research. 2015;76(6):270-7.

    Not in our library10.1002/ddr.21257

  27. 27.

    Kura B, Kalocayova B, Devaux Y, Bartekova M. Potential Clinical Implications of miR-1 and miR-21 in Heart Disease and Cardioprotection. International journal of molecular sciences 2020, 21(3).

    Not in our library10.3390/ijms21030700

  28. 28.

    McCall MN, Illei PB, Halushka MK. Complex Sources of Variation in Tissue Expression Data: Analysis of the GTEx Lung Transcriptome. Am J Hum Genet. 2016;99(3):624-35.

    Not in our library10.1016/j.ajhg.2016.07.007

  29. 29.

    de Rie D, Abugessaisa I, Alam T, Arner E, Arner P, Ashoor H, Astrom G, Babina M, Bertin N, Burroughs AM, et al. An integrated expression atlas of miRNAs and their promoters in human and mouse. Nature biotechnology. 2017;35(9):872-8.

    Not in our library10.1038/nbt.3947

  30. 30.
    A Critical Evaluation of microRNA Biomarkers in Non-Neoplastic Disease · 2014
    No notice
  31. 31.

    Pritchard CC, Kroh E, Wood B, Arroyo JD, Dougherty KJ, Miyaji MM, Tait JF, Tewari M. Blood cell origin of circulating microRNAs: a cautionary note for cancer biomarker studies. Cancer Prev Res (Phila). 2012;5(3):492-7.

    Not in our library10.1158/1940-6207.capr-11-0370

  32. 32.

    Olivieri F, Antonicelli R, Lorenzi M, D’Alessandra Y, Lazzarini R, Santini G, Spazzafumo L, Lisa R, La Sala L, Galeazzi R, et al. Diagnostic potential of circulating miR-499-5p in elderly patients with acute non ST-elevation myocardial infarction. Int J Cardiol. 2013;167(2):531-6.

    Not in our library10.1016/j.ijcard.2012.01.075

  33. 33.

    Zhang Y, Liu YJ, Liu T, Zhang H, Yang SJ. Plasma microRNA-21 is a potential diagnostic biomarker of acute myocardial infarction. Eur Rev Med Pharmacol Sci. 2016;20(2):323-9.

    Not in our library

  34. 34.

    Han H, Qu G, Han C, Wang Y, Sun T, Li F, Wang J, Luo S. MiR-34a, miR-21 and miR-23a as potential biomarkers for coronary artery disease: a pilot microarray study and confirmation in a 32 patient cohort. Exp Mol Med. 2015;47:e138.

    Not in our library10.1038/emm.2014.81

  35. 35.

    Kumar D, Narang R, Sreenivas V, Rastogi V, Bhatia J, Saluja D, Srivastava K. Circulatory miR-133b and miR-21 as Novel Biomarkers in Early Prediction and Diagnosis of Coronary Artery Disease. Genes (Basel) 2020, 11(2).

    Not in our library10.3390/genes11020164

  36. 36.

    Yao R, Ma Y, Du Y, Liao M, Li H, Liang W, Yuan J, Ma Z, Yu X, Xiao H, et al. The altered expression of inflammation-related microRNAs with microRNA-155 expression correlates with Th17 differentiation in patients with acute coronary syndrome. Cell Mol Immunol. 2011;8(6):486-95.

    Not in our library10.1038/cmi.2011.22

  37. 37.

    Jiang Y, Wang HY, Li Y, Guo SH, Zhang L, Cai JH. Peripheral blood miRNAs as a biomarker for chronic cardiovascular diseases. Scientific reports. 2014;4:5026.

    Not in our library10.1038/srep05026

  38. 38.

    Villar AV, Garcia R, Merino D, Llano M, Cobo M, Montalvo C, Martin-Duran R, Hurle MA, Nistal JF. Myocardial and circulating levels of microRNA-21 reflect left ventricular fibrosis in aortic stenosis patients. Int J Cardiol. 2013;167(6):2875-81.

    Not in our library10.1016/j.ijcard.2012.07.021

  39. 39.

    Stammet P, Goretti E, Vausort M, Zhang L, Wagner DR, Devaux Y. Circulating microRNAs after cardiac arrest. Critical care medicine. 2012;40(12):3209-14.

    Not in our library10.1097/ccm.0b013e31825fdd5e

  40. 40.

    Zahm AM, Thayu M, Hand NJ, Horner A, Leonard MB, Friedman JR. Circulating microRNA is a biomarker of pediatric Crohn disease. J Pediatr Gastroenterol Nutr. 2011;53(1):26-33.

    Not in our library10.1097/mpg.0b013e31822200cc

All 82 references

Reads

Read by people on this page

None yet.

Checked or read by AI through naulon

None yet.

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.

Are you an author?

Is this your paper?

Claim it to add your note and be paid when agents cite it. Free.