miR-21: a non‐specific biomarker of all maladies
Open accessAbstract
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.
AI snapshot
Written from the paper’s full text.
TL;DR
miR-21 is a highly conserved, abundant miRNA with important regulatory roles, but it has been claimed as a predictive or prognostic biomarker for at least 29 diseases. Because it lacks specificity to any one disease, the authors argue it should not be pursued as a fluid-based biomarker.
Key findings
- miR-21 is implicated as a biomarker in no less than 29 diseases or processes, with 45 publications spanning 2008–2020 and over 5,000 collective citations (median 68).
- miR-21 expression is highest in macrophages, monocytes, and dendritic cells: median 137,021 RPM among 75 combined macrophage, monocyte, and dendritic cell samples versus 38,281 RPM among 470 other cells from a combined 75 cell types.
- The authors argue that if miR-21 is elevated across many diseases—ranging from cardiovascular disease to cancer—it cannot be a specific biomarker for any one disease, and its use alongside other common miRNAs such as miR-155, miR-92a, and miR-122 further decreases specificity.
- They conclude that miR-21 remains functionally important and may be therapeutically targetable, but it is not a useful fluid-based biomarker; future work should focus on more cell-type-specific miRNAs such as miR-371a-3p for testicular cancer or miR-122 for liver injury.
Methods
- Narrative review/commentary dissociating miR-21’s cellular physiology and pathology from its potential as a biomarker.
- Data include two tables of published biomarker studies: Table 1 lists a subset of 16 non-neoplastic diseases, and Table 2 lists 13 neoplasias, with sample sizes, fluid sources, additional miRNA biomarkers, and predictive/prognostic status.
- Expression analysis uses the University of California, Santa Clara (UCSC) Genome Browser Human cellular microRNAome barCharts to compare miR-21 levels across cell types; no primary experimental data are reported.
Limitations
- The paper does not state a formal limitations section.
- Evident from the text: the biomarker tables are described as a “subset” of studies rather than a systematic or exhaustive review, and no primary validation or meta-analysis is performed.
- The argument focuses on miR-21 but notes that other ubiquitous miRNAs, such as let-7 family, miR-10a, and miR-22, may share the same biomarker-specificity concern.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
10 of 13 cited sources checked · 4 supported · 0 flagged · accuracy not yet measured
- Premisecitation
There is ample evidence that miR-21 expression really is altered in many disease states.
“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 [11, 20, 77, 78].”
Quote in the paperSubstantial claim3 of 4 sources checked- cites [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. source
- cites [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. source
- cites [77] Ribas J, Ni X, Haffner M, Wentzel EA, Salmasi AH, Chowdhury WH, Kudrolli TA, Yegnasubramanian S, Luo J, Rodriguez R, et al. miR-21: an androgen receptor-regulated microRNA that promotes hormone-dependent and hormone-independent prostate cancer growth. Cancer Res. 2009;69(18):7165–9. source
The Results and Discussion section, “Androgen-induced miR-21 in Prostate Cancer” (page not provided), reports significantly increased miR-21 expression in 6 of 10 prostate tumors compared with matched normal tissue. That supports altered expression in prostate cancer, but this paper’s reported expression findings do not establish the claim across many disease states. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [78] Jazbutyte V, Thum T. MicroRNA-21: from cancer to cardiovascular disease. Curr Drug Targets. 2010;11(8):926–35. source
- Premisecitation
miR-21 is clearly involved in key regulatory pathways.
“miR-21 is clearly involved in key regulatory pathways.”
Quote in the paperNot a substantial claim2 of 3 sources checked- cites [25] Sheedy FJ. Turning 21: Induction of miR-21 as a Key Switch in the Inflammatory Response. Frontiers in immunology. 2015;6:19. source
- cites [26] Pfeffer SR, Yang CH, Pfeffer LM. The Role of miR-21 in Cancer. Drug development research. 2015;76(6):270–7. source
- cites [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). source
- Premisecitation
Modulating miR-21 expression in in vivo and in vitro studies shows clear and important phenotype changes.
“Modulating its expression in in vivo and in vitro studies show clear and important phenotype changes.”
Quote in the paperSubstantial claim2 of 3 sources checked- cites [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. source
The Results section, “miR-21 expression suppresses IFN-induced apoptosis” (page unavailable), reports clear changes in apoptosis after miR-21 overexpression or knockdown in cultured cancer cells. Our copy does not report an in vivo experiment showing a phenotype change, so it supports only the in vitro part of the claim. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [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. source
Section 3.6 reports that inhibiting miR-21 increased apoptosis in hypoxic cardiomyocyte cells, supporting an in vitro phenotype change. The experiments described use cultured cells; our copy does not support the claim that this study also demonstrated phenotype changes in vivo. No page number is available in the indexed passage. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [19] Si ML, Zhu S, Wu H, Lu Z, Wu F, Mo YY. miR-21-mediated tumor growth. Oncogene. 2007;26(19):2799–803. source
- Interpretationcitation
miR-21 is commonly upregulated in a stress environment.
“It would seem to suggest that miR-21 is commonly upregulated in a stress environment [1].”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [1] Mendell JT, Olson EN. MicroRNAs in stress signaling and human disease. Cell. 2012;148(6):1172–87. source
The ‘MicroRNAs in Cardiovascular Disease’ section states that miR-21 is upregulated in response to cardiac stress. It does not establish that miR-21 is commonly upregulated across stress environments generally; the cited evidence is specific to cardiac stress. (LLM, conf=0.84)
Experimental — accuracy not yet measured
- Premisecitation
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.
“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 [79].”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [79] McCall MN, Kim MS, Adil M, Patil AH, Lu Y, Mitchell CJ, Leal-Rojas P, Xu J, Kumar M, Dawson VL, et al. Toward the human cellular microRNAome. Genome Res. 2017;27(10):1769–81. source
The Results section (‘Diverse microRNAs expression patterns’; page unavailable) reports that several let-7 family members were found in all sampled tissues, and the Abstract discusses why cellular localization matters for candidate miRNA biomarkers. But the paper does not establish that let-7, miR-10a, and miR-22 are all commonly identified disease biomarkers and common to many cell types; it cautions that presence across tissues can reflect a cell-specific miRNA. (LLM, conf=0.85)
Experimental — accuracy not yet measured
- Findingreasoning
miR-21 levels are frequently used in conjunction with other common miRNAs such as miR-155, miR-92a, and miR-122, which decreases specificity towards a particular disease.
“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).”
Quote in the paperSubstantial claim - Findingown data
miR-21 is implicated as a biomarker in no less than 29 diseases or processes.
“As one can see from the data, miR-21 is implicated as a biomarker in no less than 29 diseases or processes.”
Quote in the paperSubstantial claim - Findingreasoning
miR-21 is elevated in each of the disease states listed, ranging from cardiovascular disease to cancer.
“Of note, miR-21 is elevated in each of these disease states ranging from cardiovascular disease to cancer.”
Quote in the paperSubstantial claim - Interpretationreasoning
There are too many reasons why miR-21 levels may change to be comfortably assigned to the disease of interest.
“Again, there are too many reasons why miR-21 levels may change to be comfortably assigned to the disease of interest.”
Quote in the paperNot a substantial claim - Interpretationreasoning
miR-21 has no specificity to any one disease.
“Thus, it has no specificity to any one disease.”
- Also stated in: § Conclusions · plain
“While its levels may genuinely vary across bodily fluids in disease states, these variations have no specificity.”
Quote in the paperSubstantial claim - Also stated in: § Conclusions · plain
- Interpretationreasoning
miR-21 is a critically important miRNA in health, development, and disease.
“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.”
Quote in the paperNot a substantial claim - Interpretationreasoning
miR-21 adds nothing to a multi-miRNA biomarker panel other than to indicate a cell stressor or a change in inflammatory cell milieu.
“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.”
Quote in the paperNot a substantial claim - Interpretationreasoning
miR-21 is not a useful fluid-based biomarker.
“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.”
Quote in the paperSubstantial claim- Rests on an assumption: A biomarker must be specific to a single disease to be a viable candidate.
- Interpretationreasoning
The only way miR-21 can be associated with a disease is if the patient's diagnoses are known a priori.
“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.”
Quote in the paperSubstantial claim - Interpretationreasoning
The important role of miR-21 in disease does not make it a useful biomarker to predict those diseases.
“However, this important role in disease does not make it a useful biomarker to predict these diseases.”
Quote in the paperSubstantial claim
- May combine two claims. 6
- Classified as probably not a substantial claim. 4
May combine two claims.
PremisecitationEach of these three miRNAs (let-7 family, miR-10a, miR-22) are also implicated in a range of neoplastic and non-neoplastic disorders.
“Each of these three miRNAs are also implicated in a range of neoplastic and non-neoplastic disorders.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [79] McCall MN, Kim MS, Adil M, Patil AH, Lu Y, Mitchell CJ, Leal-Rojas P, Xu J, Kumar M, Dawson VL, et al. Toward the human cellular microRNAome. Genome Res. 2017;27(10):1769–81. source
The Results section on diverse microRNA expression patterns reports that several let-7 family members occur across tissues, and the isomiR section discusses miR-10a-5p sequence variation. Neither passage links those miRNAs—or miR-22—to a range of neoplastic and non-neoplastic disorders. Searches for the three miRNAs and disease associations found no passage establishing the claimed links. (LLM, conf=0.74)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.
Findingnone givenmiR-21 is one of the most highly expressed and highly studied miRNAs.
“Amongst miRNAs, miR-21-5p (miR-21) is one of the most highly-expressed and highly-studied.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Findingown dataThe 45 publications in Tables 1 and 2 span 2008 to 2020 and have over 5,000 collective citations (median 68).
“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.”
Quote in the paperNot a substantial claimMay combine two claims.
FindingcitationmiR-21 is robustly expressed in most cell types, with highest expression in macrophages, monocytes, and dendritic cells.
“While miR-21 is robustly expressed in most cell types, its highest expression levels appear in macrophages, monocytes, and dendritic cells.”
Quote in the paperSubstantial claimMay combine two claims.
FindingcitationMedian miR-21 expression in combined macrophage, monocyte, and dendritic cells was 137,021 RPM, whereas in other cells it was 38,281 RPM.
“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).”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Findingnone givenmiR-21 is frequently claimed to be a biomarker of diseases such as cancer and heart disease in bodily-fluid based miRNA studies.
“It is also frequently claimed to be a biomarker of diseases such as cancer and heart disease in bodily-fluid based miRNA studies.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningIf miR-21 is a marker of at least 29 diseases, then it cannot be a specific biomarker for any disease.
“If miR-21 is a marker of at least 29 diseases, then it cannot be a specific biomarker for any disease.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S4 (based).
InterpretationreasoningThe theme of multiple assignments of a miRNA as a biomarker is shared with other common, ubiquitous miRNAs.
“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.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
A biomarker must be specific to a single disease to be a viable candidate.
“As a result, it should not be considered a viable candidate to be a biomarker, despite its continued evaluation as such.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
miR-21 is nonspecific.
“Despite its nonspecificity [33], miR-21 is considered a versatile regulator in the progression of CNS disorders [34] and was suggested to have both harmful and beneficial effects [35,36,37].”
From Emerging Role of miR-21-5p in Neuron–Glia Dysregulation and Exosome Transfer Using Multiple Models of Alzheimer’s Disease (2022) · cites this paper as [33]
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- Authors
- Jenike, A. E., & Halushka, M. K.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Halushka, Marc K.
- ORCID
- Halushka, Marc K.
- Venue
- Biomarker Research
- Published
- 2021-03-12
- Volume
- 9
- Issue
- 1
- Pages
- 18-18
- ISSN
- 2050-7771 (ISSN-L)
- PMC
- PMC7953557
- OpenAlex
- W3133811159
- Cited by
- 248
- References
- 83
- Citations by year
- 2026: 32 · 2025: 48 · 2024: 68 · 2023: 43 · 2022: 38 · 2021: 17 · 2020: 1
- FWCI
- 13.66
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Biomarker Research (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute of General Medical Sciences (R01GM130564)
- National Heart, Lung, and Blood Institute (1R01HL137811)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Keywords
- miR-21, microRNA, biomarkers, biomarker specificity, disease biomarkers, cancer, heart disease, biological fluids, miRNA expression regulation
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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