The DOI matches its Crossref record; 82 of the 83 references it cites were found in a registry or an index; 10 of the 13 sources its claims cite were checked for support.
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.
Overview
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
Figures
Verification
Claims the paper makes
9 Own interpretation · 4 Partly supported · 4 No basis given · 2 Not checked yet · 2 Own result · 1 Supported so far · 1 Couldn’t confirm · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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].”
§ miR-21: a non‐specific biomarker of all maladies > What do all of these biomarker studies tell us?
What the sources say
- Supportedcites [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
The Results report significantly increased miR-21 expression in 14 of 20 primary human HCC samples compared with matched nontumoral tissue. The Discussion also reports miR-21 overexpression in many other solid tumors, supporting the broad statement that its expression is altered in multiple disease states. (LLM, conf=0.87)
- Supportedcites [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
The Results and Discussion report increased miR-21 expression in patients with idiopathic pulmonary fibrosis and in mice with bleomycin-induced lung fibrosis. The paper also discusses miR-21 regulation in cancer cells and its role in myocardial infarction models. It therefore supports the broad, multiply cited statement that miR-21 expression is altered in disease states. (LLM, conf=0.88)
- Partly supportedcites [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. sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [78] Jazbutyte V, Thum T. MicroRNA-21: from cancer to cardiovascular disease. Curr Drug Targets. 2010;11(8):926–35. source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“miR-21 is clearly involved in key regulatory pathways.”
§ miR-21: a non‐specific biomarker of all maladies > Need to separate the functional importance of a miRNA from its value as a biomarker
What the sources say
- Supportedcites [25] Sheedy FJ. Turning 21: Induction of miR-21 as a Key Switch in the Inflammatory Response. Frontiers in immunology. 2015;6:19. source
The Conclusion describes miR-21 as linked to key processes in inflammation and as regulating the balance between pro-inflammatory and immunosuppressive states. It also explicitly refers to signaling pathways and cellular processes regulated by miR-21, supporting the broad claim. (LLM, conf=0.92)
- Not checked — no full text of the sourcecites [26] Pfeffer SR, Yang CH, Pfeffer LM. The Role of miR-21 in Cancer. Drug development research. 2015;76(6):270–7. source
- Supportedcites [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
Section 2 describes miR-21 as involved in many biological processes. Section 5.2 identifies specific regulatory pathways involving miR-21, including JNK/SAPK and p38 signaling in cardiac fibroblasts, supporting the broad claim. (LLM, conf=0.93)
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Modulating its expression in in vivo and in vitro studies show clear and important phenotype changes.”
§ miR-21: a non‐specific biomarker of all maladies > Need to separate the functional importance of a miRNA from its value as a biomarker
What the sources say
- Partly supportedcites [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. sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [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. sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [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
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“It would seem to suggest that miR-21 is commonly upregulated in a stress environment [1].”
§ miR-21: a non‐specific biomarker of all maladies > What do all of these biomarker studies tell us?
What the sources say
- Partly supportedcites [1] Mendell JT, Olson EN. MicroRNAs in stress signaling and human disease. Cell. 2012;148(6):1172–87. sourceExperimental — accuracy not yet measured
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)
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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].”
§ miR-21: a non‐specific biomarker of all maladies > What do all of these biomarker studies tell us?
What the sources say
- Partly supportedcites [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. sourceExperimental — accuracy not yet measured
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)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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).”
§ miR-21: a non‐specific biomarker of all maladies > What do all of these biomarker studies tell us?
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“As one can see from the data, miR-21 is implicated as a biomarker in no less than 29 diseases or processes.”
§ miR-21: a non‐specific biomarker of all maladies > miR-21: a biomarker across a spectrum of diseases
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Of note, miR-21 is elevated in each of these disease states ranging from cardiovascular disease to cancer.”
§ miR-21: a non‐specific biomarker of all maladies > miR-21: a biomarker across a spectrum of diseases
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Again, there are too many reasons why miR-21 levels may change to be comfortably assigned to the disease of interest.”
§ miR-21: a non‐specific biomarker of all maladies > What do all of these biomarker studies tell us?
plain- Asserted: passes — The authors put it forward as true.
- Checkable: unclear — It is unclear whether it could be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ miR-21: a non‐specific biomarker of all maladies > Abstract
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Conclusions · plain
- It may state two separate claims as one. 6
- Probably not a substantial claim. 4
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“Each of these three miRNAs are also implicated in a range of neoplastic and non-neoplastic disorders.”
§ miR-21: a non‐specific biomarker of all maladies > What do all of these biomarker studies tell us?
What the sources say
- Could not verifycites [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. sourceExperimental — accuracy not yet measured
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)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Could not verify
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Amongst miRNAs, miR-21-5p (miR-21) is one of the most highly-expressed and highly-studied.”
§ miR-21: a non‐specific biomarker of all maladies > Introduction
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ miR-21: a non‐specific biomarker of all maladies > miR-21: a biomarker across a spectrum of diseases
boosted- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“While miR-21 is robustly expressed in most cell types, its highest expression levels appear in macrophages, monocytes, and dendritic cells.”
§ miR-21: a non‐specific biomarker of all maladies > miR-21: a biomarker across a spectrum of diseases
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ miR-21: a non‐specific biomarker of all maladies > miR-21: a biomarker across a spectrum of diseases
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“It is also frequently claimed to be a biomarker of diseases such as cancer and heart disease in bodily-fluid based miRNA studies.”
§ miR-21: a non‐specific biomarker of all maladies > Abstract
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“If miR-21 is a marker of at least 29 diseases, then it cannot be a specific biomarker for any disease.”
§ miR-21: a non‐specific biomarker of all maladies > What do all of these biomarker studies tell us?
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ miR-21: a non‐specific biomarker of all maladies > Abstract
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
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?
The cited source says what the claim attributes to it.
In the citing paper
“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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Metadata
- 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
- 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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