The DOI matches its Crossref record; 63 of the 64 references it cites were found in a registry or an index, and 1 are not checked yet; 15 of the 51 sources its claims cite were checked for support.
MicroRNA 21 Promotes Glioma Invasion by Targeting Matrix Metalloproteinase Regulators
Open accessAbstract
Substantial data indicate that microRNA 21 (miR-21) is significantly elevated in glioblastoma (GBM) and in many other tumors of various origins. This microRNA has been implicated in various aspects of carcinogenesis, including cellular proliferation, apoptosis, and migration. We demonstrate that miR-21 regulates multiple genes associated with glioma cell apoptosis, migration, and invasiveness, including the RECK and TIMP3 genes, which are suppressors of malignancy and inhibitors of matrix metalloproteinases (MMPs). Specific inhibition of miR-21 with antisense oligonucleotides leads to elevated levels of RECK and TIMP3 and therefore reduces MMP activities in vitro and in a human model of gliomas in nude mice. Moreover, downregulation of miR-21 in glioma cells leads to decreases of their migratory and invasion abilities. Our data suggest that miR-21 contributes to glioma malignancy by downregulation of MMP inhibitors, which leads to activation of MMPs, thus promoting invasiveness of cancer cells. Our results also indicate that inhibition of a single oncomir, like miR-21, with specific antisense molecules can provide a novel therapeutic approach for "physiological" modulation of multiple proteins whose expression is deregulated in cancer.
Verified 2026-10-19 · 1 reference not checked yet
Overview
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Written from the paper’s full text.
TL;DR
miR-21 is elevated in high-grade gliomas and promotes glioma invasion by directly targeting the MMP inhibitor RECK and indirectly regulating TIMP3, leading to increased MMP activity. Inhibiting miR-21 raises RECK/TIMP3, reduces MMP activity in vitro and in vivo, and decreases glioma cell motility and invasion, partly rescued by RECK knockdown.
Key findings
- miR-21 levels remain low in grade II gliomas and most grade III tumors but are significantly higher in GBMs; RECK mRNA is significantly lower in GBMs than normal brain and grade II/III gliomas, and TIMP3 mRNA tends to be lower in GBMs.
- Anti-miR-21 treatment changed expression of ∼570 genes (P < 0.05); upregulated transcripts were enriched for miR-21 seed hexamers (expectations 1.45e−09, 1.37e−14, and 1.82e−12), and at least 65 mRNAs were upregulated by anti-miR-21 and downregulated by miR-21 overexpression.
- miR-21 inhibition increased RECK mRNA ∼2-fold and TIMP3 mRNA about 1.6-fold; RECK was validated as a direct miR-21 target by luciferase reporter, whereas TIMP3 was not consistently directly responsive and is likely downstream.
- miR-21 inhibition reduced MMP-2 activity in A172 and U87 cells and lowered MMP activity in U87 subcutaneous tumors in nude mice; it also reduced scratch motility and Matrigel invasion, with reduced motility partly rescued by RECK siRNA and reduced invasion not observed when anti-miR-21 was cotransfected with RECK siRNA.
Methods
- Human glioma cell lines A172, U87, and LN229 (high miR-21), plus HeLa, MCF7, and U2OS cells, and human nonneoplastic brain and tumor samples; cells were transfected with 2′-O-MOE anti-miR-21, mismatch/control oligonucleotides, synthetic miR-21 duplex, or RECK siRNA.
- mRNA profiling used Agilent 44K arrays at 6 and 24 h posttreatment, with qRT-PCR, Western blot, luciferase 3′ UTR reporter assays with mutated miR-21 binding sites, gelatin zymography, scratch migration, and Matrigel invasion assays.
- In vivo, U87 cells transfected with anti-miR-21 or control were implanted subcutaneously in nude mice; MMP activity was imaged with MMPSense 680 at 3 days after implantation and 24 h later, with caliper tumor measurements.
Limitations
- Stated by the authors: the 2′-O-MOE anti-miR-21 did not significantly or consistently change glioma cell viability or reduce subcutaneous U87 tumor growth; subcutaneous U87 tumors are noninfiltrative, noninvasive, and poorly vascularized, so they are not an accurate model for studying invasiveness and tumor growth; nucleic acid chemistry can profoundly alter cellular responses to miRNA inhibition; therapeutic potential requires future research.
- Stated/evident from the text: the TIMP3 3′ UTR reporter did not consistently respond to miR-21 changes, so TIMP3 is likely a downstream effector rather than a direct target; RECK protein bands were not detectable by Western blot in U87 cells despite ∼2-fold RECK mRNA upregulation.
- Evident from the text: in vivo imaging was performed within the first week, when anti-miR-21 did not affect subcutaneous U87 tumor growth; comparison with a prior intracranial LNA-DNA anti-miR-21 study is limited because tumor locations differed.
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Claims the paper makes
35 Own result · 20 Own interpretation · 18 No full text of the sources · 6 Supported · 6 Own method · 4 Supported so far · 4 Partly supported · 2 No basis given · accuracy not yet measured
Every source the paper cites for this claim was checked and supports it.
In the paper
“Among the molecules tested, the 2′-O-MOE ASO was the most potent in repressing miR-21 activity (Fig. 2A), in agreement with previous data (10), whereas the uniform 2′-O-methyl ASO was the least potent, and mixed locked nucleic acid (LNA)-DNA oligonucleotides were variable (data not shown).”
What the sources say
- Supportedcites [10] source
The Discussion explicitly identifies the uniformly modified 2′-O-MOE-PO oligonucleotide as the best anti-miRNA ASO tested. This supports the attributed comparison for miR-21 activity, although the passage specifies the oligonucleotide’s backbone as PO. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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- 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
“Concurring with previously published reports (12, 46), our data indicate that these MMP inhibitors regulate MMP activity posttranslationally.”
What the sources say
- Supportedcites [12] source
The paper describes TIMPs as inhibitors of metalloproteinase activity and shows that TIMP-3 controls the cell-surface activation of pro-MMP-2 (Abstract and Discussion; page numbers unavailable). Its gene-expression analysis found comparable MMP-2 levels in wild-type and TIMP-3-deficient cells despite altered processing, supporting regulation after translation. (LLM, conf=0.91)
- Not checked — no full text of the sourcecites [46] source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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- Rests on an assumption: MMPs are a group of peptidases involved in degradation of the ECM.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“However, we have not detected any correlation between miR-21-modulated expression in several glioma cell lines and protein level of phosphatase and tensin homolog (data not shown), the reported miR-21 target in hepatocellular carcinomas (44).”
What the sources say
- Supportedcites [44] source
The citation supports the identification of PTEN as a reported miR-21 target in hepatocellular carcinoma: the Results state that PTEN was shown to be a direct target of miR-21 in HCC cells. The preceding statement about no correlation in glioma cell lines is the citing authors’ own unpublished observation, not a finding attributed to this source. (LLM, conf=0.94)
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Our data suggest that this can be at least partly due to miR-21 regulation, in addition to the reported chromosome 12q22-23 loss of heterozygosity and hypermethylation (56).”
What the sources say
- Partly supportedcites [56] Watanabe T., 2003, Brain Pathol. sourceExperimental — accuracy not yet measured
The Abstract (page unavailable) reports chromosome 12q22–23 loss of heterozygosity in glioblastomas and its association with low Apaf-1 expression. It mentions hypermethylation only as a possible mechanism in some malignancies; the reported study did not measure it in glioblastomas. The miR-21 proposal is presented as the citing authors’ own conclusion, not as a finding attributed to this source. (LLM, conf=0.83)
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In gliomas, APAF1 is often inactivated or downregulated (56).”
What the sources say
- Partly supportedcites [56] Watanabe T., 2003, Brain Pathol. sourceExperimental — accuracy not yet measured
The Abstract reports low APAF1 mRNA and protein expression in many glioblastomas with chromosome 12q22–23 loss of heterozygosity. The study examined glioblastoma, however, so it does not establish that APAF1 is often inactivated or downregulated across gliomas generally. (LLM, conf=0.85)
plain- Asserted: passes — The authors put it forward as true.
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- Partly supported
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
“The numbers of invasive A172 and U87 cells in cultures with inhibited miR-21 were significantly reduced relative to those in cultures transfected with the control oligonucleotide (Fig. 7A and B).”
plaindirect- Asserted: passes — The authors put it forward as true.
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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
“Specific inhibition of miR-21 with antisense oligonucleotides leads to elevated levels of RECK and TIMP3 and therefore reduces MMP activities in vitro and in a human model of gliomas in nude mice.”
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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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
“Moreover, downregulation of miR-21 in glioma cells leads to decreases of their migratory and invasion abilities.”
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“RECK mRNA expression was significantly lower in GBMs than in normal brain tissue and, especially, in grade II and III gliomas.”
plaincorrelational- Asserted: passes — The authors put it forward as true.
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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
“When miR-21 was suppressed, the amount of gelatin digested that reflects the levels of MMP-2 proteolytic activity was significantly reduced relative to the amount for the cells transfected with the control oligonucleotide (Fig. 5A).”
plaindirect- Asserted: passes — The authors put it forward as true.
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- It may state two separate claims as one. 28
- Probably not a substantial claim. 21
- The quote only partly states this claim. 2
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Accumulated data suggested that MMP levels and activities are significantly elevated in human gliomas, which contributes to glioma cell invasion of the surrounding normal tissues, metastasis, and angiogenesis through cell surface ECM degradation (21, 45).”
What the sources say
- Not checked — no full text of the sourcecites [21] Hu B., 2003, Proc. Natl. Acad. Sci. USA source
- Partly supportedcites [45] sourceExperimental — accuracy not yet measured
The Abstract and §4.1 link elevated MMP levels in human gliomas to invasiveness, and describe ECM degradation and cell-surface activation. But the Abstract discusses metastasis in cancer generally, not specifically gliomas; §4.2 links MMP-9 to angiogenesis only tentatively and says its activity in invasive glioma tissue is unproven. The copy therefore does not establish significantly elevated MMP activities across human gliomas or the claimed glioma metastasis and angiogenesis mechanism. Page numbers were not supplied. (LLM, conf=0.88)
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Rests on an assumption: MMPs are a group of peptidases involved in degradation of the ECM.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“TIMP3 is a tissue inhibitor of MMPs that inhibits angiogenesis and tumor cell infiltration and also induces apoptosis (2, 48).”
What the sources say
- Partly supportedcites [2] sourceExperimental — accuracy not yet measured
The paper’s Summary (p. 1347) identifies TIMP-3 as a tissue inhibitor of metalloproteinases, and its discussion reports inhibited invasion of HeLa and HT1080 cancer cells and apoptotic death in three cancer cell lines. The copy does not report that TIMP-3 inhibits angiogenesis; searches for angiogenesis and blood-vessel formation found no supporting passage. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [48] source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may state two separate claims as one.
- Partly 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
“This microRNA has been implicated in various aspects of carcinogenesis, including cellular proliferation, apoptosis, and migration.”
- Also stated in: § Abstract · plain
“miR-21 has been identified in controlling apoptosis, cell proliferation, and migration of cell lines in breast, colorectal, and other cancers (1, 44, 51, 59).”
What the sources say
- Not checked — no full text of the sourcecites [1] source
- Supportedcites [44] source
The Results report that changing miR-21 expression affects proliferation and migration in HCC cells. The Discussion also reports anti-apoptotic properties of miR-21 in glioblastoma and cholangiocarcinoma, supporting the broader statement that it has been implicated in all three processes. (LLM, conf=0.92)
- Not checked — no full text of the sourcecites [51] source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Also stated in: § Abstract · plain
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
“Our analysis also confirmed tropomyosin 1 (TPM1) regulation by miR-21, previously reported to occur in MCF7 cells (59, 60).”
What the sources say
- Supportedcites [59] source
The Abstract reports that experiments using tumors derived from MCF-7 cells identified TPM1 as a miR-21 target and confirmed that miR-21 down-regulates its expression. The Results section also reports increased endogenous TPM1 in anti-miR-21-treated, MCF-7-derived tumors. The paper therefore supports the cited prior report, although its tumor measurements were made in MCF-7-derived tumors rather than isolated cells. (LLM, conf=0.90)
- Not checked — no full text of the sourcecites [60] source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Another factor that can induce miR-21 expression is hypoxia, a general feature of all solid tumors (30).”
What the sources say
- Supportedcites [30] source
The Results report miR-21 among the hypoxia-regulated microRNAs and say its microarray result was checked by quantitative RT-PCR. The introductory passage describes hypoxia as an essential feature of the neoplastic microenvironment. (LLM, conf=0.90)
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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Every source the paper cites for this claim was checked and supports it.
In the paper
“The miR-21 gene contains two conserved STAT3 binding sites within its enhancer region and is induced by interleukin 6 (IL-6) in a STAT3-dependent way.”
What the sources say
- Supportedcites [39] source
The Results and discussion section identifies two conserved Stat3 binding sites in the miR-21 upstream regulatory region. It also reports that IL-6 increased miR-21 expression and that Stat3 knockdown inhibited this induction. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“MMPs can degrade ECM components and therefore play important roles in mediating GBM tumor cell motility and invasion (45).”
What the sources say
- Supportedcites [45] source
The Introduction says MMPs can degrade nearly all ECM macromolecules in the brain and are believed to play a major role in tumor invasion. The Abstract links MMP-mediated ECM degradation to glioblastoma invasion, while Section 4 describes how ECM degradation may permit glioma-cell migration. (LLM, conf=0.92)
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“APAF1 (apoptotic protease activating factor 1) is the molecular core of apoptosome. It is typically required for activation of the caspases that initiate apoptosis (3, 26).”
What the sources say
- Supportedcites [3] source
The Introduction describes Apaf-1 oligomerization as forming the apoptosome, while the Results and discussion state that Apaf-1 normally recruits and activates caspases-9 and -3. The Concluding remarks add that caspase-9 activity depends on interaction with oligomerized Apaf-1. Page numbers are not provided in our copy. (LLM, conf=0.90)
- Supportedcites [26] Johnson C. E., 2007, Proc. Natl. Acad. Sci. USA source
The paper’s introductory discussion (page not specified in our copy) says cytochrome c binds Apaf-1, leading to recruitment of procaspase-9 and formation of the apoptosome; the apoptosome then activates caspase-9. In the section on Apaf-1 expression levels (page not specified), adding Apaf-1 enabled cytochrome c to activate caspases in neural extracts, supporting its required role in the pathway described. (LLM, conf=0.91)
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- 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
“Elevated miR-21 expression has been causally linked to proliferation, apoptosis, and migration of several cancer cell lines (1, 5, 44, 60).”
What the sources say
- Not checked — no full text of the sourcecites [1] source
- Not checked — no full text of the sourcecites [5] source
- Supportedcites [44] source
The Results report that experimentally increasing or inhibiting miR-21 changed proliferation and migration in HCC cell lines. The Discussion reports anti-apoptotic properties of miR-21 in glioblastoma and cholangiocarcinoma, supporting the apoptosis part as a finding the paper reports from other studies. (LLM, conf=0.87)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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
“miR-21 levels remain low in grade II gliomas and in most grade III tumors and are significantly higher in GBMs (Fig. 1).”
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“This expression pattern is different from those of the other cancer-associated miRNAs, for example, miR-10b, which is often elevated in grade III and even grade II gliomas (Fig. 1) and dysregulated in some other cancers (41).”
What the sources say
- Not checked — no full text of the sourcecites [41] source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. 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
“RECK mRNA level increased consistently ∼2-fold and TIMP3 mRNA about 1.6-fold in the cells transfected with anti-miR-21.”
plaindirect- Asserted: passes — The authors put it forward as true.
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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 experiments demonstrated that inhibition of miR-21 reduced the motility of glioma cells (Fig. 6B and C).”
boosteddirect- Asserted: passes — The authors put it forward as true.
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The quote only partly states this claim.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“We note that, though 2′-O-MOE miR-21 ASO induced many proapoptotic and cell cycle arrest genes (Fig. 2C; also see Table S1 in the supplemental material), it did not significantly and consistently change the viability of glioma cell lines, which was reported for other, less potent miR-21 inhibitors (5, 8).”
What the sources say
plain- Asserted: passes — The authors put it forward as true.
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A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“STAT3, the other gene that may play a tumor suppressor function in GBM (11), is also negatively regulated by miR-21 according to the microarray data (see Table S1 in the supplemental material) and is a predicted miR-21 target (29, 34).”
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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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
“As identified in our study, TIMP3 or both TIMP3 and RECK are also induced by anti-miR-21 in MCF7 (breast carcinoma) and U2OS (osteosarcoma) cells (Fig. 4D).”
plaindirect- Asserted: passes — The authors put it forward as true.
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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
“In glioma progression from less invasive grade II gliomas to very invasive GBMs, RECK and TIMP3 levels drop (Fig. 4B), whereas miR-21 expression increases (Fig. 1).”
plaincorrelational- Asserted: passes — The authors put it forward as true.
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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
“Here, we show that a 2′-O-MOE ASO not only is potent but also upregulates miR-21 seed-containing mRNAs (Fig. 2 and 3).”
boosteddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Substantial data indicate that microRNA 21 (miR-21) is significantly elevated in glioblastoma (GBM) and in many other tumors of various origins.”
- Also stated in: § Abstract · boosted
“Using high-throughput profiling of miRNA expression, we have previously identified a specific miRNA, miRNA 21 (miR-21), as most strongly elevated in nearly all analyzed human GBM specimens (5).”
- Also stated in: § Abstract · boosted
“Other groups demonstrated overexpression of this miRNA in a wide range of other cancers, including breast, lung, colon, prostate, pancreas, ovarian, and stomach cancers, as well as in chronic lymphocytic leukemia (33, 54).”
What the sources say
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.
It may state two separate claims as one.
- Also stated in: § Abstract · boosted
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
“mRNAs carrying RECK and TIMP3 are predicted conserved miR-21 targets with one and two putative binding sites, respectively (Fig. 4A).”
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The sequences of the control and mismatch oligonucleotides have been analyzed using BLAST searches to exclude potential hits in the human transcriptome.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“RECK is a membrane-anchored MMP inhibitor whose reduced expression or inactivation seems to be critical for the invasiveness and metastasis of various cancers, including glioma cancer (7, 46).”
What the sources say
hedgedconditional- 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
“The high level of miR-21 expression in GBMs compared to that in anaplastic astrocytomas suggests the involvement of miR-21 in one of these key processes.”
hedgedconditional- 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 quote only partly states this claim.
In the paper
“Its expression level is also an important prognostic factor for multiple cancer types (6).”
What the sources say
- Not checked — no full text of the sourcecites [6] source
plaincorrelational- 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.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“It has been demonstrated to inhibit MMP activity and tumor growth in malignant gliomas in vivo (31, 32).”
What the sources say
boosteddirect- 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.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Since modified oligonucleotides can induce a wide range of nonspecific, off-target-mediated effects, several ASO molecules of different chemistries have been used for miR-21 inhibition.”
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.
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
“Our data suggest that miR-21 contributes to glioma malignancy by downregulation of MMP inhibitors, which leads to activation of MMPs, thus promoting invasiveness of cancer cells.”
hedgeddirect- 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.
- Rests on an assumption: MMPs are a group of peptidases involved in degradation of the ECM.
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
“Such overrepresentation of the hexamers suggests an abundance of direct miR-21 targets among the genes upregulated by 2′-O-MOE anti-miR-21 and indicates that the effects of this molecule on glioma cells are indeed mediated through the miR-21 pathway.”
hedgeddirect- 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.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“These experiments have been performed with the miR-21 inhibitor and with a mismatched control oligonucleotide to ensure that any observed effects are driven by miR-21.”
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.
Probably not a substantial claim.
In the paper
“Importantly, it inhibits tumor necrosis factor alpha-converting enzyme and induces apoptosis through the stabilization of tumor necrosis factor alpha receptors on the cell surface (42).”
What the sources say
- Not checked — no full text of the sourcecites [42] source
plaindirect- 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.
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
“Moreover, it leads to reduction of glioma cell motility and invasion, which is mediated by elevated RECK expression and was partly rescued by RECK siRNA (Fig. 6 and 7).”
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.
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 implies that miR-21 regulates RECK and TIMP3 expression and thus MMP activities and glioma tumor invasiveness.”
hedgeddirect- 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.
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
“In this study, we have demonstrated in vitro and in vivo, using U87 glioma xenografts in nude mice, that miR-21 regulates MMPs and glioma cell invasiveness by directly controlling the MMP inhibitor RECK.”
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.
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
“These combined results indicate that miR-21 regulates overlapping though not identical sets of genes in different cells and therefore shares common signaling pathways in different cancers.”
hedgeddirect- 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
“The APAF1 3′ UTR contains a strong miR-21 binding site (9-mer binding at miR-21 5′ end), and therefore, it is likely one of the direct miR-21 targets.”
hedgedconditional- 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.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Its expression is highly upregulated in a variety of solid tumors, including GBM, breast, lung, colon, prostate, pancreas, and stomach cancers (5, 54).”
What the sources say
plaincorrelational- 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.
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
“Our mRNA expression analysis suggests that miR-21 regulates the expression of multiple mRNA targets and thereby induces several cellular programs in glioma cells, including those associated with the tumor invasiveness and microvascular proliferation typical for the GBM as well as those involved in cell cycle regulation and apoptosis.”
hedgeddirect- 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.
In the paper
“Its ectopic expression in glioma cells induces upregulation of genes associated with angiogenesis, growth factors, cytokines, death receptors, and substrates of the various MMPs (31).”
What the sources say
- Not checked — no full text of the sourcecites [31] Lam P., 2005, Mol. Ther. source
plaindirect- 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.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“RECK, a membrane-anchored regulator, and TIMP3, the ECM-bound protease regulator, are key inhibitors of several MMPs, and their expression is prognostic in a number of common cancers (28, 53).”
What the sources say
plaincorrelational- 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.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“TIMP3 has been demonstrated to activate caspases and therefore induce apoptosis of human glioma cells in vitro and the growth inhibition of human glioma tumors in a mouse model (31, 32).”
What the sources say
boosteddirect- 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.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Though mRNA expression analysis does not allow identification of targets whose translation is regulated without modulation of mRNA levels”
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.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Such a bidirectional approach to manipulating miR-21 levels enabled narrowing of the lists of regulated genes and identification of those whose expression correlated negatively with miR-21 levels”
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.
It may state two separate claims as one.
In the paper
“In these experiments, we used tumorigenic U87 cells, a common model of human gliomas (23).”
What the sources say
- Not checked — no full text of the sourcecites [23] source
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: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
MMPs are a group of peptidases involved in degradation of the ECM.
“MMPs are a group of peptidases involved in degradation of the ECM.”
The paper relies on this without support.
Subcutaneous U87 tumors are noninfiltrative, noninvasive, and poorly vascularized.
“We should also note that subcutaneous U87 tumors are noninfiltrative, noninvasive, and poorly vascularized.”
The paper relies on this without support.
Knowledge of the molecular mechanisms mediating miR-21 function in cancer generally and in gliomas specifically is limited.
“However, our knowledge of the molecular mechanisms mediating miR-21 function in cancer generally and gliomas specifically is limited.”
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 source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“miR-21 is a well-known miRNA, found to be overexpressed in almost all cancer types, where its upregulation promotes cell proliferation, invasion, and metastatic behavior.”
From Potential Therapeutic Effects of Exosomes Packed With a miR-21-Sponge Construct in a Rat Model of Glioblastoma (2019) · cites this paper as [17]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Previous studies have proven that PDCD4, HNRNPK and RECK are TSGs among the direct targets of miR-21-5p (13,(27)(28)(29).”
From Functional interaction between miR-505-3p and miR-21 contributes to GBM suppression (2026) · cites this paper as [28]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“miR-21 targets several genes such as PDCD4, TIMP3, and RECK, which are key regulators of apoptotic and metastatic pathways (17–23).”
From Potential Therapeutic Effects of Exosomes Packed With a miR-21-Sponge Construct in a Rat Model of Glioblastoma (2019) · cites this paper as [17]
The cited source says what the claim attributes to it.
In the citing paper
“Our data on the effects of miR-21 enriched exosomes is in agreement with the previous reports demonstrating that overexpressed miR-21 in cell lines can increase the proliferation rate and malignant behavior of the cells (17–23).”
From Potential Therapeutic Effects of Exosomes Packed With a miR-21-Sponge Construct in a Rat Model of Glioblastoma (2019) · cites this paper as [17]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ DISCUSSION
“Its overexpression by viral transduction induces apoptosis in glioma cells and may be beneficial in glioma treatment (50).”
§ REFERENCES
“50.Shinoura, N., N. Yamamoto, Y. Yoshida, A. Asai, T. Kirino, and H. Hamada. 2000. Adenovirus-mediated transfer of caspase-8 in combination with superrepressor of NF-kappaB drastically induced apoptosis in gliomas.”
Citations
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BackgroundHuber, R. M., Rajski, M., Sivasankaran, B., Moncayo, G. E., Hemmings, B. A., & Merlo, A. (2013) · PLoS ONE · doi:10.1371/journal.pone.0057793 · Cited by 44
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“miR-21-5p, in addition to regulating metalloproteinases directly, targets TIMP3 and RECK, two negative metalloproteinase regulators [82].”
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Current Progress for the Use of miRNAs in Glioblastoma Treatment
Tivnan, A., & McDonald, K. L. (2013) · Molecular Neurobiology · doi:10.1007/s12035-013-8464-0 · Cited by 40
“Conversely, miR-21 has been extensively studied due to its significant upregulation in glioblastoma and the noted observation that miR-21 inhibition induced apoptosis in glioblastoma cells in vitro [32, 54–56] and in vivo [40, 57, 58].”
BackgroundIllustrating the interplay between the extracellular matrix and micro RNA s
Piccinini, A. M., & Midwood, K. S. (2014) · International Journal of Experimental Pathology · doi:10.1111/iep.12079 · Cited by 41
Zhu, W., Shao, Y., & Peng, Y. (2017) · Molecular Carcinogenesis · doi:10.1002/mc.22612 · Cited by 39
MicroRNAs as efficient biomarkers in high-grade gliomas
Barciszewska, A. (2016) · Folia Neuropathologica · doi:10.5114/fn.2016.64812 · Cited by 40
MicroRNA-21 is involved in ionizing radiation-promoted liver carcinogenesis.
Zhu, Y., Yu, X., Fu, H., Wang, H., Wang, P., Zheng, X., & Wang, Y. (2010) · PubMed · Cited by 39
MicroRNA-23a promotes neuroblastoma cell metastasis by targeting CDH1
Cheng, L., Yang, T., Kuang, Y.-Q., et al. (2014) · Oncology Letters · doi:10.3892/ol.2014.1794 · Cited by 39
“…consistent with the model in which tumor onco-miRs were found to promote tumor development by targeting and negatively regulating tumor suppressors (13). miRNA‑23a is upregulated in metastatic NB tissues and regulates NB cell migration and invasion. miR-23a has been previously reported to play a…”
Zhang, S., Han, L., WEI, J., et al. (2015) · International Journal of Oncology · doi:10.3892/ijo.2015.2841 · Cited by 39
“Through targeting of PTEN, PDCD4, RECK and other signal transduction pathways, miR-21 regulates the proliferation, apoptosis, and invasion of hepatocellular cancer, colorectal cancer, breast cancer (15-19).”
BackgroundMicroRNA and HER2-overexpressing Cancer
Wang, S., & Lin, R.-J. (2013) · MicroRNA · doi:10.2174/22115366113029990011 · Cited by 42
“We will discuss these regulations by focusing on a few better studied miRNAs, such as miR-205, miR-21, and miR-125 (Table 2, 3, & 4). miRNA Regulation by HER2 Validated Target Genes with a Potential Role In cancer miR-205 Downregulated ERBB3; VEGF-A; E2F1; LAMC1; ZEB1; SHIP2 miR-21 Upregulated PDCD4; PTEN; TPM1; SERPI…”
BackgroundMicroRNAs involved in the EGFR/PTEN/AKT pathway in gliomas
Wang, Y., Wang, X., Zhang, J., Sun, G., Luo, H., Kang, C., Pu, P., Jiang, T., Liu, N., & You, Y. (2011) · Journal of Neuro-Oncology · doi:10.1007/s11060-011-0679-1 · Cited by 39
“RECK and TIMP-3: miR-21 regulated MMP activities by targeting MMP inhibitors RECK and TIMP-3, thereby contributing to the glioma malignant phenotype [48].”
BackgroundAkula, S. M., Candido, S., Libra, M., Abrams, S. L., Steelman, L. S., Lertpiriyapong, K., Ramazzotti, G., Ratti, S., Follo, M. Y., Martelli, A. M., et al. (2019) · Advances in Biological Regulation · doi:10.1016/j.jbior.2019.04.003 · Cited by 39
Integrated microRNA/mRNA expression profiling of the skin of psoriasis patients
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“It is reported that RECK is a direct target of miR-21 (Gabriely et al., 2008).”
BackgroundInfluentialDetection of MicroRNAs in Microglia by Real-time PCR in Normal CNS and During Neuroinflammation
Veremeyko, T., Starossom, S. C., Weiner, H. L., & Ponomarev, E. D. (2012) · Journal of Visualized Experiments · doi:10.3791/4097 · Cited by 37
A hybrid model for cell proliferation and migration in glioblastoma
Kim, Y., & Roh, S. (2013) · Discrete and Continuous Dynamical Systems - B · doi:10.3934/dcdsb.2013.18.969 · Cited by 39
Demarchi, A. C. C. D. O., Zambuzzi, W. F., Paiva, K. B. S., da Silva‐Valenzuela, M. D. G., Nunes, F. D., Figueira, R. D. C. S., Sasahara, R. M., Demasi, M. A. A., Winnischofer, S. M. B., Sogayar, M. C., et al. (2010) · Cell and Tissue Research · doi:10.1007/s00441-010-0931-6 · Cited by 38
“Micro-RNA inhibition (miR-21) has been shown to upregulate RECK and to decrease MMPs (Gabriely et al. 2008).”
BackgroundUnraveling the impact of miR-21 on apoptosis regulation in glioblastoma
Shaikh, M. A. J., Altamimi, A. S. A., Afzal, M., Gupta, G., Singla, N., Gilhotra, R., almalki, W. H., Kazmi, I., Alzarea, S. I., Prasher, P., et al. (2024) · Pathology - Research and Practice · doi:10.1016/j.prp.2024.155121 · Cited by 37
Bullock, M. D., Pickard, K. M., Mitter, R., Sayan, E., Primrose, J. M., Ivan, C., Călin, G. A., Thomas, G. J., Packham, G., & Mirnezami, A. H. (2015) · Oncotarget · doi:10.18632/oncotarget.3225 · Cited by 38
“Amongst the miRNA candidates upregulated more than X2-fold were miR-19a and -19b and miR-21, which are recognized oncogenes [22–26].”
BackgroundZhang, G., Shi, H., Wang, L., Zhou, M., Wang, Z., Liu, X., Cheng, L., Li, W., & Li, X. (2015) · PLoS ONE · doi:10.1371/journal.pone.0135339 · Cited by 39
“In addition, according to this pathway module, the miR-29 family might participate in the process of apoptosis and angiogenesis through indirectly modulating the expression of FASLG and VEGFA.”
BackgroundInfluentialMasalha, M., Sidi, Y., & Avni, D. (2018) · Experimental Dermatology · doi:10.1111/exd.13520 · Cited by 36
Koenig, A. B., Barajas, J. M., Guerrero, M. J., & Ghoshal, K. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19030851 · Cited by 37
“miR-21, in turn, suppresses the expression of tumor suppressors such as phosphatase and tensin homolog (PTEN) [15], programmed cell death protein 4 (PDCD4) [16–18], reversion-inducing-cysteine-rich protein with kazal motifs (RECK), and metalloproteinase inhibitor 3 (TIMP3) by direct targeting [19].”
The role of microRNAs in the healing of diabetic ulcers
Goodarzi, G., Maniati, M., & Qujeq, D. (2019) · International Wound Journal · doi:10.1111/iwj.13070 · Cited by 36
MiRNAs in Lung Cancer: Diagnostic, Prognostic, and Therapeutic Potential
Wani, J. A., Majid, S., Imtiyaz, Z., Rehman, M. U., Alsaffar, R. M., Shah, N. N., Alshehri, S., Ghoneim, M. M., & Imam, S. S. (2022) · Diagnostics · doi:10.3390/diagnostics12071610 · Cited by 39
Chen, Y., Tsai, Y., & Tseng, S. (2012) · Journal of Neuro-Oncology · doi:10.1007/s11060-012-0871-y · Cited by 37
Hur, K. (2015) · BMB Reports · doi:10.5483/bmbrep.2015.48.4.007 · Cited by 36
“Mir-21 directly targets several tumor suppressor genes including programmed cell death 4 (PDCD4) (17, 18), sprouty homolog 2 (SPRY2) (19), tropomyosin 1 (TPM1) (20), chemokine (C-C motif) ligand 20 (CCL2) (21), cell division cycle 25A (CDC25A) (22), maspin, phosphatase, and tensin homolog (PTEN) (23), and metallopepti…”
BackgroundThe Role of miRNAs as Key Regulators in the Neoplastic Microenvironment
Wentz‐Hunter, K., & Potashkin, J. A. (2011) · Molecular Biology International · doi:10.4061/2011/839872 · Cited by 36
“In gliomas, miR-21 levels have been correlated with higher-grade tumors including glioblastomas [38].”
BackgroundEpigenetic inactivation of DNA repair in breast cancer
Nowsheen, S., Aziz, K., Tran, P. T., Gorgoulis, V. G., Yang, E. S.-H., & Georgakilas, A. G. (2012) · Cancer Letters · doi:10.1016/j.canlet.2012.05.015 · Cited by 36
“The anti-apoptotic miR-21 is upregulated in glioblastomas and breast cancers [65,66].”
BackgroundMicroRNA-200b inhibits the growth and metastasis of glioma cells via targeting ZEB2
Li, J., Yuan, J., Yuan, X., Zhao, J., Zhang, Z., Weng, L., & Liu, J. (2015) · International Journal of Oncology · doi:10.3892/ijo.2015.3267 · Cited by 36
“miR-21 promotes glioma invasion by targeting matrix metalloproteinase (MMP) inhibitors (22).”
RetractedNoncoding RNAs in Glioblastoma
Zhang, Y., Cruickshanks, N. A., Pahuski, M., Yuan, F., Dutta, A., Schiff, D., Purow, B. W., & Abounader, R. (2017) · Codon Publications eBooks · doi:10.15586/codon.glioblastoma.2017.ch6 · Cited by 38
“By targeting multiple molecules, such as RECK, TIMP3, ANP32A, and SPRY2, miR-21 can induce the expression and activity of various MMPs, increase Ras/Raf binding, and activate ERK phosphorylation, thereby enhancing the invasive potential of GBM cells (27, 68, 86).”
BackgroundMicroRNA and pediatric tumors: Future perspectives
Gulino, R., Forte, S., Parenti, R., Memeo, L., & Gulisano, M. (2015) · Acta Histochemica · doi:10.1016/j.acthis.2015.02.007 · Cited by 37
Downregulation of miR-21 as a promising strategy to overcome drug resistance in cancer
Akhtarkhavari, T., Bahrami, A. R., & Matin, M. M. (2022) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2022.175233 · Cited by 38
Li, J., Zhang, Y., Zhang, W., et al. (2013) · International Journal of Surgical Oncology · doi:10.1155/2013/875078 · Cited by 35
MicroRNAs in human lung cancer
Kang, S., & Lee, H. (2014) · Experimental Biology and Medicine · doi:10.1177/1535370214533887 · Cited by 35
Anti-cancer Therapies in High Grade Gliomas
Tănase, C., Enciu, A., Mihai, S., Neagu, A. I., Calenic, B., & Cruceru, M. L. (2013) · Current Proteomics · doi:10.2174/1570164611310030007 · Cited by 36
“Its overexpression is driven by the transcription factors STAT3 and AP-1 [91, 92], and its relevant targets appear to include tumorsuppressive genes such as PDCD4, PTEN, TPM1, RECK, and TIMP3 [93-96].”
BackgroundmiR-21 increases c-kit+ cardiac stem cell proliferation in vitro through PTEN/PI3K/Akt signaling
Shi, B., Deng, W., Long, X., Zhao, R., Wang, Y., Chen, W., Xu, G., Sheng, J., Wang, D., & Cao, S. (2017) · PeerJ · doi:10.7717/peerj.2859 · Cited by 35
Capri, M., Morsiani, C., Santoro, A., Moriggi, M., Conte, M., Martucci, M., Bellavista, E., Fabbri, C., Giampieri, E., Albracht, K., et al. (2019) · The FASEB Journal · doi:10.1096/fj.201801625r · Cited by 36
MiR-21 Regulates Keloid Formation by Downregulating Smad7 via the TGF-β/Smad Signaling Pathway
Wu, J., Lü, F., Cen, Y., Qing, Y., Chen, J., & Li, Z. (2019) · Journal of Burn Care & Research · doi:10.1093/jbcr/irz089 · Cited by 35
Guan, C.-Y., Shi, T., Cao, J., Wang, X., Ma, X., & Xia, H. (2020) · Diabetes Metabolic Syndrome and Obesity · doi:10.2147/dmso.s253920 · Cited by 38
Burgess, R. J., Jenkins, R. B., & Zhang, Z. (2008) · Cancer Biology & Therapy · doi:10.4161/cbt.7.9.6992 · Cited by 34
Engineered smart materials for RNA based molecular therapy to treat Glioblastoma
Singh, R. R., Mondal, I., Janjua, T. I., Popat, A., & Kulshreshtha, R. (2023) · Bioactive Materials · doi:10.1016/j.bioactmat.2023.11.007 · Cited by 36
“…targeting various genes associated with cancer initiation/progression and thus regulate different hallmarks of cancers, such as enhancing cell proliferation, resisting cell death, autophagy, enabling replicative immortality, activating invasion and metastasis, and inducing angiogenesis [99 – 107].”
BackgroundSong, H.-J., Oh, B., Choi, M., Oh, J., & Lee, M. (2015) · Journal of drug targeting · doi:10.3109/1061186x.2014.1000336 · Cited by 34
XIAO, B., Zhou, X., Ye, M., et al. (2015) · Molecular Medicine Reports · doi:10.3892/mmr.2015.4537 · Cited by 34
“Gabriely et al (27) specifically inhibited miR‑21 in glioma, which reduced the invasiveness and malignancy of the cancer cells.”
Deng, W., Wang, Y., Long, X., Zhao, R., Wang, Z., Liu, Z., Cao, S., & Shi, B. (2016) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2016/5389181 · Cited by 34
“In addition, miR-21 promotes glioma invasion by targeting RECK and TIMP3 genes, which are suppressors of malignancy and inhibitors of matrix metalloproteinases [73].”
BackgroundNunes, S., Bonyek-Silva, Í., Ampuero, M. R., de Noronha, A. L. L., de Souza, L. C. L., Correia, T. C., Khouri, R., Boaventura, V. S., Barral, A. M. P., Ramos, P. I. P., et al. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00640 · Cited by 36
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“…in BrdU incorporation assays, although which ER is involved will require further study. miR-21 is known to play a role in invasion based on its ability to downregulate PDCD4 (Asangani et al., 2008), RECK and TIMP3 (Gabriely et al., 2008) (Zhu et al., 2008), and SULF1 (Bao et al., 2013).”
BackgroundMicroRNA-21 is Overexpressed in Renal Cell Carcinoma
Lv, L., Huang, F., Mao, H., Li, M., Li, X., Yang, M. G., & Yu, X. (2013) · The International Journal of Biological Markers · doi:10.5301/jbm.2013.10831 · Cited by 33
“As a tumor suppressor gene, PDCD4 could upregulate apoptosis-related proteins (10) and it has been shown that PDCD4 is regulated by miR-21 in colorectal cancer (11), breast cancer (12, 13) and glioma (14) cells.”
BackgroundmiR-31: A Master Regulator of Metastasis?
Schmittgen, T. D. (2009) · Future Oncology · doi:10.2217/fon.09.150 · Cited by 34
MiRNAs as major players in brain health and disease: current knowledge and future perspectives
Kapplingattu, S. V., Bhattacharya, S., & Adlakha, Y. K. (2025) · Cell Death Discovery · doi:10.1038/s41420-024-02283-x · Cited by 44
MicroRNA Targeting as a Therapeutic Strategy Against Glioma
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Edeleva, E. V., & Shcherbata, H. R. (2013) · Frontiers in Genetics · doi:10.3389/fgene.2013.00305 · Cited by 34
Tumor-Suppressive miR148a Is Silenced by CpG Island Hypermethylation in IDH1 -Mutant Gliomas
Li, S., Chowdhury, R., Liu, F., Chou, A. P., Li, T., Mody, R. R., Lou, J. J., Chen, W., Reiss, J., Soto, H., et al. (2014) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-0234 · Cited by 34
“miRNA deregulation has been implicated in cancers (13-15) such as glioma (16-18); and similar to coding genes, CpG island methylation-associated silencing of miRNAs with tumor suppressor features have been discovered in human cancer (19-22).”
Polymorphisms and Plasma Levels of Tissue Inhibitor of Metalloproteinase-3
Su, C., Huang, Y.-W., Chen, M., Su, S., Yang, S., & Lin, C.-W. (2015) · Medicine · doi:10.1097/md.0000000000002092 · Cited by 33
MicroRNA Regulation of Glycolytic Metabolism in Glioblastoma
Alfardus, H., McIntyre, A., & Smith, S. J. (2017) · BioMed Research International · doi:10.1155/2017/9157370 · Cited by 33
Besheer, T. A., Elalfy, H., El-Maksoud, M. A., et al. (2019) · World Journal of Gastroenterology · doi:10.3748/wjg.v25.i11.1366 · Cited by 33
The Role of miRNAs in Extracellular Matrix Repair and Chronic Fibrotic Lung Diseases
Usman, K., Hsieh, A., & Hackett, T. (2021) · Cells · doi:10.3390/cells10071706 · Cited by 37
“ECM-Related Molecule miRNA Direction of miRNA Change Direction of ECM Molecule Change Mechanism Cell Type Disease/DevelopMental PROCESS Reference MMP-3 miR-155 ↑ ↓ targets LPS signalling, TNF-receptor superfamilyinteracting serine-threonine kinase 1 and IkB kinase activity synovial fibroblasts rheumatoid arthritis Sta…”
BackgroundYang, W., Qin, W., Hu, Z., Suo, Y., Zhao, R., Ma, X., Ma, W., Wang, T., Liang, J., Tian, J., et al. (2012) · Nuclear Medicine and Biology · doi:10.1016/j.nucmedbio.2012.05.004 · Cited by 33
Yeh, W., Lin, H., Huang, C.-Y., Huang, B., Lin, C., Lu, D., & Wei, K. (2015) · Oncotarget · doi:10.18632/oncotarget.6092 · Cited by 32
MicroRNAs in Cancer Translational Research
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Kitajima, S., Miki, T., Takegami, Y., Kido, Y., Noda, M., Hara, E., Shamma, A., & Takahashi, C. (2010) · Oncogene · doi:10.1038/onc.2010.448 · Cited by 33
“…oncogenes (Takahashi et al., 1998), oncogenic DNA virus products (Liu et al., 2003) and the so-called 'oncomir' (oncogenic microRNA) miR-21 (Gabriely et al., 2008; Hu et al., 2008; Zhang et al., 2008; reviewed in Nicoloso et al., 2009; Loayza-Puch et al., 2010) were demonstrated to…”
BackgroundInfluentialBuechner, J., Henriksen, J. R., Haug, B. H., Tømte, E., Flægstad, T., & Einvik, C. (2010) · Differentiation · doi:10.1016/j.diff.2010.09.184 · Cited by 33
Nedaeinia, R., Avan, A., Ahmadian, M., Nia, S. N., Ranjbar, M., Sharifi, M., Goli, M., Piroozmand, A., Nourmohammadi, E., Manian, M., et al. (2017) · Journal of Cellular Biochemistry · doi:10.1002/jcb.26047 · Cited by 32
“Other miR-21 targets are tumor suppressors, including PTEN [Meng et al., 2007], PDCD4 [Asangani et al., 2008], Tropomyosin (TPM1) [Papagiannakopoulos et al., 2008], Sprouty 1 [Thum et al., 2008], Sprouty 2 [Sayed et al., 2008], Bcl2 [Wickramasinghe et al., 2009], RECK [Gabriely et al., 2008], IL-12p35 [Lu et al., 2009…”
InfluentialComprehensive analysis of expression, prognosis and immune infiltration for TIMPs in glioblastoma
Han, J., Jing, Y., Han, F., & Sun, P. (2021) · BMC Neurology · doi:10.1186/s12883-021-02477-1 · Cited by 31
AND Logic-Gate-Based Dual-Locking Probe System for the Sensitive Detection of microRNA and APE1
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Metadata
- Authors
- Gabriely, G., Wurdinger, T., Kesari, S., Esau, C. C., Burchard, J., Linsley, P. S., & Krichevsky, A. M.
- Affiliations
- Brigham and Women's Hospital (US)
- Harvard University (US)
- Regulus Therapeutics (United States) (US)
- Corresponding author
- Krichevsky, Anna M.
- ORCID
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2008-09-01
- Volume
- 28
- Issue
- 17
- Pages
- 5369-5380
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC2519720
- OpenAlex
- W2163655902
- Cited by
- 888
- References
- 62
- Citations by year
- 2026: 13 · 2025: 19 · 2024: 21 · 2023: 29 · 2022: 20 · 2021: 21 · 2020: 43 · 2019: 41 · 2018: 33 · 2017: 56 · 2016: 56 · 2015: 75 · 2014: 76 · 2013: 86 · 2012: 91
- FWCI
- 21.02
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- PubMed Central (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- National Institutes of Health (CA86355)
- National Cancer Institute (R21 CA116141, P50 CA86355-04, P50CA086355)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
- Keywords
- miR-21, glioma invasion, glioblastoma, matrix metalloproteinases, RECK, TIMP-3, matrix metalloproteinase inhibitors, cell migration, apoptosis, antisense oligonucleotides, microRNA inhibition, tumor malignancy
- MeSH terms
- Animals, Base Sequence, Cell Movement, Enzyme Inhibitors, Extracellular Matrix, Glioma, Humans, Molecular Sequence Data, Neoplasm Invasiveness, Neoplasm Transplantation, RNA, Messenger, Down-Regulation, Gene Expression Regulation, Neoplastic, Apoptosis, Disease Progression, Oligonucleotide Array Sequence Analysis, Matrix Metalloproteinases, Gene Expression Profiling, MicroRNAs, Cell Line, Tumor, Mice, Genes, Neoplasm, Matrix Metalloproteinase Inhibitors
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