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
Cites
Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT Method
Livak, K. J., & Schmittgen, T. D. (2001) · Methods · doi:10.1006/meth.2001.1262 · Cited by 180,860
Lewis, B. P., Burge, C. B., & Bartel, D. P. (2005) · Cell · doi:10.1016/j.cell.2004.12.035 · Cited by 11,855
Oncomirs—MicroRNAs with a role in cancer
Esquela-Kerscher, A., & Slack, F. J. (2006) · Nature Reviews Cancer · doi:10.1038/nrc1840 · Cited by 5,884
A microRNA expression signature of human solid tumors defines cancer gene targets
Volinia, S., Calin, G. A., Liu, C.-G., Ambs, S., Cimmino, A., Petrocca, F., Visone, R., Iorio, M., Roldo, C., Ferracin, M., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0510565103 · Cited by 5,697
Summaries of Affymetrix GeneChip probe level data
Irizarry, R. A. (2003) · Nucleic Acids Research · doi:10.1093/nar/gng015 · Cited by 4,837
Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs
Lim, L. P., Lau, N. C., Garrett-Engele, P., Grimson, A., Schelter, J. M., Castle, J., Bartel, D. P., Linsley, P. S., & Johnson, J. M. (2005) · Nature · doi:10.1038/nature03315 · Cited by 4,755
Self-citationIn vitro scratch assay: a convenient and inexpensive method for analysis of cell migration in vitro
Liang, C.-C., Park, A. Y., & Guan, J.-L. (2007) · Nature Protocols · doi:10.1038/nprot.2007.30 · Cited by 4,696
Combinatorial microRNA target predictions
Krek, A., Grün, D., Poy, M. N., Wolf, R., Rosenberg, L., Epstein, E. J., MacMenamin, P., da Piedade, I., Gunsalus, K. C., Stoffel, M., et al. (2005) · Nature Genetics · doi:10.1038/ng1536 · Cited by 4,603
miRBase: microRNA sequences, targets and gene nomenclature
Griffiths-Jones, S. (2006) · Nucleic Acids Research · doi:10.1093/nar/gkj112 · Cited by 3,950
John, B., Enright, A. J., Aravin, A., Tuschl, T., Sander, C., & Marks, D. S. (2004) · PLoS Biology · doi:10.1371/journal.pbio.0020363 · Cited by 3,796
Research works printed but not linked: 1
- Gao F., 2007, Oncol. Rep., 17, 123
Cited by
Sorted by citations
Leva, G. D., Garofalo, M., & Croce, C. M. (2013) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathol-012513-104715 · Cited by 1,705
Comprehensive modeling of microRNA targets predicts functional non-conserved and non-canonical sites
Betel, D., Koppal, A., Agius, P., Sander, C., & Leslie, C. (2010) · Genome Biology · doi:10.1186/gb-2010-11-8-r90 · Cited by 1,592
“[17], and three microRNA inhibition experiments followed by mRNA expression profiling [21-23].”
BackgroundMethodMicroRNAs in Development and Disease
Sayed, D. H., & Abdellatif, M. (2011) · Physiological Reviews · doi:10.1152/physrev.00006.2010 · Cited by 1,101
“It targets the metalloproteinase (MMP) inhibitors, reversion-inducing-cysteine-rich protein with kazal motifs (RECK) and tissue inhibitor of metalloproteinase-3 (TIMP3) and, thus, activates MMPs and facilitates cell motility and metastasis both in vitro and in vivo (192).”
BackgroundmiR‐21: a small multi‐faceted RNA
Krichevsky, A. M., & Gabriely, G. (2009) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2008.00556.x · Cited by 987
“Several computational algorithms predict hundreds of mRNAs as possible targets for miR-21 [55–57 [49, 53] and proteomics [58], each with certain advantages and flaws, have been used after cell treatments with anti-miR-21.”
BackgroundMethodInfluentialSelf-citationMicroRNAs — the micro steering wheel of tumour metastases
Nicoloso, M. S., Spizzo, R., Shimizu, M., Rossi, S., & Calin, G. A. (2009) · Nature reviews. Cancer · doi:10.1038/nrc2619 · Cited by 753
“In fact, miR-21 was found to stimulate cell invasion and metastasis in different tumour models (breast cancer, colon cancer and gliomas) using similar in vitro and in vivo assay”
MethodmicroRNAs in cancer management
Kong, Y. W., Ferland-McCollough, D., Jackson, T. J., & Bushell, M. (2012) · The Lancet Oncology · doi:10.1016/s1470-2045(12)70073-6 · Cited by 742
Garofalo, M., Leva, G. D., Romano, G., Nuovo, G. J., Suh, S., Ngankeu, A., Taccioli, C., Pichiorri, F., Alder, H., Secchiero, P., et al. (2009) · Cancer Cell · doi:10.1016/j.ccr.2009.10.014 · Cited by 743
RetractedThe extracellular matrix in tumor progression and metastasis
Eble, J. A., & Niland, S. (2019) · Clinical & Experimental Metastasis · doi:10.1007/s10585-019-09966-1 · Cited by 613
MicroRNA-21 Promotes Fibrosis of the Kidney by Silencing Metabolic Pathways
Chau, B. N., Xin, C., Hartner, J. C., Ren, S., Castaño, A. P., Linn, G. R., Li, J., Tran, P. T., Kaimal, V., Huang, X., et al. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3003205 · Cited by 611
“Although it is structurally distinct from tissue inhibitors of metalloproteinases (Timp), it shares functions with Timp2 and Timp3 and may synergize with these inhibitors (33).”
BackgroundMatrix metalloproteinases: Evolution, gene regulation and functional analysis in mouse models
Fanjul‐Fernández, M., Folgueras, A. R., Cabrera, S., & López-Otı́n, C. (2009) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2009.07.004 · Cited by 601
“Similarly, mir-21 downregulates TIMP3 (tissue inhibitor of metalloproteinase3),which, in turn, leads to the activation ofMMPs and the subsequent promotion of cancer cell invasiveness [123].”
BackgroundMicroRNA-21 Is Up-Regulated in Allergic Airway Inflammation and Regulates IL-12p35 Expression
Lu, T. X., Munitz, A., & Rothenberg, M. E. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0803560 · Cited by 580
“Notably, MiR-21 has been shown to regulate the level of the matrix metalloprotease inhibitor RECK (42, 73, 74), and indeed we have identified this gene to be down-regulated by IL-13 in the lung (Table II); it is interesting to speculate that this could account for some of increased matrix metalloprotease activity seen…”
BackgroundZhang, J.-G., Wang, J., Zhao, F., Liu, Q., Jiang, K., & Yang, G. (2010) · Clinica Chimica Acta · doi:10.1016/j.cca.2010.02.074 · Cited by 574
Coding and noncoding landscape of extracellular RNA released by human glioma stem cells
Wei, Z., Batagov, A. O., Schinelli, S., Wang, J., Wang, Y., Fatimy, R. E., Rabinovsky, R., Balaj, L., Chen, C. C., Hochberg, F. H., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-01196-x · Cited by 546
Self-citationHuse, J. T., Brennan, C., Hambardzumyan, D., Wee, B., Pena, J., Rouhanifard, S. H., Sohn-Lee, C., le Sage, C., Agami, R., Tuschl, T., et al. (2009) · Genes & Development · doi:10.1101/gad.1777409 · Cited by 431
“This discrepancy also raises the possibility that the reported oncogenic effects of miR-21 in glioma cell lines may result from the targeting of other proteins (Chan et al. 2005; Corsten et al. 2007; Zhu et al. 2007, 2008; Gabriely et al. 2008; Papagiannakopoulos et al. 2008).”
BackgroundMiR-21 Induced Angiogenesis through AKT and ERK Activation and HIF-1α Expression
Liu, L.-Z., Li, C.-Y., Chen, Q., Yi, J., Carpenter, R. L., Jiang, Y., Kung, H., Lai, L., & Jiang, B. (2011) · PLoS ONE · doi:10.1371/journal.pone.0019139 · Cited by 509
“[6,7], maspin [8], and matrix metalloproteinases inhibitors RECK and TIMP3 [9] were targets of miR-21, suggesting that miR-21 is”
BackgroundModulating inflammatory monocytes with a unique microRNA gene signature ameliorates murine ALS
Butovsky, O., Siddiqui, S., Gabriely, G., Lanser, A. J., Dake, B., Murugaiyan, G., Doykan, C. E., Wu, P. M., Gali, R. R., Iyer, L. K., et al. (2012) · Journal of Clinical Investigation · doi:10.1172/jci62636 · Cited by 481
“ed using the ΔCt method as described elsewhere (81) and normalized to”
Self-citationGiovannetti, E., Funel, N., Peters, G. J., Chiaro, M. D., Erozenci, L. A., Vasile, E., León, L. G., Pollina, L. E., Groen, A., Falcone, A., et al. (2010) · Cancer Research · doi:10.1158/0008-5472.can-09-4467 · Cited by 460
Recent advances in the molecular understanding of glioblastoma
Bleeker, F. E., Molenaar, R. J., & Leenstra, S. (2012) · Journal of Neuro-Oncology · doi:10.1007/s11060-011-0793-0 · Cited by 468
Emerging role of microRNA-21 in cancer
Feng, Y., & Tsao, C. (2016) · Biomedical Reports · doi:10.3892/br.2016.747 · Cited by 464
“1) (28).”
Raitoharju, E., Lyytikäinen, L., Levula, M., Oksala, N., Mennander, A., Tarkka, M. R., Klopp, N., Illig, T., Kähönen, M. A. P., Karhunen, P. J., et al. (2011) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2011.07.020 · Cited by 456
Turning 21: Induction of miR-21 as a Key Switch in the Inflammatory Response
Sheedy, F. J. (2015) · Frontiers in Immunology · doi:10.3389/fimmu.2015.00019 · Cited by 496
MicroRNA-451 Regulates LKB1/AMPK Signaling and Allows Adaptation to Metabolic Stress in Glioma Cells
Godlewski, J. A., Nowicki, M. O., Bronisz, A., Nuovo, G. J., Palatini, J., Lay, M. D. D., Brocklyn, J. R. V., Ostrowski, M. C., Chiocca, E. A., & Lawler, S. E. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.02.018 · Cited by 426
“Alterations previously associated with cell migration were observed, including upregulation of miR-21 (Gabriely et al., 2008) and downregulation of miR-126 (Crawford et al.”
Broderick, J. A., & Zamore, P. D. (2011) · Gene Therapy · doi:10.1038/gt.2011.50 · Cited by 393
Apoptosis and the target genes of microRNA-21
Buscaglia, L. E. B., & Li, Y. (2011) · 癌症：英文版 · doi:10.5732/cjc.011.10132 · Cited by 383
Li, T., Li, D., Sha, J., Sun, P., & Huang, Y. (2009) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2009.03.077 · Cited by 377
Zhou, X., Ren, Y., Moore, L. M., Mei, M., You, Y., Xu, P., Wang, B., Wang, G., Jia, Z., Pu, P., et al. (2010) · Laboratory Investigation · doi:10.1038/labinvest.2009.126 · Cited by 363
“MiR-21 also regulated RECK and TIMP-3 gene to promote human cancer cell (A172, U87, LN229 GBM cells, Hela human cervix carcinoma cell, and MCF-7 breast cancer cell) anti-apoptosis, migration, and invasiveness effect by activating matrix metalloproteinases (MMPs).(37) Furthermore, miR-21 post-transcriptional inhibiting…”
BackgroundMicroRNAs in colorectal cancer: translation of molecular biology into clinical application
Slabý, O., Svoboda, M., Michálek, J., & Vyzula, R. (2009) · Molecular Cancer · doi:10.1186/1476-4598-8-102 · Cited by 361
“Particular signaling pathways affected by miRNAs are described in detail in the review (APC - adenomatous polyposis coli, CTGF - connective tissue growth factor, TSP1 -thrombospondin 1, EGFR - epidermal growth factor receptor, mTOR - mechanistic target of rapamycin, PTEN - phosphatase and tensin homolog, DCC - deleted…”
BackgroundInfluentialTGFβ-mediated upregulation of hepatic miR-181b promotes hepatocarcinogenesis by targeting TIMP3
Wang, B., Hsu, S., Majumder, S., Kutay, H., Huang, W., Jacob, S. T., & Ghoshal, K. (2009) · Oncogene · doi:10.1038/onc.2009.468 · Cited by 350
Shi, L., Chen, J., Yang, J., Pan, T., Zhang, S., & Wang, Z. (2010) · Brain Research · doi:10.1016/j.brainres.2010.07.009 · Cited by 353
“Inhibiting miR-21 expression leads to proliferation inhibition and apoptotic cell death in multiple glioblastoma cell lines (Silber et al., 2009; Conti et al., 2009; Corsten et al., 2007; Shi et al., 2008; Gabriely et al., 2008; Chan et al., 2005).”
BackgroundAkhtar, N., Rasheed, Z., Ramamurthy, S., Anbazhagan, A. N., Voss, F. R., & Haqqi, T. M. (2010) · Arthritis & Rheumatism · doi:10.1002/art.27329 · Cited by 327
“Studies have also shown that microRNA are involved in the regulation of MMP-2 expression in heart and the invasion in glioma by targeting MMP regulators (21,22).”
Physical exercise as an epigenetic modulator of brain plasticity and cognition
Fernandes, J., Arida, R. M., & Gómez‐Pinilla, F. (2017) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2017.06.012 · Cited by 365
“…apoptosis by targeting genes encoding the phosphatase and tensin homolog (PTEN), programmed cell death 4 (PDCD4), reversion-inducing-cysteine-rich protein with kazal motifs (RECK), and tissue inhibitor of metalloproteinases-3 (TIMP3) (Sayed et al., 2010, Chen et al., 2008, Gabriely et al., 2008).”
BackgroundmiRNA control of tumor cell invasion and metastasis
Baranwal, S., & Alahari, S. K. (2009) · International Journal of Cancer · doi:10.1002/ijc.25014 · Cited by 316
“Moreover, repression of miR-21 in glioma cells leads to a decrease in their migratory and invasion abilities, suggesting that miR-21 contributes to glioma malignancy by downregulation of MMP inhibitors such as RECK and TIMP3 (Figure 1).(17) Interestingly, miR-21 has multiple Figure 1.”
BackgroundMicroRNAs in idiopathic pulmonary fibrosis
Pandit, K. V., Milošević, J., & Kaminski, N. (2011) · Translational research · doi:10.1016/j.trsl.2011.01.012 · Cited by 318
“Reversion-inducing-cysteine-rich protein with kazal motifs (RECK), an inhibitor of metalloproteinases (MMPs) may be another fibrosis relevant target of mir-21.(51) In glioma, reduction of RECK by miR-21 results in invasiveness and possibly in angiogenesis by releasing the inhibition of MMP-2, MMP-9, and other MMPs.”
BackgroundUp-regulation of miR-21 Mediates Resistance to Trastuzumab Therapy for Breast Cancer
Gong, C., Yao, Y., Wang, Y., Liu, B., Wu, W. G., Chen, J., Su, F., Yao, H., & Song, E. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.216887 · Cited by 313
The role of microRNAs in endometriosis and associated reproductive conditions
Ohlsson Teague, E. M. C., Print, C. G., & Hull, M. L. (2010) · Human Reproduction Update · doi:10.1093/humupd/dmp034 · Cited by 309
The role of microRNAs in colorectal cancer
Schetter, A. J., Okayama, H., & Harris, C. C. (2012) · The Cancer Journal · doi:10.1097/ppo.0b013e318258b78f · Cited by 252
Teplyuk, N. M., Mollenhauer, B., Gabriely, G., Giese, A., Kim, E. L., Smolsky, M., Kim, R. Y., Saria, M. G., Pastorino, S., Kesari, S. P., et al. (2012) · Neuro-Oncology · doi:10.1093/neuonc/nos074 · Cited by 304
Self-citationMatrix metalloproteinases in tumorigenesis: an evolving paradigm
Hua, H., Li, M., Luo, T. L., Yin, Y., & Jiang, Y. (2011) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-011-0763-x · Cited by 304
“A recent study demonstrated that miR-21 could inhibit the expression of RECK and TIMP-3, two tumor suppressors and MMP inhibitors [ 164 ].”
BackgroundHuman Glioma Growth Is Controlled by MicroRNA-10b
Gabriely, G., Yi, M., Narayan, R. S., Niers, J. M., Wurdinger, T., Imitola, J., Ligon, K. L., Kesari, S., Esau, C., Stephens, R. M., et al. (2011) · Cancer Research · doi:10.1158/0008-5472.can-10-3568 · Cited by 266
Self-citationMetastamir: The Field of Metastasis-Regulatory microRNA Is Spreading
Hurst, D. R., Edmonds, M. D., & Welch, D. R. (2009) · Cancer Research · doi:10.1158/0008-5472.can-09-2111 · Cited by 305
TGF-β1/Smads and miR-21 in Renal Fibrosis and Inflammation
Łoboda, A., Sobczak, M., Józkowicz, A., & Dulak, J. (2016) · Mediators of Inflammation · doi:10.1155/2016/8319283 · Cited by 302
“In fact, this relationship has been alreadywell documented in cancers [73, 74].”
BackgroundWong, H.-K. A., Veremeyko, T., Patel, N., Lemere, C. A., Walsh, D. M., Esau, C., Vanderburg, C., & Krichevsky, A. M. (2013) · Human Molecular Genetics · doi:10.1093/hmg/ddt164 · Cited by 271
Self-citationKumarswamy, R., Volkmann, I. R., Jazbutyte, V., Dangwal, S., Park, D., & Thum, T. (2011) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.111.234286 · Cited by 301
Absalon, S., Kochanek, D. M., Raghavan, V., & Krichevsky, A. M. (2013) · The Journal of Neuroscience · doi:10.1523/jneurosci.1327-13.2013 · Cited by 302
“Western blot analysis was performed according to standard protocol as described previously (Gabriely et al., 2008).”
MethodSelf-citationmicroRNA-21 promotes tumor proliferation and invasion in gastric cancer by targeting PTEN
ZHANG, B. G., Li, J. F., YU, B. Q., Zhu, Z., Liu, B., & Yan, M. (2012) · Oncology Reports · doi:10.3892/or.2012.1645 · Cited by 291
Selaru, F. M., Olaru, A., Kan, T., David, S., Cheng, Y., Mori, Y., Yang, J. P., Paun, B. C., Jin, Z., Agarwal, R., et al. (2009) · Hepatology · doi:10.1002/hep.22838 · Cited by 288
Shi, R., Wang, P.-Y., Li, X., Chen, J.-X., Li, Y., Zhang, X., Zhang, C., Jiang, T., Li, W., Ding, W., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.4699 · Cited by 286
“The level of miR-21 was up-regulated in the tissue of higher grade gliomas (grade III and glioblastomas) compared with that of the non-neoplastic brain tissues and promote cell survival and invasion in glioblastoma cells [11, 12] A range of target genes have been identified for miR-21, among which, PTEN [13], RECK4 [1…”
BackgroundPathological and Molecular Features of Glioblastoma and Its Peritumoral Tissue
D’Alessio, A., Proietti, G., Sica, G., & Scicchitano, B. M. (2019) · Cancers · doi:10.3390/cancers11040469 · Cited by 289
“The contribution of miRNAs to the development and progression of gliomas refers to their regulation of crucial mechanisms, such as apoptosis [86], proliferation and the cell cycle [87,88], the remodeling of the extracellular matrix, tumor infiltration and angiogenesis [86,89], invasiveness [90], stem-cell renewal [91–…”
BackgroundEpigenetics of Colorectal Cancer
Goel, A., & Boland, C. R. (2012) · Gastroenterology · doi:10.1053/j.gastro.2012.09.032 · Cited by 280
Nielsen, B. S., Jørgensen, S., Fog, J. U., Søkilde, R., Christensen, I. J., Hansen, U., Brünner, N., Baker, A., Møller, S., & Nielsen, H. J. (2010) · Clinical & Experimental Metastasis · doi:10.1007/s10585-010-9355-7 · Cited by 279
“Several mRNAs have been identified as targets of miR-21 mediated regulation including PDCD4 [17, 18], SPRY1 and 2 [19, 20], NFI-B [16], RECK [21], and PTEN [22–24].”
BackgroundMøller, H. G., Rasmussen, A. P., Andersen, H. H., Johnsen, K. B., Henriksen, M., & Duroux, M. C. (2012) · Molecular Neurobiology · doi:10.1007/s12035-012-8349-7 · Cited by 273
“These results were further substantiated by decreased tumor growth in immunodeficient mice [35, 43, 51]. miR-21 inhibition does also result in significantly increased levels of caspases, leading to an increase in apoptosis, mediated by decreased targeting of HNRPK, TAp63, and PDCD4 [40, 42, 51]. miR-21 affects invasio…”
BackgroundThe LATS1 and LATS2 tumor suppressors: beyond the Hippo pathway
Furth, N., & Aylon, Y. (2017) · Cell Death and Differentiation · doi:10.1038/cdd.2017.99 · Cited by 262
Yu, Y., Kanwar, S. S., Patel, B. B., Oh, P., Nautiyal, J., Sarkar, F. H., & Majumdar, A. P. N. (2011) · Carcinogenesis · doi:10.1093/carcin/bgr246 · Cited by 259
miR-124 Inhibits STAT3 Signaling to Enhance T Cell–Mediated Immune Clearance of Glioma
Wei, J., Wang, F., Kong, L.-Y., Xu, S., Doucette, T. A., Ferguson, S. D., Yang, Y., McEnery, K., Jethwa, K. R., Gjyshi, O., et al. (2013) · Cancer Research · doi:10.1158/0008-5472.can-12-4318 · Cited by 253
“miR-21 has been shown to be significantly elevated in GBMs and can regulate multiple genes associated with preventing glioma cell apoptosis (44) and enhancingmigration and invasion (15).”
BackgroundGlioblastoma Therapy: Past, Present and Future
Obrador, E., Moreno-Murciano, P., Oriol-Caballo, M., López-Blanch, R., Pineda, B., Gutiérrez-Arroyo, J., Loras, A., Gonzalez-Bonet, L., Martinez-Cadenas, C., Estrela, J., et al. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25052529 · Cited by 271
Han, M., Liu, M., Wang, Y., Chen, X., Xu, J., Sun, Y., Zhao, L., Qu, H., Fan, Y., & Wu, C. (2012) · PLoS ONE · doi:10.1371/journal.pone.0039520 · Cited by 255
“Recent studies indicated that several tumor suppressors including phosphatase and tensin homolog deleted on chromosome ten (PTEN) [20], tumor suppressor gene tropomyosin 1 (TPM1) [21], programmed cell death 4 (PDCD4) [22], maspin [23], and matrix metalloproteinases inhibitors RECK and TIMP3 [24] were targets of miR-21…”
BackgroundSong, B., Wang, C., Liu, J., Wang, X., Lv, L., Wei, L., Xie, L., Zheng, Y., & Song, X. (2010) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/1756-9966-29-29 · Cited by 249
“Recent evidence suggests that miR-21 promotes glioma [15] and cholangiocarcinoma [16] invasion by targeting MMP regulators.”
BackgroundMicroRNAs as potential biomarkers in human solid tumors
Shen, J., Stass, S. A., & Jiang, F. (2012) · Cancer Letters · doi:10.1016/j.canlet.2012.11.001 · Cited by 243
“A high expression level of mir-2 and a lower level of mir-128 were found in surgical tissues of glioblastoma, as compared with normal tissues [137,138].”
Tardif, G., Hum, D., Pelletier, J., Duval, N., & Martel‐Pelletier, J. (2009) · BMC Musculoskeletal Disorders · doi:10.1186/1471-2474-10-148 · Cited by 241
“Indirect regulation of MMP activity by miRNAs has also been recently reported in cancer cells [43]; miR21 is over-expressed in glioblastomas and targets tissue inhibitor metalloprotease-3, a regulator of some MMPs.”
BackgroundNew Concepts in Cancer Biomarkers: Circulating miRNAs in Liquid Biopsies
Larrea, E., Solé, C., Manterola, L., Goicoechea, I., Armesto, M., Arestin, M., Caffarel, M. M., Araujo, A. M., Araiz, M., Fernández‐Mercado, M., et al. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms17050627 · Cited by 243
MicroRNA-193b Represses Cell Proliferation and Regulates Cyclin D1 in Melanoma
Chen, J., Feilotter, H. E., Paré, G. C., Zhang, X., Pemberton, J. G., Garady, C., Lai, D., Yang, X., & Tron, V. A. (2010) · American Journal Of Pathology · doi:10.2353/ajpath.2010.091061 · Cited by 242
“Since first reported as an antiapoptotic factor in human glioblastoma cells,(33) miR-21 has been shown to repress a number of tumor suppressors, including phosphatase and tensin homolog (PTEN) in human hepatocellular cancer cells,(34) tromopyosin 1 (TPM1) and programmed cell death 4(PDCD4) in breast cancer cells, as w…”
BackgroundMetzincin proteases and their inhibitors: foes or friends in nervous system physiology?
Rivera, S., Khrestchatisky, M., Kaczmarek, L., Rosenberg, G. A., & Jaworski, D. M. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.3467-10.2010 · Cited by 223
“, 2010a) or microRNA-21 (Gabriely et al., 2008).”
BackgroundGao, W., Shen, H., Liu, L., Xu, J., Xu, J., & Shu, Y. (2011) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-010-0918-4 · Cited by 237
“Regulation of PTEN expression by miR-21 was also identi-Wed in colon cancer (Asangani et al. 2008); however, researchers did not Wnd this regulatory role in breast cancer MCF-7 cells (Frankel et al. 2008), lung adenocarcinoma A549 cells (Blower et al., 2008), or glioma cells ( Gabriely et al. 2008 ).”
BackgroundSmits, M., Nilsson, J. A., Mir, S. E., van der Stoop, P. M., Hulleman, E., Niers, J. M., Hamer, P. C. D. W., Márquez, V. E., Cloos, J. J., Krichevsky, A. M., et al. (2010) · Oncotarget · doi:10.18632/oncotarget.205 · Cited by 242
“Recent studies have identified several miRNAs that are altered in GBM tumor cells themselves [6,7] as well as in GBM-associated endothelial cells [8].”
Self-citationMicroRNAs and cancer—new paradigms in molecular oncology
Negrini, M., Nicoloso, M. S., & Calin, G. A. (2009) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2009.03.002 · Cited by 240
“com directly modeling the cell cytoskeleton via TPM1 suppression [67,68], and by indirectly regulating the expression of the pro-metastatic UPAR (via maspin and PDCD4 direct suppression) [68] and of matrix metalloproteinases (via RECK,TIMP3 [69], and via PTEN [70] direct suppression).”
BackgroundCurrent State of Circulating MicroRNAs as Cancer Biomarkers
He, Y., Lin, J., Kong, D., Huang, M., Xu, C., Kim, T., Etheridge, A., Luo, Y., Ding, Y., & Wang, K. (2015) · Clinical Chemistry · doi:10.1373/clinchem.2015.241190 · Cited by 236
Asl, E. R., Amini, M. A., Najafi, S., Mansoori, B., Mokhtarzadeh, A., Mohammadi, A., Lotfinejad, P., Bagheri, M., Shirjang, S., Lotfi, Z., et al. (2021) · Life Sciences · doi:10.1016/j.lfs.2021.119499 · Cited by 236
Yang, M., Shen, H., Qiu, C., Yang, N., Wang, L., Dong, W., Liao, Y., & Du, J. (2012) · European Journal of Cancer · doi:10.1016/j.ejca.2012.09.031 · Cited by 226
Marquez, R. T., Bandyopadhyay, S., Wendlandt, E. B., Keck, K., Hoffer, B. A., Icardi, M. S., Christensen, R. N., Schmidt, W. N., & McCaffrey, A. P. (2010) · Laboratory Investigation · doi:10.1038/labinvest.2010.126 · Cited by 224
“A microarray study indicated that miR-21 may regulate, directly or indirectly, TGF-b2, bone morphogenetic protein 4 and epidermal growth factor.(47) These studies suggest that miR-21 forms negative feedback cycles regulating TGF-b signaling.”
BackgroundYao, J., Liang, L., Huang, S., Ding, J., Tan, N., Zhao, Y., Yan, M., Ge, C., Zhang, Z., Chen, T., et al. (2009) · Hepatology · doi:10.1002/hep.23443 · Cited by 224
MicroRNAs and potential target interactions in psoriasis
Zibert, J. R., Løvendorf, M. B., Litman, T., Olsen, J., Kaczkowski, B., & Skov, L. (2010) · Journal of Dermatological Science · doi:10.1016/j.jdermsci.2010.03.004 · Cited by 222
“MicroRNA-21 has previously been shown to target TIMP3 and was chosen as a positive control for the downregulation of TIMP3 [21].”
InfluentialEpithelial-to-mesenchymal(-like) transition as a relevant molecular event in malignant gliomas
Kahlert, U. D., Nikkhah, G., & Maciaczyk, J. (2012) · Cancer Letters · doi:10.1016/j.canlet.2012.12.010 · Cited by 228
Zhao, X., Dou, W., He, L., Liang, S., Tie, J., Liu, C., Li, T., Lu, Y., Mo, P., Shi, Y., et al. (2012) · Oncogene · doi:10.1038/onc.2012.156 · Cited by 220
Ren, Y., Zhou, X., Mei, M., Yuan, X.-B., Han, L., Wang, G., Jia, Z.-F., Xu, P., Pu, P., & Kang, C. (2010) · BMC Cancer · doi:10.1186/1471-2407-10-27 · Cited by 220
“Besides, multiple cancer cell apoptosis or metastasis related genes including PDCD4[10], P53 signaling network[11], RECK[20], S-TRAIL[27] etc were validated to be miR-21’s function targets in both brain tumors and other epithelium original human cancers.”
BackgroundJiang, L., Huang, Q. M., Zhang, S., Zhang, Q., Chang, J., Qiu, X., & Wang, E. (2010) · BMC Cancer · doi:10.1186/1471-2407-10-318 · Cited by 215
“MiRNAs are commonly thought to posttranscriptionally regulate mRNA degradation and inhibition of mRNA translation via interactions with the 3'-untranslated regions (UTRs) of target mRNAs in animals [16-18].”
BackgroundDong, L., Wang, X., Tan, J., Li, H., Qian, W., Chen, J., Chen, Q., Wang, J., Xu, W., Tao, C., et al. (2014) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.12353 · Cited by 217
“We speculate that miR-21 can inhibit inflammation by positively regulating Treg cell development [35, 56] or negatively regulating STAT3 [22, 23] under normal settings.”
BackgroundInfluentialA long non-coding RNA, GAS5, plays a critical role in the regulation of miR-21 during osteoarthritis
Song, J., Ahn, C., Chun, C. H., & Jin, E. (2014) · Journal of Orthopaedic Research® · doi:10.1002/jor.22718 · Cited by 214
“Two major inhibitors of MMPs, namely RECK and TIMP3, have been known as targets of miR-21 in glioma cells.(47) Consistent with this finding, MMP-13 was not found to be a direct target of miR-21 in OA chondrocytes, indicating the possibility that miR-21 may target an inhibitory regulator of MMP-13.”
BackgroundLong non-coding RNA CASC2 suppresses malignancy in human gliomas by miR-21
Wang, P., Liu, Y., Yao, Y., Li, Z., Li, Z., Ma, J., & Xue, Y. (2014) · Cellular Signalling · doi:10.1016/j.cellsig.2014.11.011 · Cited by 211
Yamanaka, Y., Tagawa, H., Takahashi, N., Watanabe, A., Guo, Y.-M., Iwamoto, K., Yamashita, J., Saitoh, H., Kameoka, Y., Shimizu, N., et al. (2009) · Blood · doi:10.1182/blood-2009-06-222794 · Cited by 212
Tu, Y., Gao, X., Li, G., Fu, H., Cui, D., Liu, H., Jin, W., & Zhang, Y. (2013) · Cancer Research · doi:10.1158/0008-5472.can-13-0358 · Cited by 209
“Many miRNAs have been reported to regulate glioma development, including miR-124, miR-137 (8), miR-128 (9), miR-10b (10), miR-21 (2, 11), and miR-218 (12–14).”
BackgroundMicroRNAs in glioblastoma multiforme pathogenesis and therapeutics
Shea, A. A., Harish, V., Afzal, Z., Chijioke, J., Kedir, H., Dusmatova, S., Roy, A., Ramalinga, M., Harris, B. T., Blancato, J. K., et al. (2016) · Cancer Medicine · doi:10.1002/cam4.775 · Cited by 211
“Through the targeting of matrix metalloproteinase (MMP) inhibitors, such as RECK and TIMP3, as well as tumor suppressors including ANP32A and SPRY2, miR21 can increase the expression and activity of various MMPs, facilitate Ras/Raf binding, and induce ERK phosphorylation, thereby enhancing the invasive potential of GB…”
BackgroundA Ten-microRNA Expression Signature Predicts Survival in Glioblastoma
Srinivasan, S., Patric, I. R. P., & Somasundaram, K. (2011) · PLoS ONE · doi:10.1371/journal.pone.0017438 · Cited by 208
Xia, X., Wang, Y., Huang, Y., Zhang, H., Lu, H., & Zheng, J. C. (2019) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2019.101694 · Cited by 202
“Recent findings revealed that exosomal miRNAs could be one key contributing factor in various CNS diseases (Gabriely et al., 2008; Kimura et al., 2018; Liu et al., 2014).”
Kinetic analysis reveals successive steps leading to miRNA‐mediated silencing in mammalian cells
Béthune, J., Artus-Revel, C. G., & Filipowicz, W. (2012) · EMBO Reports · doi:10.1038/embor.2012.82 · Cited by 212
“We used the 3 0 UTRs of hmga2, a target of let7 miRNA containing six let7 binding sites [18], and of reck, a target of miR21 containing a single miRNA-binding site [19].”
Xiong, B., Cheng, Y., Ma, L., & ZHANG, C. (2012) · International Journal of Oncology · doi:10.3892/ijo.2012.1707 · Cited by 207
Traumatic brain injury: classification, models, and markers
Najem, D., Rennie, K., Ribecco‐Lutkiewicz, M., Ly, D., Haukenfrers, J., Liu, Q., Nzau, M., Fraser, D. D., & Bani‐Yaghoub, M. (2018) · Biochemistry and Cell Biology · doi:10.1139/bcb-2016-0160 · Cited by 222
“MiR-21 targets B-cell lymphoma-2 (Bcl2), phosphatase and tensin homolog (PTEN) and cell death protein 4 (CDP4) (Gabriely et al. 2008; Ge et al. 2014; Hashimi et al. 2009; Kim et al. 2009; Lei et al. 2009; Liu et al. 2009a; Lu et al. 2009; Meissner et al. 2016; Papagiannakopoulos et al. 2008; Redell…”
BackgroundAbels, E. R., Maas, S. L. N., Nieland, L., Wei, Z., Cheah, P. S., Tai, E., Kolsteeg, C.-J., Dusoswa, S. A., Ting, D. T., Hickman, S., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.08.036 · Cited by 199
“Interference with miR-21 reduces the malignant potential, as downregulation of miR-21 has been shown to inhibit cell proliferation and invasion in vitro and tumor progression in vivo (Belter et al., 2016; Corsten et al., 2007; Gabriely et al., 2008; Põlajeva et al., 2012).”
BackgroundSelf-citationIdentification of microRNAs in the cerebrospinal fluid as biomarker for the diagnosis of glioma
Baraniskin, A., Kuhnhenn, J., Schlegel, U. S., Maghnouj, A., Zollner, H., Schmiegel, W., Hahn, S. A., & Schroers, R. (2011) · Neuro-Oncology · doi:10.1093/neuonc/nor169 · Cited by 197
Signature of Circulating MicroRNAs as Potential Biomarkers in Vulnerable Coronary Artery Disease
Ren, J., Zhang, J., Xu, N., Han, G.-P., Geng, Q., Song, J., Li, S., Zhao, J., & Chen, H. (2013) · PLoS ONE · doi:10.1371/journal.pone.0080738 · Cited by 200
“leading to matrix metalloproteinase activation and subsequent ECM degradation [27].”
BackgroundSaito, M., Schetter, A. J., Mollerup, S. K., Kohno, T., Skaug, V., Bowman, E. D., Mathé, E. A., Takenoshita, S., Yokota, J., Haugen, A., et al. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-10-2961 · Cited by 198
“43), TIMP3 (43), maspin (44), nuclear factor 1 B-type (NFIB; ref.”
Pericellular proteolysis in cancerPreprint
Sevenich, L., & Joyce, J. A. (2014) · Genes & Development · doi:10.1101/gad.250647.114 · Cited by 198
“It has also been reported that miRNAs contribute to the down-regulation of inhibitors and other protease regulators, which in turn leads to protease activation (Gabriely et al. 2008; Reis et al. 2012).”
BackgroundMicroRNA in Cancer: The Involvement of Aberrant MicroRNA Biogenesis Regulatory Pathways
Davis‐Dusenbery, B. N., & Hata, A. (2010) · Genes & Cancer · doi:10.1177/1947601910396213 · Cited by 199
MicroRNAs in the Pathogenesis of Cancer
Lovat, F., Valeri, N., & Croce, C. M. (2011) · Seminars in Oncology · doi:10.1053/j.seminoncol.2011.08.006 · Cited by 188
The microRNA network and tumor metastasis
Zhang, H., Li, Y., & Lai, M. (2009) · Oncogene · doi:10.1038/onc.2009.406 · Cited by 189
“, 2009a), RECK (Gabriely et al., 2008), TiMP3 (Selaru et al.”
BackgroundMetastamirs: a stepping stone towards improved cancer management
White, N. M. A., Fatoohi, E., Metias, M., Jung, K., Stephan, C., & Yousef, G. M. (2010) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2010.173 · Cited by 184
miR-21 Promotes Keratinocyte Migration and Re-epithelialization During Wound Healing
Yang, X., Wang, J., Guo, S.-L., Fan, K.-J., Li, J., Wang, Y.-L., Teng, Y., & Yang, X. (2011) · International Journal of Biological Sciences · doi:10.7150/ijbs.7.685 · Cited by 180
“Tissue inhibitor of metalloproteinase-3 (TIMP3) is capable of inhibiting migration in glioma cell and in breast cancer cell [11, 18], and is downregulated during wound healing [19] and in psoriatic epidermis [20].”
InfluentialBao, L., Yan, Y., Xu, C., Ji, W., Shen, S., Xu, G., Zeng, Y., Sun, B., Qian, H., Chen, L., et al. (2013) · Cancer Letters · doi:10.1016/j.canlet.2013.05.007 · Cited by 187
“Recent studies showed that several tumor suppressors including PTEN, TPM1, PDCD4, maspin, and TIMP3 were targets of miR-21 [14–18], suggesting that miR-21 is an important oncogenic miRNA which is closely related to tumor growth and metastasis [2].”
BackgroundMarquez, R. T., Wendlandt, E. B., Galle, C. S., Keck, K., & McCaffrey, A. P. (2010) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00338.2009 · Cited by 183
“Furthermore, miR-21 has been shown to target tumor suppressor genes, such as Pdcd4 (1, 16), Pten (38), Maspin (51), and Tpm1 (50) as well as matrix metalloproteinase inhibitors, such as Timp3 (43) and Reck (20).”
BackgroundDownregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo
Gaur, A. B., Holbeck, S. L., Colburn, N. H., & Israel, M. A. (2011) · Neuro-Oncology · doi:10.1093/neuonc/nor033 · Cited by 180
Liu, Y., Li, Y., Li, N., Teng, W., Wang, M., Zhang, Y., & Xiao, Z. (2016) · Scientific Reports · doi:10.1038/srep32231 · Cited by 179
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
About these checks
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.
A language model drew the claims from the paper on 2026-10-19, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-19 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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