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
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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.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
15 of 51 cited sources checked · 11 supported · 0 flagged · accuracy not yet measured
- Findingown data§ RESULTS
The 2'-O-MOE ASO was the most potent in repressing miR-21 activity among molecules tested.
“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).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [10] source
- Interpretationcitation§ RESULTS
These MMP inhibitors regulate MMP activity posttranslationally.
“Concurring with previously published reports (12, 46), our data indicate that these MMP inhibitors regulate MMP activity posttranslationally.”
Quote in the paperSubstantial claim1 of 2 sources checked- Rests on an assumption: MMPs are a group of peptidases involved in degradation of the ECM.
- Findingown data§ DISCUSSION
No correlation was detected between miR-21-modulated expression in several glioma cell lines and the protein level of phosphatase and tensin homolog (PTEN).
“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).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [44] source
- Interpretationreasoning§ DISCUSSION
APAF1 inactivation or downregulation in gliomas can be at least partly due to miR-21 regulation, in addition to chromosome 12q22-23 loss of heterozygosity and hypermethylation.
“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).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [56] Watanabe T., 2003, Brain Pathol. source
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)
Experimental — accuracy not yet measured
- Premisecitation§ DISCUSSION
In gliomas, APAF1 is often inactivated or downregulated.
“In gliomas, APAF1 is often inactivated or downregulated (56).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [56] Watanabe T., 2003, Brain Pathol. source
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)
Experimental — accuracy not yet measured
- Findingown data§ RESULTS
The numbers of invasive A172 and U87 cells in cultures with inhibited miR-21 were significantly reduced relative to control-oligonucleotide cultures.
“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).”
Quote in the paperSubstantial claim - Findingreasoning§ Abstract
Specific inhibition of miR-21 reduces MMP activities in vitro and in a human model of gliomas in nude mice.
“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.”
Quote in the paperSubstantial claim - Findingown data§ Abstract
Downregulation of miR-21 in glioma cells leads to decreases of their migratory and invasion abilities.
“Moreover, downregulation of miR-21 in glioma cells leads to decreases of their migratory and invasion abilities.”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
RECK mRNA expression was significantly lower in GBMs than in normal brain tissue and in grade II and III gliomas.
“RECK mRNA expression was significantly lower in GBMs than in normal brain tissue and, especially, in grade II and III gliomas.”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
When miR-21 was suppressed, the amount of gelatin digested that reflects levels of MMP-2 proteolytic activity was significantly reduced relative to control.
“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).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
DNA damage response genes, regulators of cell cycle arrest, and positive regulators of apoptosis were enriched among genes upregulated at 24 h.
“DNA damage response genes, regulators of cell cycle arrest, and positive regulators of apoptosis have been enriched among genes upregulated at 24 h.”
Quote in the paperNot a substantial claim - Findingown data§ RESULTS
RECK and TIMP3 mRNA elevation was confirmed in miR-21 knocked-down A172 cells by qRT-PCR.
“To validate miR-21 regulation of RECK and TIMP3, we first confirmed RECK and TIMP3 mRNA elevation in miR-21 knocked-down A172 cells by qRT-PCR (Fig. 4C).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
In vivo, tumors produced from miR-21-inhibited U87 cells showed significantly lower MMP activity than control tumors.
“All tumors produced from miR-21-inhibited cells demonstrated significantly lower MMP activity than control tumors (Fig. 5B and C).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
The 2'-O-MOE ASO induced expression of an mRNA population significantly enriched in miR-21 seeds.
“In addition to being the most potent ASO, the 2′-O-MOE ASO also induced expression of an mRNA population significantly enriched in miR-21 seeds.”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
A large group of miR-21 octamer- and/or heptamer-containing mRNAs (at least 65) upregulated by anti-miR-21 were also downregulated by miR-21 overexpression.
“Notably, a large group of miR-21 octamer- and/or heptamer-containing mRNAs (at least 65) that were upregulated by anti-miR-21 (P < 0.05) has been also downregulated by miR-21 overexpression (P < 0.05) (Fig. 3).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
RECK is a direct miR-21 target.
“These results indicate that RECK is a direct miR-21 target (Fig. 4E).”
Quote in the paperSubstantial claim - Findingown data§ Abstract
Specific inhibition of miR-21 with antisense oligonucleotides leads to elevated levels of RECK and TIMP3.
“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.”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
TIMP3 is not likely to be a direct miR-21 target.
“The TIMP3 3′ UTR construct did not consistently respond to changes in miR-21 levels, indicating that TIMP3 is not likely to be a direct miR-21 target (Fig. 4E).”
Quote in the paperNot a substantial claim - Findingown data§ RESULTS
The anti-miR-21 oligonucleotide used did not affect subcutaneous U87 tumor growth within the first week after cell implantation, when the imaging was performed.
“The anti-miR-21 oligonucleotide used in this study did not affect subcutaneous U87 tumor growth within the first week after cell implantation, when the imaging was performed (data not shown).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
mRNA levels of two major inhibitors of MMPs, RECK and TIMP3, have been affected by both miR-21 knockdown and its overexpression.
“Remarkably, the mRNA levels of two major inhibitors of MMPs, RECK and TIMP3, have been affected by both miR-21 knockdown and its overexpression.”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
In glioma U87 cells, qRT-PCR showed a twofold upregulation of RECK mRNA expression by anti-miR-21.
“Nevertheless, using qRT-PCR, we observed a twofold upregulation of RECK mRNA expression by anti-miR-21 (data not shown), similar to the effect demonstrated for the A172 glioma cell line (Fig. 4C).”
Quote in the paperNot a substantial claim - Findingown data§ RESULTS
The reduced-motility phenotype of miR-21-inhibited glioma cells was partly rescued by cotransfection of anti-miR-21 with RECK siRNA.
“Notably, this reduced-motility phenotype was partly rescued by cotransfection of anti-miR-21 with small interfering RNA (siRNA) to RECK (Fig. 6B and D)”
Quote in the paperSubstantial claim - Findingown data§ Abstract
miR-21 regulates multiple genes associated with glioma cell apoptosis, migration, and invasiveness, including RECK and TIMP3.
“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).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
In glioma U87 cells, TIMP3 was upregulated by anti-miR-21.
“In glioma U87 cells, TIMP3 was also upregulated by anti-miR-21; however, we could not detect distinct RECK bands by Western blot analyses.”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
TIMP3 mRNA expression tended to be lower in GBM tumors than in grade II and III gliomas.
“TIMP3 mRNA expression also tended to be lower in GBM tumors than in grade II and III gliomas (Fig. 4B).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Analysis of miR-21 array data identified a number of important ECM remodeling factors that are computationally predicted miR-21 targets.
“In addition to apoptosis- and cell cycle-related genes, analysis of miR-21 array data identified a number of important ECM remodeling factors that are computationally predicted miR-21 targets (Fig. 3; also see Table S1 in the supplemental material).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Both RECK and TIMP3 proteins were upregulated by miR-21 inhibition in glioma A172 and LN229 cells.
“We then examined the protein levels of RECK and TIMP3 and found that both proteins were upregulated by miR-21 inhibition in glioma A172 and LN229 cells (Fig. 4D).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Total protein levels of secreted MMP-2 were not affected by miR-21 suppression.
“Notably, total protein levels of secreted MMP-2 were not affected by miR-21 suppression (data not shown).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Transcriptional profiling of knocked-down miR-21 cells revealed changes in expression levels of approximately 570 genes (P < 0.05) associated with various biological functions.
“Transcriptional profiling of knocked-down miR-21 cells revealed changes in the expression levels of ∼570 genes (P < 0.05) associated with various biological functions (Fig. 2C).”
Quote in the paperNot a substantial claim - Findingown data§ RESULTS
Three hexamers corresponding to nucleotides 1-6, 2-7, and 3-8 of miR-21 were strongly overrepresented in upregulated transcripts but not downregulated transcripts.
“In fact, three hexamers, corresponding to nucleotides 1 to 6, 2 to 7, and 3 to 8 of miR-21, were strongly overrepresented in the population of upregulated transcripts (with expectations of 1.45e−09, 1.37e−14, and 1.82e−12, respectively) but not in the population of downregulated transcripts (Fig. 2B).”
Quote in the paperSubstantial claim - Findingown data§ DISCUSSION
miR-21 negatively regulates the mRNA and protein levels of RECK and TIMP3 in cultured glioma cells.
“miR-21 negatively regulates the mRNA and protein levels of RECK and TIMP3 in cultured glioma cells (Fig. 4C and D).”
Quote in the paperSubstantial claim - Findingown data§ DISCUSSION
The 2'-O-MOE anti-miR-21 ASO did not cause a reduction of subcutaneous tumor growth in a U87 glioma model.
“This strong and specific 2′-O-MOE anti-miR-21 ASO also did not cause a reduction of subcutaneous tumor growth in a U87 glioma model (data not shown).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
The reduced invasiveness of miR-21-inhibited cells was not observed when anti-miR-21 was cotransfected with RECK siRNA.
“This reduced invasiveness was not observed, however, when anti-miR-21 was cotransfected with RECK siRNA (Fig. 7C)”
Quote in the paperSubstantial claim - Findingown data§ DISCUSSION
Inhibition of miR-21 decreases MMP activities both in vitro and in vivo.
“Inhibition of miR-21 decreases MMP activities both in vitro and in vivo (Fig. 5).”
Quote in the paperSubstantial claim - Interpretationown data§ RESULTS
TIMP3 is likely to be a downstream effector of miR-21 signaling.
“However, since TIMP3 mRNA and protein levels were modulated by miR-21 expression (Fig. 4C and D), TIMP3 is likely to be a downstream effector of miR-21 signaling.”
Quote in the paperSubstantial claim - Premisecitation§ RESULTS
miR-21 expression is upregulated in GBMs.
“We have previously demonstrated that miR-21 expression is upregulated in GBMs (5).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [5] source
- Interpretationown data§ Abstract
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.
“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.”
Quote in the paperSubstantial claim - Interpretationown data§ RESULTS
The reverse correlation between modulated miR-21 level and expression levels of this set of mRNAs suggests this mRNA population is enriched in direct miR-21 targets.
“Such reverse correlation between modulated miR-21 level and expression levels of this set of mRNAs suggests that this mRNA population is enriched in direct miR-21 targets.”
Quote in the paperSubstantial claim - Interpretationown data§ RESULTS
Our mRNA array analysis suggested that RECK and TIMP3 mRNAs may be regulated by miR-21.
“Our mRNA array analysis suggested that RECK and TIMP3 mRNAs may be regulated by miR-21.”
Quote in the paperSubstantial claim - Interpretationown data§ RESULTS
miR-21 regulates multiple genes involved in several cellular programs in glioma cells.
“This molecular profiling suggested that miR-21 regulates multiple genes involved in several cellular programs in glioma cells.”
Quote in the paperSubstantial claim - Interpretationown data§ RESULTS
These data suggest that RECK and TIMP3 may represent natural miR-21 targets in vivo.
“These data suggest that RECK and TIMP3 may represent natural miR-21 targets in vivo.”
Quote in the paperSubstantial claim - Interpretationown data§ RESULTS
miR-21 regulation of glioma cell motility is mediated, at least partly, by RECK.
“indicating that miR-21 regulation of glioma cell motility is mediated, at least partly, by RECK.”
Quote in the paperSubstantial claim - Interpretationreasoning§ DISCUSSION
By modulating the expression and/or activity of one miRNA with specific tools such as inhibitors or mimics, it is possible to control the expression of multiple oncogenic or tumor-suppressing genes and simultaneously trigger several cellular programs that these genes mediate.
“Our data suggest that by modulating expression and/or activity of one miRNA with specific tools, e.g., inhibitors or mimics, it is possible to control the expression of multiple oncogenic or tumor-suppressing genes and simultaneously trigger several cellular programs that these genes mediate.”
Quote in the paperSubstantial claim - Premisecitation§ DISCUSSION
An LNA-DNA anti-miR-21 oligonucleotide was previously shown to reduce tumors in an intracranial U87 glioma model.
“In contrast, an LNA-DNA anti-miR-21 oligonucleotide was previously shown to reduce tumors in an intracranial U87 glioma model (8).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [8] source
- Interpretationreasoning§ DISCUSSION
The likely explanation for the conflicting results between the 2'-O-MOE and LNA-DNA anti-miR-21 oligonucleotides is that the suboptimally designed LNA-DNA oligonucleotide killed glioma cells by an off-target mechanism.
“the likely explanation for these conflicting results might be that the suboptimally designed LNA-DNA oligonucleotide used in the earlier study killed glioma cells by an off-target mechanism.”
Quote in the paperNot a substantial claim - Premisecitation§ DISCUSSION
Several mRNAs regulated by miR-21 and anti-miR-21 in glioma cells, including PDCD4, APAF1, FAM3C, SESN1, and GLCCI1, were also identified in an mRNA expression analysis of miR-21 knocked-down MCF7 breast carcinoma cells.
“Several mRNAs regulated by miR-21 and anti-miR-21 in glioma cells (Fig. 3; also see Table S1 in the supplemental material) have recently been identified in an mRNA expression analysis of miR-21 knocked-down MCF7 breast carcinoma cells (14).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [14] source
- Interpretationown data§ DISCUSSION
Differences in nucleic acid chemistry can, in some cases, profoundly alter cellular responses to miRNA inhibition.
“Considered together, this study and previous reports show that differences in nucleic acid chemistry can, in some cases, profoundly alter cellular responses to miRNA inhibition.”
Quote in the paperSubstantial claim - Interpretationreasoning§ DISCUSSION
Subcutaneous U87 tumors do not represent an accurate model for studying invasiveness and its effects on tumor growth of human GBMs.
“Therefore, though commonly used and very robust, they do not represent an accurate model for studying invasiveness and its effects on tumor growth of human GBMs.”
Quote in the paperSubstantial claim- Rests on an assumption: Subcutaneous U87 tumors are noninfiltrative, noninvasive, and poorly vascularized.
- Premisecitation§ RESULTS
MMP-2 and MMP-9 activities correlate well with glioma cell migration and invasiveness.
“Moreover, MMP-2 and MMP-9 activities correlate well with glioma cell migration and invasiveness (58).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [58] source
- Interpretationown data§ RESULTS
RECK is the major factor mediating miR-21 function in glioma invasion, at least in vitro.
“suggesting that RECK is the major factor that mediates miR-21 function in glioma invasion, at least in vitro.”
Quote in the paperSubstantial claim - Premisecitation§ RESULTS
The MMPSense 680 probe allows in vivo imaging of key MMPs, including MMP-2 as well as MMP-3, -9, -7, -12, and -13.
“It allows in vivo imaging of key MMPs, including MMP-2 as well as MMP-3, -9, -7, -12, and -13 (4, 32).”
Quote in the paperSubstantial claim0 of 2 sources checked - Study design and conductreasoning§ DISCUSSION
Enrichment of predicted targets among negatively regulated genes validates the specificity of the cellular response to miRNA inhibition.
“enrichment of the predicted targets among negatively regulated genes validates the specificity of the response”
Quote in the paperSubstantial claim
- May combine two claims. 28
- Classified as probably not a substantial claim. 21
- The quote only partly states this claim. 2
May combine two claims.
Premisecitation§ RESULTSAccumulated data suggest MMP levels and activities are significantly elevated in human gliomas, which contributes to glioma cell invasion, metastasis, and angiogenesis through cell surface ECM degradation.
“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).”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [21] Hu B., 2003, Proc. Natl. Acad. Sci. USA source
- cites [45] source
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)
Experimental — accuracy not yet measured
- Rests on an assumption: MMPs are a group of peptidases involved in degradation of the ECM.
Classified as probably not a substantial claim. May combine two claims.
Premisecitation§ RESULTSTIMP3 is a tissue inhibitor of MMPs that inhibits angiogenesis and tumor cell infiltration and also induces apoptosis.
“TIMP3 is a tissue inhibitor of MMPs that inhibits angiogenesis and tumor cell infiltration and also induces apoptosis (2, 48).”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [2] source
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)
Experimental — accuracy not yet measured - cites [48] source
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ AbstractmiR-21 has been implicated in cellular proliferation, apoptosis, and migration in carcinogenesis.
“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).”
Quote in the paperNot a substantial claim1 of 3 sources checked- Also stated in: § Abstract · plain
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown data§ DISCUSSIONThis analysis confirmed regulation of tropomyosin 1 (TPM1) by miR-21, previously reported in MCF7 cells.
“Our analysis also confirmed tropomyosin 1 (TPM1) regulation by miR-21, previously reported to occur in MCF7 cells (59, 60).”
Quote in the paperNot a substantial claim1 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DISCUSSIONHypoxia, a general feature of all solid tumors, can induce miR-21 expression.
“Another factor that can induce miR-21 expression is hypoxia, a general feature of all solid tumors (30).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [30] source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ DISCUSSIONThe miR-21 gene contains two conserved STAT3 binding sites within its enhancer region and is induced by interleukin 6 in a STAT3-dependent way.
“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.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [39] source
May combine two claims.
Premisecitation§ RESULTSMMPs can degrade ECM components and therefore play important roles in mediating GBM tumor cell motility and invasion.
“MMPs can degrade ECM components and therefore play important roles in mediating GBM tumor cell motility and invasion (45).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [45] source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ DISCUSSIONAPAF1 is the molecular core of the apoptosome and is typically required for activation of the caspases that initiate apoptosis.
“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).”
Quote in the paperNot a substantial claim2 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DISCUSSIONElevated miR-21 expression has been causally linked to proliferation, apoptosis, and migration of several cancer cell lines.
“Elevated miR-21 expression has been causally linked to proliferation, apoptosis, and migration of several cancer cell lines (1, 5, 44, 60).”
Quote in the paperNot a substantial claim1 of 3 sources checkedMay combine two claims.
Findingown data§ RESULTSmiR-21 levels remain low in grade II gliomas and in most grade III tumors and are significantly higher in GBMs.
“miR-21 levels remain low in grade II gliomas and in most grade III tumors and are significantly higher in GBMs (Fig. 1).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Findingcitation§ RESULTSmiR-10b is often elevated in grade III and even grade II gliomas and dysregulated in some other cancers.
“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).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [41] source
May combine two claims.
Findingown data§ RESULTSRECK mRNA level increased consistently approximately 2-fold and TIMP3 mRNA about 1.6-fold in cells transfected with anti-miR-21.
“RECK mRNA level increased consistently ∼2-fold and TIMP3 mRNA about 1.6-fold in the cells transfected with anti-miR-21.”
Quote in the paperSubstantial claimThe quote only partly states this claim.
Findingown data§ RESULTSInhibition of miR-21 reduced the motility of glioma (A172) cells in a scratch motility assay.
“These experiments demonstrated that inhibition of miR-21 reduced the motility of glioma cells (Fig. 6B and C).”
Quote in the paperSubstantial claimMay combine two claims.
Findingcitation§ DISCUSSIONThe 2'-O-MOE miR-21 ASO induced many proapoptotic and cell cycle arrest genes but did not significantly and consistently change the viability of glioma cell lines.
“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).”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
Findingown data§ DISCUSSIONSTAT3 is negatively regulated by miR-21 according to the microarray data and is a predicted miR-21 target.
“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).”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
Findingown data§ DISCUSSIONTIMP3, or both TIMP3 and RECK, are also induced by anti-miR-21 in MCF7 breast carcinoma and U2OS osteosarcoma cells.
“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).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown data§ DISCUSSIONIn glioma progression from less invasive grade II gliomas to very invasive GBMs, RECK and TIMP3 levels drop whereas miR-21 expression increases.
“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).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ DISCUSSIONThe 2'-O-MOE anti-miR-21 ASO is potent and upregulates miR-21 seed-containing mRNAs.
“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).”
Quote in the paperSubstantial claimMay combine two claims.
Premisecitation§ AbstractmiR-21 is significantly elevated in glioblastoma (GBM) and in many other tumors of various origins.
“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).”
Quote in the paperNot a substantial claim0 of 3 sources checked- Also stated in: § Abstract · boosted
May combine two claims.
Premiseown data§ RESULTSmRNAs carrying RECK and TIMP3 are predicted conserved miR-21 targets with one and two putative binding sites, respectively.
“mRNAs carrying RECK and TIMP3 are predicted conserved miR-21 targets with one and two putative binding sites, respectively (Fig. 4A).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown data§ MATERIALS AND METHODSThe sequences of the control and mismatch oligonucleotides have been analyzed using BLAST searches to exclude potential hits in the human transcriptome.
“The sequences of the control and mismatch oligonucleotides have been analyzed using BLAST searches to exclude potential hits in the human transcriptome.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Premisecitation§ RESULTSRECK is a membrane-anchored MMP inhibitor whose reduced expression or inactivation seems critical for invasiveness and metastasis of various cancers, including glioma.
“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).”
Quote in the paperSubstantial claim0 of 2 sources checkedThe quote only partly states this claim.
Interpretationreasoning§ RESULTSThe high level of miR-21 expression in GBMs compared to anaplastic astrocytomas suggests involvement of miR-21 in microvascular proliferation/ECM reorganization or high proliferative capacity.
“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.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ RESULTSRECK expression level is an important prognostic factor for multiple cancer types.
“Its expression level is also an important prognostic factor for multiple cancer types (6).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [6] source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ RESULTSTIMP3 inhibits MMP activity and tumor growth in malignant gliomas in vivo.
“It has been demonstrated to inhibit MMP activity and tumor growth in malignant gliomas in vivo (31, 32).”
Quote in the paperNot a substantial claim0 of 2 sources checkedClassified as probably not a substantial claim.
Study design and conductreasoning§ RESULTSSeveral ASO molecules of different chemistries have been used for miR-21 inhibition to control for nonspecific off-target effects.
“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.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown data§ AbstractmiR-21 contributes to glioma malignancy by downregulation of MMP inhibitors, which leads to activation of MMPs, thus promoting invasiveness of cancer cells.
“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.”
Quote in the paperSubstantial claim- Rests on an assumption: MMPs are a group of peptidases involved in degradation of the ECM.
May combine two claims.
Interpretationown data§ RESULTSThe overrepresentation of miR-21 seed hexamers suggests an abundance of direct miR-21 targets among genes upregulated by 2'-O-MOE anti-miR-21 and indicates effects mediated through the miR-21 pathway.
“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.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductown data§ RESULTSThese 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.
“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.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ DISCUSSIONTIMP3 inhibits tumor necrosis factor alpha-converting enzyme and induces apoptosis through stabilization of tumor necrosis factor alpha receptors on the cell surface.
“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).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [42] source
May combine two claims.
Interpretationown data§ DISCUSSIONInhibition of miR-21 leads to reduction of glioma cell motility and invasion, which is mediated by elevated RECK expression and is partly rescued by RECK siRNA.
“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).”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationreasoning§ DISCUSSIONmiR-21 regulates RECK and TIMP3 expression and thus MMP activities and glioma tumor invasiveness.
“This implies that miR-21 regulates RECK and TIMP3 expression and thus MMP activities and glioma tumor invasiveness.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown data§ DISCUSSIONmiR-21 regulates MMPs and glioma cell invasiveness by directly controlling the MMP inhibitor RECK, as shown in vitro and in vivo using U87 glioma xenografts in nude mice.
“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.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown data§ DISCUSSIONmiR-21 regulates overlapping though not identical sets of genes in different cells and therefore shares common signaling pathways in different cancers.
“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.”
Quote in the paperNot a substantial claimMay combine two claims.
Premisereasoning§ DISCUSSIONThe APAF1 3' UTR contains a strong miR-21 binding site (9-mer binding at the miR-21 5' end), and APAF1 is therefore likely one of the direct miR-21 targets.
“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.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DISCUSSIONmiR-21 expression is highly upregulated in a variety of solid tumors, including GBM, breast, lung, colon, prostate, pancreas, and stomach cancers.
“Its expression is highly upregulated in a variety of solid tumors, including GBM, breast, lung, colon, prostate, pancreas, and stomach cancers (5, 54).”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
Interpretationown data§ DISCUSSIONmiR-21 regulates the expression of multiple mRNA targets and thereby induces several cellular programs in glioma cells, including those associated with tumor invasiveness and microvascular proliferation typical for GBM as well as those involved in cell cycle regulation and apoptosis.
“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.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DISCUSSIONEctopic expression of TIMP3 in glioma cells induces upregulation of genes associated with angiogenesis, growth factors, cytokines, death receptors, and substrates of various MMPs.
“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).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [31] Lam P., 2005, Mol. Ther. source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ DISCUSSIONRECK and TIMP3 are key inhibitors of several MMPs, and their expression is prognostic in a number of common cancers.
“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).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ DISCUSSIONTIMP3 activates caspases and thereby induces apoptosis of human glioma cells in vitro and growth inhibition of human glioma tumors in a mouse model.
“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).”
Quote in the paperNot a substantial claim0 of 2 sources checkedClassified as probably not a substantial claim.
Study design and conductnone given§ DISCUSSIONmRNA expression analysis does not allow identification of targets whose translation is regulated without modulation of mRNA levels.
“Though mRNA expression analysis does not allow identification of targets whose translation is regulated without modulation of mRNA levels”
Quote in the paperSubstantial claimMay combine two claims.
Study design and conductown data§ DISCUSSIONThe bidirectional approach of manipulating miR-21 levels enabled narrowing of the lists of regulated genes and identification of those whose expression correlated negatively with miR-21 levels.
“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”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ RESULTSU87 cells are a common model of human gliomas.
“In these experiments, we used tumorigenic U87 cells, a common model of human gliomas (23).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [23] source
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?
miR-21 is overexpressed in almost all cancer types, and its upregulation promotes cell proliferation, invasion, and metastatic behavior.
“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]
The Discussion reports miR-21 upregulation in a variety of cancers and links elevated expression to proliferation and migration; the Results show that inhibiting miR-21 reduces glioma-cell invasion. It does not establish overexpression in almost all cancer types or show metastatic behavior, which goes beyond the invasion and migration measured here. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPDCD4, HNRNPK, and RECK are tumor suppressor genes and direct targets of miR-21-5p.
“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]
The Results (page unavailable) identify PDCD4 as a tumor suppressor and a validated direct miR-21 target, and report experimental evidence that RECK is a direct miR-21 target. They describe RECK as an inhibitor of cancer invasion, but our copy does not call it a tumor suppressor gene. No retrieved passage identifies HNRNPK as a tumor suppressor or miR-21 target; the paper also uses “miR-21” rather than the specific designation “miR-21-5p.” (LLM, conf=0.87)
Experimental — accuracy not yet measuredmiR-21 targets several genes such as PDCD4, TIMP3, and RECK, which are key regulators of apoptotic and metastatic pathways.
“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]
Overexpressed miR-21 in cell lines can increase the proliferation rate and malignant behavior of the cells.
“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.
APAF1 overexpression claim cites a caspase-8 study
MinorIn the APAF1 discussion, the paper attributes apoptosis induced by viral overexpression to APAF1 and cites reference 50. The cited reference instead describes adenovirus-mediated transfer of caspase-8 in combination with a superrepressor of NF-kappaB.
“Its overexpression by viral transduction induces apoptosis in glioma cells and may be beneficial in glioma treatment (50).”
“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.”
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Frequent LOH at Chromosome 12q22‐23 and Apaf‐1 Inactivation in Glioblastoma
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Prognostic relevance of uPAR-del4/5 and TIMP-3 mRNA expression levels in breast cancer
Kotzsch, M., Farthmann, J., Meye, A., Fuessel, S., Baretton, G., Tjan-Heijnen, V. C. G., Schmitt, M., Luther, T., Sweep, F. C. G. J., Magdolen, V., et al. (2005) · European Journal of Cancer · doi:10.1016/j.ejca.2005.09.002 · Cited by 50 · see citing works
Downregulation of the <i>RECK</i>‐tumor and metastasis suppressor gene in glioma invasiveness
Corrẽa, T. C. S., Brohem, C. A., Winnischofer, S. M. B., da Silva Cardeal, L. B., Sasahara, R. M., Taboga, S. R., Sogayar, M. C., & Maria‐Engler, S. S. (2006) · Journal of Cellular Biochemistry · doi:10.1002/jcb.20917 · Cited by 32 · see citing works
A microarray study to characterize the molecular mechanism of TIMP-3-mediated tumor rejection
Lam, P., Sian Lim, K., Mei Wang, S., & Hui, K. M. (2005) · Molecular Therapy · doi:10.1016/j.ymthe.2005.02.028 · Cited by 22 · see citing works
Erratum: Tumour invasion and metastasis initiated by microRNA-10b in breast cancer
Ma, L., Teruya‐Feldstein, J., & Weinberg, R. A. (2008) · Nature · doi:10.1038/nature07316 · Cited by 18 · see citing works
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P-132 RECK expression in non-small cell lung cancer
Takenaka, K., Tanaka, F., Ishikawa, S., et al. (2003) · Lung Cancer · doi:10.1016/s0169-5002(03)92101-5
TAKENAKA, K. (2004) · European Journal of Cancer · doi:10.1016/s0959-8049(04)00282-5
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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 1,674 · see citing works
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 · see citing works
“[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 1,074 · see citing works
“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 · see citing works
“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 748 · see citing works
“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 731 · see citing works
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 731 · see citing works
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 · see citing works
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 589 · see citing works
“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 583 · see citing works
“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 569 · see citing works
“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 564 · see citing works
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 532 · see citing works
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 511 · see citing works
“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 492 · see citing works
“[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 · see citing works
“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 453 · see citing works
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 453 · see citing works
Emerging role of microRNA-21 in cancer
Feng, Y., & Tsao, C. (2016) · Biomedical Reports · doi:10.3892/br.2016.747 · Cited by 456 · see citing works
“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 448 · see citing works
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 · see citing works
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 417 · see citing works
“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 387 · see citing works
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 374 · see citing works
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 370 · see citing works
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 358 · see citing works
“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 356 · see citing works
“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 347 · see citing works
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 340 · see citing works
“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 · see citing works
“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 326 · see citing works
“…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 · see citing works
“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 310 · see citing works
“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 310 · see citing works
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 · see citing works
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 309 · see citing works
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 302 · see citing works
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 297 · see citing works
“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. D., 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 301 · see citing works
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 299 · see citing works
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 298 · see citing works
“In fact, this relationship has been alreadywell documented in cancers [73, 74].”
BackgroundWong, H. K., Veremeyko, T., Patel, N., Lemere, C. A., Walsh, D. M., Esau, C., Vanderburg, C. R., & Krichevsky, A. M. (2013) · Human Molecular Genetics · doi:10.1093/hmg/ddt164 · Cited by 293 · see citing works
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 294 · see citing works
Absalon, S., Kochanek, D. M., Raghavan, V., & Krichevsky, A. M. (2013) · The Journal of Neuroscience · doi:10.1523/jneurosci.1327-13.2013 · Cited by 259 · see citing works
“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 287 · see citing works
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 286 · see citing works
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 · see citing works
“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 280 · see citing works
“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 273 · see citing works
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 276 · see citing works
“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 266 · see citing works
“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 · see citing works
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 258 · see citing works
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 · see citing works
“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., Bonet, L. G. G., Martínez‐Cadenas, C., Estrela, J. M., et al. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25052529 · Cited by 263 · see citing works
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 248 · see citing works
“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 246 · see citing works
“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 · see citing works
“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 · see citing works
“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 239 · see citing works
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 238 · see citing works
“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) · Journal of Neuroscience · doi:10.1523/jneurosci.3467-10.2010 · Cited by 237 · see citing works
“, 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 · see citing works
“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 236 · see citing works
“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 236 · see citing works
“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 231 · see citing works
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 232 · see citing works
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 · see citing works
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 · see citing works
“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 223 · see citing works
MicroRNAs and potential target interactions in psoriasis.
Zibert, J., Løvendorf, M., Litman, T., Olsen, J., Kaczkowski, B., & Skov, L. (2010) · Journal of dermatological science (Amsterdam) · doi:10.1016/j.jdermsci.2010.03.004 · Cited by 227 · see citing works
“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 220 · see citing works
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 218 · see citing works
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 216 · see citing works
“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 214 · see citing works
“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 213 · see citing works
“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., et al. (2014) · Journal of Orthopaedic Research® · doi:10.1002/jor.22718 · Cited by 211 · see citing works
“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 209 · see citing works
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 209 · see citing works
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 · see citing works
“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 207 · see citing works
“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 · see citing works
Xia, X., Wang, Y., Huang, Y., Zhang, H., Lu, H., & Zheng, J. (2019) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2019.101694 · Cited by 206 · see citing works
“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 201 · see citing works
“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 204 · see citing works
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 206 · see citing works
“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 · see citing works
“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., et al. (2011) · Neuro-Oncology · doi:10.1093/neuonc/nor169 · Cited by 198 · see citing works
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 197 · see citing works
“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 197 · see citing works
“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 192 · see citing works
“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 195 · see citing works
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 · see citing works
The microRNA network and tumor metastasis
Zhang, H., Li, Y., & Lai, M. (2009) · Oncogene · doi:10.1038/onc.2009.406 · Cited by 185 · see citing works
“, 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 185 · see citing works
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 · see citing works
“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 184 · see citing works
“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 182 · see citing works
“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).”
BackgroundLiu, Y., Li, Y., Li, N., Teng, W., Wang, M., Zhang, Y., & Xiao, Z. (2016) · Scientific Reports · doi:10.1038/srep32231 · Cited by 179 · see citing works
Downregulation 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 · see citing works
- 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 › Genetics › 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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