The DOI matches its Crossref record; 44 of the 45 references it cites were found in a registry or an index; 5 of the 26 sources its claims cite were checked for support.
MicroRNA-21 Targets a Network of Key Tumor-Suppressive Pathways in Glioblastoma Cells
Open accessPublished version of a preprint
Abstract
MicroRNA dysregulation is observed in different types of cancer. MiR-21 up-regulation has been reported for the majority of cancers profiled to date; however, knowledge is limited on the mechanism of action of miR-21, including identification of functionally important targets that contribute to its proproliferative and antiapoptotic actions. In this study, we show for the first time that miR-21 targets multiple important components of the p53, transforming growth factor-β (TGF-β), and mitochondrial apoptosis tumor-suppressive pathways. Down-regulation of miR-21 in glioblastoma cells leads to derepression of these pathways, causing repression of growth, increased apoptosis, and cell cycle arrest. These phenotypes are dependent on two of the miR-21 targets validated in this study, HNRPK and TAp63. These findings establish miR-21 as an important oncogene that targets a network of p53, TGF-β, and mitochondrial apoptosis tumor suppressor genes in glioblastoma cells. [Cancer Res 2008;68(19):8164–72]
Overview
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Written from the paper’s full text.
TL;DR
In glioblastoma cells, miR-21 directly targets and represses a network of p53, TGF-β, and mitochondrial apoptosis tumor-suppressive genes. Knockdown derepresses these pathways, increasing apoptosis and cell-cycle arrest and suppressing growth, with HNRPK and TAp63 required for key phenotypes.
Key findings
- miR-21 knockdown in U251 cells caused 2- to 16-fold increases in mRNA levels of major p53/TGF-β/apoptotic pathway components; protein levels of examined targets increased 2- to 3-fold.
- Luciferase assays validated direct targeting of JMY, TGFBR2, TGFBR3, HNRPK, TP73L (TAp63), APAF1, BMPR2, TOPORS, DAXX, TP53BP2, and PPIF; IGFBP3 did not change. The positive anti-miR-21 reporter showed a 70% decrease, and PDCD4 showed a ~30% decrease.
- LNA-miR-21 increased Annexin V 1.5- to 2-fold at 24/48 h; siRNA against TAp63 or HNRPK reduced Annexin V induction by ~25%. miR-21 overexpression blocked doxorubicin-induced caspase-3/7 activation in U251 and U87 cells.
- Knockdown suppressed growth over 4 days (most significant on day 3) and increased G0-G1 arrest in U251 by 21% with nocodazole and 25% with doxorubicin; siRNA-HNRPK/TAp63 produced a 2-fold decrease in G0-G1 arrest.
Methods
- U251, U87, and HeLa cells were used; miR-21 was down-regulated with LNA-miR-21 or 2′-O-me-miR-21, and overexpressed in HeLa cells via lentivirus. Assays included real-time PCR, immunoblotting, dual luciferase reporters containing 60-bp 3′UTR sequences, CellTiter Glo growth assays, Annexin V and caspase-3/7 apoptosis assays, and PI cell-cycle analysis after nocodazole/doxorubicin synchronization.
- Target prediction used TargetScan 3.1 (1,398 human miR-21 targets including duplicates), and network analysis used Ingenuity Pathway Analysis 3.0, yielding 765 network-eligible genes after filtering. Statistics used ANOVA or Student’s t test, with significance at P < 0.05 or P < 0.01; growth and apoptosis results represent means of three separate experiments.
Limitations
- Stated: knockdown of HNRPK and TAp63 did not completely rescue the proapoptotic and cell-cycle arrest phenotypes, suggesting other critical miR-21 targets are involved.
- Evident: all functional experiments were performed in cell lines (U251, U87, HeLa), with no in vivo tumor model or patient tumor samples in this paper.
- Evident: luciferase validation used 60-bp 3′UTR fragments containing predicted sites rather than full 3′UTRs, and only selected predicted targets were validated.
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Claims the paper makes
34 Own result · 27 Own interpretation · 13 No full text of the sources · 5 No basis given · 4 Not checked yet · 2 Partly supported · 1 Supported · 1 Supported so far · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“These data are also consistent with findings in glioblastomas that significant effects of miRNAs occur indirectly rather than by direct targeting (24,43).”
§ MicroRNA-21 Targets a Network of Key Tumor-Suppressive Pathways in Glioblastoma Cells > Discussion
What the sources say
- Could not verifycites [24] Li Q, Wang X, Wu X, et al. Daxx Cooperates with the Axin/HIPK2/p53 complex to induce cell death. Cancer Res 2007; 67: 66–74. sourceExperimental — accuracy not yet measured
The Discussion passages describe Daxx, Axin, p53 and apoptosis, including experiments using siRNA against Axin. Searches for glioblastoma, miRNAs and indirect versus direct targeting found no passage in our copy addressing the attributed finding. The paper’s use of siRNA does not establish a claim about miRNA effects in glioblastomas. (LLM, conf=0.76)
- Partly supportedcites [43] Johnson CD, Esquela-Kerscher A, Stefani G, et al. The let-7 MicroRNA represses cell proliferation pathways in human cells. Cancer Res 2007; 67: 7713–22. sourceExperimental — accuracy not yet measured
The Discussion (page unavailable) says that only 25 of 176 early repressed genes were likely direct let-7 targets, and the cell-cycle section describes indirect changes downstream of direct targets. But the experiments used liver and lung cancer cell lines, not glioblastomas, so the glioblastoma-specific claim is not supported by this paper. (LLM, conf=0.85)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Could not verify
Every source the paper cites for this claim was checked and supports it.
In the paper
“Interestingly, a transcriptional target of the functional convergence of these pathways is SERPINB5, the transcript most highly up-regulated in response to miR-21 knockdown (Fig. 2A; ref. 42).”
§ MicroRNA-21 Targets a Network of Key Tumor-Suppressive Pathways in Glioblastoma Cells > Discussion
What the sources say
- Supportedcites [42] Wang SE, Narasanna A, Whitell CW, Wu FY, Friedman DB, Arteaga CL. Convergence of p53 and transforming growth factor β (TGFβ) signaling on activating expression of the tumor suppressor gene maspin in mammary epithelial cells. J Biol Chem 2007; 282: 5661–9. source
The paper states that TGFβ induces maspin expression through Smads and that p53 binding to the maspin promoter is required for TGFβ-induced transcription. Its discussion explicitly describes maspin as an example of gene-expression co-regulation by the p53 and TGFβ pathways. The citation supports the pathway claim; the sentence attributes the miR-21 knockdown result to Fig. 2A, not to this source. (LLM, conf=0.93)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Supported
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Down-regulation of miR-21 in glioblastoma cells leads to derepression of these pathways, causing repression of growth, increased apoptosis, and cell cycle arrest.”
§ MicroRNA-21 Targets a Network of Key Tumor-Suppressive Pathways in Glioblastoma Cells > Abstract
plaindirect- 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
“Upon down-regulation of miR-21 with LNA, we observed significant increases ranging from 2-fold to 16-fold in the levels of major components of the p53/TGF-h/apoptotic pathways, including many of the predicted targets (Fig. 2).”
§ MicroRNA-21 Targets a Network of Key Tumor-Suppressive Pathways in Glioblastoma Cells > MiR-21 predicted targets form network of interactions.
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“p53 pathway predicted targets included the tumor-suppressive homologue of p53, TP73L (TAp63), and activating cofactors of p53, such as JMY, TOPORS, HNRPK, and TP53BP2 (19, 21-26).”
§ MicroRNA-21 Targets a Network of Key Tumor-Suppressive Pathways in Glioblastoma Cells > MiR-21 predicted targets form network of interactions.
plaincorrelational- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“In addition, PDCD4, which is involved in mediating TGFh-induced apoptosis, increased f8-fold (35).”
§ MicroRNA-21 Targets a Network of Key Tumor-Suppressive Pathways in Glioblastoma Cells > MiR-21 predicted targets form network of interactions.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Several of the genes involved in mitochondrial apoptosis were also up-regulated in response to miR-21 down-regulation, including APAF1, PPIF, and caspase-3 (CASP3).”
§ MicroRNA-21 Targets a Network of Key Tumor-Suppressive Pathways in Glioblastoma Cells > MiR-21 predicted targets form network of interactions.
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
“Additionally, we observed increases in several transactivation targets of p53, such as IGFBP3, TNSFRSF10B, NOXA, p21 (CDKN1A), and GADD45A, which are expected due to the increase of p53 and its homologues (Fig. 2A; refs.19,34).”
§ MicroRNA-21 Targets a Network of Key Tumor-Suppressive Pathways in Glioblastoma Cells > MiR-21 predicted targets form network of interactions.
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
“The p53 pathway was derepressed to a great extent in response to miR-21 knockdown.”
§ MicroRNA-21 Targets a Network of Key Tumor-Suppressive Pathways in Glioblastoma Cells > MiR-21 predicted targets form network of interactions.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These phenotypes are dependent on two of the miR-21 targets validated in this study, HNRPK and TAp63.”
§ MicroRNA-21 Targets a Network of Key Tumor-Suppressive Pathways in Glioblastoma Cells > Abstract
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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- Probably not a substantial claim. 6
- It may state two separate claims as one. 21
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Three miR-21 targets have, thus far, been described: phosphatase and tensin homologue (PTEN), programmed cell death 4 (PDCD4) and Tropomyosin 1 (TPM1; refs.10,[14][15][16].”
§ MicroRNA-21 Targets a Network of Key Tumor-Suppressive Pathways in Glioblastoma Cells > Introduction
What the sources say
- Partly supportedcites [10] Meng F, Henson R, Lang M, et al. Involvement of human micro-RNA in growth and response to chemotherapy in human cholangiocarcinoma cell lines. Gastroenterology 2006; 130: 2113–29. sourceExperimental — accuracy not yet measured
The section “miR-21 Directly Alters PTEN Expression” (page unavailable) reports that miR-21 directly modulates expression through PTEN’s 3′-UTR, supporting PTEN as a target. Searches for PDCD4 and TPM1 found no passages in our copy describing either as a miR-21 target, so this source does not support those two parts of the list. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [14] Asangani IA, Rasheed SAK, Nikolova DA, et al. MicroRNA-21 (miR-21) post-transcriptionally down-regulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer. Oncogene 2007; 27: 2128–36. source
- Not checked — no full text of the sourcecites [15] Frankel LB, Christoffersen NR, Jacobsen A, Lindow M, Krogh A, Lund AH. Programmed cell death 4 (PDCD4) is an important functional target of the microRNA miR-21 in breast cancer cells. J Biol Chem 2008; 283: 1026–33. source
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
- 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
“TAp63 is a homologue of p53 and is known to mediate both cell cycle arrest and apoptosis (19,38).”
§ MicroRNA-21 Targets a Network of Key Tumor-Suppressive Pathways in Glioblastoma Cells > Discussion
What the sources say
- Not checked — no full text of the sourcecites [19] Stiewe T. The p53 family in differentiation and tumorigenesis. Nat Rev Cancer 2007; 7: 165–7. source
- Supportedcites [38] Gressner O, Schilling T, Lorenz K, et al. TAp63α induces apoptosis by activating signaling via death receptors and mitochondria. EMBO J 2005; 24: 2458–71. source
The Introduction identifies TAp63 as a p53-like protein in the p53 family. In ‘Induction of apoptosis in TAp63α-inducible p53-negative cells,’ the authors report both G1 cell-cycle arrest and apoptosis after inducing TAp63α. (LLM, conf=0.93)
boosteddirect- 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.
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
“APAF1 and PPIF are both predicted targets of miR-21 (Fig. 2C).”
§ MicroRNA-21 Targets a Network of Key Tumor-Suppressive Pathways in Glioblastoma Cells > MiR-21 predicted targets form network of interactions.
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
“We also observed increases in proteins, such as p53, DNA damage-activated p53 (Ser 15 ), and p21, which are not targets but are indirectly negatively regulated by miR-21 (Fig. 2).”
§ MicroRNA-21 Targets a Network of Key Tumor-Suppressive Pathways in Glioblastoma Cells > MiR-21 target validation.
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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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
“For both U251 and U87 cell lines, cells expressing the scrambled control showed a predicted dose-dependent increase in caspase-3/ caspase-7 activity, whereas the cells expressing miR-21 did not respond to the drug treatment even at higher doses (Fig. 5C).”
§ MicroRNA-21 Targets a Network of Key Tumor-Suppressive Pathways in Glioblastoma Cells > MiR-21 target validation.
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.
- Rests on an assumption: The p53 pathway is functional and can mediate apoptosis in the U251 and U87 cell lines used.
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
“We have shown that miR-21 regulates sets of genes, and the regulation is direct through targeting of certain transcripts, and in other cases, the effects are indirect.”
§ MicroRNA-21 Targets a Network of Key Tumor-Suppressive Pathways in Glioblastoma Cells > Discussion
boosteddirect- Asserted: passes — The authors put it forward as true.
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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
“In addition, miR-21 down-regulation significantly represses growth and leads to cell cycle arrest at G 0 -G 1 , which can be explained by the up-regulation of p21 (Figs.2A and 4A), a protein that is known to regulate cell cycle checkpoints in response to its transactivation by p53.”
§ MicroRNA-21 Targets a Network of Key Tumor-Suppressive Pathways in Glioblastoma Cells > Discussion
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
“This retarded growth continued throughout the 4 days with the most significant difference observed on day 3.”
§ MicroRNA-21 Targets a Network of Key Tumor-Suppressive Pathways in Glioblastoma Cells > MiR-21 target validation.
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.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“High levels of miR-21 were first reported in glioblastoma tumors and cell lines (6).”
§ MicroRNA-21 Targets a Network of Key Tumor-Suppressive Pathways in Glioblastoma Cells > Introduction
What the sources say
- Not checked — no full text of the sourcecites [6] Chan JA, Krichevsky AM, Kosik KS. MicroRNA-21 Is an antiapoptotic factor in human glioblastoma cells. Cancer Res 2005; 65: 6029–33. 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.
In the paper
“In the same study, inhibition of miR-21 by LNA or 2 ¶O-Me-miR-21 led to increased caspase-dependent apoptosis, suggesting that miR-21 could be acting as an oncogene to inhibit apoptosis in glioblastoma cells (6).”
§ MicroRNA-21 Targets a Network of Key Tumor-Suppressive Pathways in Glioblastoma Cells > Introduction
What the sources say
- Not checked — no full text of the sourcecites [6] Chan JA, Krichevsky AM, Kosik KS. MicroRNA-21 Is an antiapoptotic factor in human glioblastoma cells. Cancer Res 2005; 65: 6029–33. 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.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“A subset of the derepressed transcripts, APAF1, BMPR2, PDCD4, and p21 were reported to be up-regulated in MCF-7 breast cancer cells with LNA-miR-21 treatment (15).”
§ MicroRNA-21 Targets a Network of Key Tumor-Suppressive Pathways in Glioblastoma Cells > MiR-21 predicted targets form network of interactions.
What the sources say
- Not checked — no full text of the sourcecites [15] Frankel LB, Christoffersen NR, Jacobsen A, Lindow M, Krogh A, Lund AH. Programmed cell death 4 (PDCD4) is an important functional target of the microRNA miR-21 in breast cancer cells. J Biol Chem 2008; 283: 1026–33. source
plaindirect- 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
“The majority of these profiling studies have reported increased levels of miR-21 in most human cancers (6,(8)(9)(10).”
§ MicroRNA-21 Targets a Network of Key Tumor-Suppressive Pathways in Glioblastoma Cells > Introduction
What the sources say
- Not checked — no full text of the sourcecites [6] Chan JA, Krichevsky AM, Kosik KS. MicroRNA-21 Is an antiapoptotic factor in human glioblastoma cells. Cancer Res 2005; 65: 6029–33. source
- Not checked — no full text of the sourcecites [8] Volinia S, Calin GA, Liu C-G, et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci U S A 2006; 103: 2257–61. source
- Not checked — no full text of the sourcecites [9] Iorio MV, Ferracin M, Liu C-G, et al. MicroRNA gene expression deregulation in human breast cancer. Cancer Res 2005; 65: 7065–70. source
plaincorrelational- 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.
- 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
“DAXX, which can stabilize p53 in addition to mediating TGF-h apoptosis, plays a role in both pathways and, therefore, may be a key target in disrupting crosstalk between the two pathways (Supplementary Fig. S3).”
§ MicroRNA-21 Targets a Network of Key Tumor-Suppressive Pathways in Glioblastoma Cells > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- 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
“MiR-21 repressed p53-mediated apoptosis in response to chemotherapeutic (doxorubicin)-induced DNA damage, therefore contributing to drug resistance in glioblastoma cells.”
§ MicroRNA-21 Targets a Network of Key Tumor-Suppressive Pathways in Glioblastoma Cells > Discussion
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.
- Rests on an assumption: The p53 pathway is functional and can mediate apoptosis in the U251 and U87 cell lines used.
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 result indicates that miR-21 up-regulation in cancer cells is sufficient to inhibit p53-mediated apoptosis, thus protecting the cells from p53-mediated apoptosis in response to DNA damage induced by a chemotherapeutic agent.”
§ MicroRNA-21 Targets a Network of Key Tumor-Suppressive Pathways in Glioblastoma Cells > MiR-21 target validation.
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: The p53 pathway is functional and can mediate apoptosis in the U251 and U87 cell lines used.
In the paper
“In accordance, we observe a significant increase in the protein levels of p53 (Ser 15 ; Fig. 4A), which occurs in response to DNA damage and can mediate cell cycle arrest at G 0 -G 1 by transactivation of p21 (19).”
§ MicroRNA-21 Targets a Network of Key Tumor-Suppressive Pathways in Glioblastoma Cells > Discussion
What the sources say
- Not checked — no full text of the sourcecites [19] Stiewe T. The p53 family in differentiation and tumorigenesis. Nat Rev Cancer 2007; 7: 165–7. source
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. It may state two separate claims as one.
In the paper
“This finding is in agreement with limited data from other laboratories that suggests that many miRNAs have evolved to regulate multiple components of certain pathways, thus mediating a more effective negative regulation on those pathways (33).”
§ MicroRNA-21 Targets a Network of Key Tumor-Suppressive Pathways in Glioblastoma Cells > Discussion
What the sources say
- Not checked — no full text of the sourcecites [33] Esau C, Davis S, Murray SF, et al. miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metabol 2006; 3: 87–98. source
hedgeddirect- 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
“The miR-21 targets we identified included p53 homologue, p63, p53 activators JMY, TOPORS, TP53BP2, DAXX, and HNRPK, which can stabilize p53 protein levels by interfering with MDM2 and/or act as p53 transcriptional cofactors, assisting p53 in transactivating genes that can induce apoptosis and growth arrest (21)(22)(23)(24)(25)(26).”
§ MicroRNA-21 Targets a Network of Key Tumor-Suppressive Pathways in Glioblastoma Cells > Discussion
What the sources say
- Not checked — no full text of the sourcecites [21] Coutts AS, La Thangue NB. The p53 response: emerging levels of co-factor complexity. Biochem Biophys Res Commun 2005; 331: 778–85. source
- Not checked — no full text of the sourcecites [22] Moumen A, Masterson P, O'Connor MJ, Jackson SP. hnRNP K: an HDM2 target and transcriptional coactivator of p53 in response to DNA damage. Cell 2005; 123: 1065–78. source
- Not checked — no full text of the sourcecites [23] Samuels-Lev Y, O'Connor DJ, Bergamaschi D, et al. ASPP proteins specifically stimulate the apoptotic function of p53. Mol Cell 2001; 8: 781–94. source
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
“Our approach links putative targets around a function and succeeds in identifying not only multiple targets but uncover an entire network under miRNA control.”
§ MicroRNA-21 Targets a Network of Key Tumor-Suppressive Pathways in Glioblastoma Cells > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“MiR-21 suppression of the p53 response may take place in most cancers where miR-21 is up-regulated, and this oncogenic mechanism may be even more significant contributor to malignancy in tumors with wild-type p53.”
§ MicroRNA-21 Targets a Network of Key Tumor-Suppressive Pathways in Glioblastoma Cells > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
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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 resistance may be partly due to the negative regulation of multiple components of the pathway of miR-21, including the indirect regulation of TGFB1/2 and the direct targeting of the receptors TGFBR2/3 and the apoptotic mediator DAXX.”
§ MicroRNA-21 Targets a Network of Key Tumor-Suppressive Pathways in Glioblastoma Cells > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
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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 broad effects enable miR-21 to act as a key oncogene modulating cell growth, desensitizing cells to apoptosis and cell cycle arrest (Supplementary Fig. S3).”
§ MicroRNA-21 Targets a Network of Key Tumor-Suppressive Pathways in Glioblastoma Cells > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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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
“Due to the functional relationship among miR-21 targets, changes in the level of miR-21 is likely to dampen the robustness of a highly interconnected tumor-suppressive network and result in global regulation or dysregulation of the network functions.”
§ MicroRNA-21 Targets a Network of Key Tumor-Suppressive Pathways in Glioblastoma Cells > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“The effects we describe when we knockdown miR-21 suggest that miR-21 lies embedded in a nexus of tumor suppression genes and has multiple specific targets in the network that lead to the observed phenotypes.”
§ MicroRNA-21 Targets a Network of Key Tumor-Suppressive Pathways in Glioblastoma Cells > Discussion
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Cancer cells therefore only survive if the apoptotic response is dampened or disrupted, cell cycle checkpoints are evaded, and unrestricted cell proliferation occurs (44).”
§ MicroRNA-21 Targets a Network of Key Tumor-Suppressive Pathways in Glioblastoma Cells > Discussion
What the sources say
- Not checked — no full text of the sourcecites [44] Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100: 57–70. source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
The paper relies on this without support.
The mechanism of action of miR-21, including its functionally important targets, is largely unknown.
“Although miR-21 is emerging as a novel oncogene, its mechanism of action is largely unknown.”
“knowledge is limited on the mechanism of action of miR-21, including identification of functionally important targets that contribute to its proproliferative and antiapoptotic actions.”
The paper relies on this without support.
The known miR-21 targets PTEN, PDCD4, and TPM1 do not fully explain the antiapoptotic function of miR-21 in glioblastomas and other cancers.
“However, these targets do not fully elucidate the antiapoptotic function of miR-21 in glioblastomas and other types of cancer.”
The paper relies on this without support.
Knowledge on the contribution of PDCD4 and TPM1 to the malignant phenotype of glioblastomas is limited.
“On the other hand, knowledge is limited on the contribution of PDCD4 and TPM1 to the malignant phenotype of glioblastomas.”
The paper relies on this without support.
U251 and U87 cell lines are representative models of glioblastoma for generalizing miR-21 function to glioblastoma.
“We were able to show these effects in two established glioblastoma cells lines, U251 and U87.”
“These results suggest that miR-21 plays an essential role in the proliferative capacity of glioblastoma cells.”
The paper relies on this without support.
The siRNA-mediated knockdown of HNRPK and TAp63 is specific and does not produce off-target effects that confound the cell cycle and apoptosis results.
“In the presence of siRNA-HNRPK and siRNA-TAp63, we observed a 2-fold decrease in the proportion of cells arrested in G 0 -G 1 in response to miR-21 down-regulation.”
“we used the same siRNAs previously tested in the Annexin V assays.”
The paper relies on this without support.
The p53 pathway is functional and can mediate apoptosis in the U251 and U87 cell lines used.
“For both U251 and U87 cell lines, cells expressing the scrambled control showed a predicted dose-dependent increase in caspase-3/ caspase-7 activity, whereas the cells expressing miR-21 did not respond to the drug treatment even at higher doses (Fig. 5C).”
“This result indicates that miR-21 up-regulation in cancer cells is sufficient to inhibit p53-mediated apoptosis, thus protecting the cells from p53-mediated apoptosis in response to DNA damage induced by a chemotherapeutic agent.”
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 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 [19]
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
“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 [19]
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
“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 [19]
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 [13]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“In particular, miRNA-21 (miR-21) has been shown to be a strong antiapoptotic factor [5, 9–11].”
From MicroRNA‐21 protects neurons from ischemic death (2010) · cites this paper as [11]
The cited source says what the claim attributes to it.
In the citing paper
“We explored miR-21 as a potential biomarker due to its reported association with GBM aggressiveness in previous studies by various research groups [8,23,24].”
From miR-21 as a diagnostic and prognostic biomarker in glioma: tissue and serum expression analysis in a Pakistani cohort (2026) · cites this paper as [23]
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
§ MicroRNA-21 Targets a Network of Key Tumor-Suppressive Pathways in Glioblastoma Cells > Dual luciferase assay.
“At 24 h later, three different concentrations 0/12.5/25/50Amol/L of doxorubicin were added to the cells.”
§ MicroRNA-21 Targets a Network of Key Tumor-Suppressive Pathways in Glioblastoma Cells > Discussion
“48 h after transduction, cells were treated with indicated doses of doxorubicin, and apoptosis was assayed 24 h later by caspase-3/7 activity using the Caspase-3/7 Glo.”
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
§ MicroRNA-21 Targets a Network of Key Tumor-Suppressive Pathways in Glioblastoma Cells > MiR-21 knockdown led to cell cycle arrest.
“At 24 h posttransfection of each siRNA with LNA-scr or LNA-miR-21, we added nocodazole to synchronize cells.At 16 to 20 h later, we harvested the cells and performed PI staining for cell cycle analysis.”
§ MicroRNA-21 Targets a Network of Key Tumor-Suppressive Pathways in Glioblastoma Cells > Discussion
“C, PI staining performed 24 h posttransfection of siRNA sequences for HNRPK, TAp63, and negative control scramble in the presence of LNA-scr or LNA-miR-21.”
Cited works that were retracted
Works this paper cites that were later retracted, from the retraction notices publishers deposit. Major when the notice came out before this paper was published.
A note, not an issue: for example, a cited work that was retracted only after this paper was published, which its authors could not have known.
In the paper
“Moumen A, Masterson P, O'Connor MJ, Jackson SP. hnRNP K: an HDM2 target and transcriptional coactivator of p53 in response to DNA damage. Cell 2005; 123: 1065–78.”
Cited work 10.1016/j.cell.2005.09.032 · retracted 2024-10-31 · notice 10.1016/j.cell.2024.10.008 · this paper published 2008-09-30
Citations
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Molecular mechanisms and microRNAs in osteosarcoma pathogenesis
Кушлинский, Н. Е., Fridman, M. V., & Александровна, Б. Э. (2016) · Biochemistry (Moscow) · doi:10.1134/s0006297916040027 · Cited by 126
“Inhibition of the MIR 21 gene in vitro causes caspase activation and apop tosis [24].”
Monfared, H., Jahangard, Y., Nikkhah, M., Mirnajafi-Zadeh, J., & Mowla, S. J. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.00782 · Cited by 123
The effects of environmental chemical carcinogens on the microRNA machinery
Izzotti, A., & Pulliero, A. (2014) · International Journal of Hygiene and Environmental Health · doi:10.1016/j.ijheh.2014.01.001 · Cited by 126
Targeting apoptosis pathways in cancer stem cells
Signore, M., Ricci‐Vitiani, L., & Maria, R. D. (2011) · Cancer Letters · doi:10.1016/j.canlet.2011.01.013 · Cited by 126
“In glioblastoma cells, mir-21 acts as an anti-apoptotic factor [76,77], while in breast tumor tissues, it modulates tumorigenesis by regulating Bcl-2 and Programmed Cell Death 4 (PDCD4) [78].”
BackgroundOncogenic role of microRNAs in brain tumors
Pang, J. C.-S., Kwok, W. K., Chen, Z., & Ng, H.-K. (2009) · Acta Neuropathologica · doi:10.1007/s00401-009-0525-0 · Cited by 101
MicroRNAs as regulators of death receptors signaling
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MicroRNAs in glioblastoma pathogenesis and therapy: A comprehensive review
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“The majority of its reported target genes are tumor suppressors.(44) In particular, miR-21-5p exerts its oncogenic function predominantly through the inhibition of cellular apoptosis by targeting some important tumor suppressor genes including Fas ligand (FasL), pten, TAp63, and bax.”
BackgroundEshel, O., Shirak, A., Dor, L., Band, M., Zak, T., Markovich-Gordon, M., Caspi, V. C., Feldmesser, E., Weller, J. I., Seroussi, E., et al. (2014) · BMC Genomics · doi:10.1186/1471-2164-15-774 · Cited by 114
“[77] reported that mir-21 targets several genes in the TGF-β and apoptosis pathways.”
BackgroundNanoparticle-mediated intratumoral inhibition of miR-21 for improved survival in glioblastoma
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Foxo3a Regulates Apoptosis by Negatively Targeting miR-21
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MicroRNA Deregulations in Head and Neck Squamous Cell Carcinomas
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“A large number of target genes for miR-21 have been identified and experimentally confirmed, and most of them are established tumour suppressors (e.g., PTEN [41], PDCD4 [40], Tropomyosin [46], Sprouty 1 and 2 [47,48], Bcl2 [49], RECK [50], JAG1 [51], HNRPK [46], TGFBRII [52], P12/CDK2AP1 [53], MEF2C [54], RhoB [55] an…”
BackgroundmirConnX: condition-specific mRNA-microRNA network integrator
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“Among the highest ranking targets we predict for miR-21, SOX2 (39) and TGFB pathway (40) were shown to be regulated by the miRNA.”
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“Its overexpression has been linked to inhibition of apoptosis and promotion of cell proliferation (11, 14-16).”
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MicroRNAs and the resolution phase of inflammation in macrophages
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BackgroundEffect of miR-21 and miR-30b/c on TRAIL-induced apoptosis in glioma cells
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“In summary, it has been found that the expression of miR21 was associated with the pathological grade of glioma and the key roles for miR-21 in tumor-related pathways [16,42], apoptosis via PDCD4, caspase 9 and 3 [28–31], invasion via RECK and TIMP [21], chemosensitivity via Bax/Bcl-2 ratio, caspase-3, and LRRFIP1 [32…”
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“Particularly, since the miR-21-targeted genes identified till now are mostly tumor suppressors, miR-21 is closely related to various types of cancers including hepatocellular cancer [8], glioblastoma [9], glioma [10], and laryngeal carcinoma [11] and has been designated as an oncomir [12–14].”
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“The following direct targets have been experimentally validated: reversion-inducing cysteine-rich protein with kazal motifs [67], LRRFIPI [68], Tap63 [69], HNRPK [69], PDCD4 [70], PTEN [71], tropomyosin 1 [72], ras homolog gene family and member B [73], sprouty homolog 1/2 [74], Fas ligand [75], Cdc25a [76], B-cell tr…”
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“This has not been shown for the NF-κB pathway before, but has previously been seen in the transforming growth factor-β (TGF-β) pathway, where both miR-21 and the miR-1792 cluster target several mRNAs coding for proteins in the TGF-β pathway [51,52].”
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“Downregulation of miR-21 in glioblastoma cells leads to increased expression of p53 and activators of the p53 pathway, including JMY, TOPORS, TP53BPS and DAXX, leading to cell cycle arrest and apoptosis [27].”
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“In addition, mir-21 inhibition also permits increased expression of the ligands TGFB1 and TGFB2 and SMAD3 at the mRNA level (25).”
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“Downregulation of miR-21 in glioblastoma cells caused de-repression of these pathways, causing repression of growth, increased apoptosis, and cell-cycle arrest.(70) Several well-known glioma tumor-suppressor genes”
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MicroRNAs in the DNA Damage/Repair Network and Cancer
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“MiR-21 was already described to participate in a miRNA targeting a network including p53, TGF-beta, andmitochondrial apoptosis tumor suppressor genes in glioblastoma [88].”
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“miR-21 is highly enriched in EVs and is considered to be an oncogene, as it promotes tumor cell proliferation, migration, and invasiveness by targeting a number of tumor-suppressor genes, such as various components of the p53 network (43), PTEN (44), and antagonists of the RAS pathway PDCD4, BTG2, SPRY2, and others (4…”
BackgroundmiR-15b and miR-21 as Circulating Biomarkers for Diagnosis of Glioma
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“Other predicted targets include programmed cell death gene 4 (PDCD4), the phosphatase and tensin homolog tumor suppressor and reversioninducing cysteine-rich precursor with Kazal motifs [31, 34].”
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The Roles of MicroRNAs in the Cancer Invasion-Metastasis Cascade
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Antiangiogenic Therapy and Mechanisms of Tumor Resistance in Malignant Glioma
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MicroRNAs in cancer: Glioblastoma and glioblastoma cancer stem cells
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“Due to the known aberrant expression of microRNAs in cancer, and data suggesting a significant role for these microRNAs in stem cells, normal and cancer, various studies have demonstrated the presence of microRNA aberrations in GBM and GBM cancer stem cells (Chan et al., 2005; Ciafre et al., 2005; Luan et al., 2010; P…”
BackgroundMethodInfluentialInduction of miR-21 by Retinoic Acid in Estrogen Receptor-positive Breast Carcinoma Cells
Terao, M., Fratelli, M., Kurosaki, M., Zanetti, A., Guarnaccia, V., Paroni, G., Tsykin, A., Lupi, M., Gianni’, M., Goodall, G. J., et al. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.184994 · Cited by 91
Bekenstein, U., & Soreq, H. (2012) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2012.12.002 · Cited by 91
Using microRNA Networks to Understand Cancer
Dragomir, M. P., Mafra, A. C. P., Dias, S. M. G., Vasilescu, C., & Călin, G. A. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19071871 · Cited by 93
“For example, the identification of miR-21 as being one of the key players of tumorigenesis in glioblastoma, and how it mainly acts by the identification of its targets [84].”
BackgroundMicroRNA-21's role in PTEN suppression and PI3K/AKT activation: Implications for cancer biology
Chawra, H. S., Agarwal, M., Mishra, A., Chandel, S. S., Singh, R. P., Dubey, G., Kukreti, N., & Singh, M. (2024) · Pathology - Research and Practice · doi:10.1016/j.prp.2024.155091 · Cited by 91
MicroRNA expression signatures of stage, grade, and progression in clear cell RCC
Gowrishankar, B., Ibragimova, I., Zhou, Y., Slifker, M. J., Devarajan, K., Al‐Saleem, T., Uzzo, R. G., & Cairns, P. (2013) · Cancer Biology & Therapy · doi:10.4161/cbt.27314 · Cited by 90
“miR-21 has been shown to target tumor suppressor genes including the PTEN pathway, the RAS pathway through PDCD4,(18) and the p53 network.(19) miR-142-3p is not as well studied; however, using a mouse model of cancer, Olson et al.”
BackgroundDeng, J., Deng, H., Liu, C., Liang, Y., & Wang, S. (2017) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2017.12.031 · Cited by 91
Wang, L., Yao, J., Shi, X., Hu, L., Li, Z., Song, T., & Huang, C. Y. (2013) · BMC Cancer · doi:10.1186/1471-2407-13-448 · Cited by 88
“themselves have been demonstrated to serve as tumor suppressor genes or oncogenes in tumors [13-15].”
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Extracellular vesicles shed by glioma cells: pathogenic role and clinical value
Chistiakov, D. A., & Chekhonin, V. P. (2014) · Tumor Biology · doi:10.1007/s13277-014-2262-9 · Cited by 87
Role of microRNAs in gliomagenesis: targeting miRNAs in glioblastoma multiforme therapy
Nikaki, A. V., Piperi, C., & Papavassiliou, A. G. (2012) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.2012.710199 · Cited by 84
“that mir-21 targets are factors associated with TGF-b, mitochondrial apoptosis and p53 in GBM [55].”
BackgroundQuantitative Prediction of miRNA-mRNA Interaction Based on Equilibrium Concentrations
Ragan, C., Zuker, M., & Ragan, M. A. (2011) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1001090 · Cited by 84
The role of P63 in cancer, stem cells and cancer stem cells
Nekulová, M., Holčáková, J., Coates, P. J., & Vojtěšek, B. (2011) · Cellular & Molecular Biology Letters · doi:10.2478/s11658-011-0009-9 · Cited by 84
“miR-21 knockdown increases the protein level of TAp63 in glioblastoma cells [167], and it can therefore be a part of the molecular mechanism of its oncogenic function.”
BackgroundDEAD-box RNA helicase DDX23 modulates glioma malignancy via elevating miR-21 biogenesis
Yin, J., Park, G., Lee, J. E., Choi, E. Y., Park, J. Y., Kim, T. H., Park, N., Jin, X. J., Jung, J.-E., Shin, D., et al. (2015) · Brain · doi:10.1093/brain/awv167 · Cited by 85
“…cell line by guest on S eptem ber 3, 2015 D ow nloaded from were largely similar to the miR-21-mediated phenotypes, such as cell proliferation and invasion, previously observed by our group and others (Gabriely et al., 2008; Papagiannakopoulos et al., 2008; Kim et al., 2011; Kwak et al., 2011).”
BackgroundResultInfluentialZhang, Y., Fan, K., Sun, Q., Chen, A., Shen, W., Zhao, Z., Zheng, X., & Yang, X. Y. (2012) · Nucleic Acids Research · doi:10.1093/nar/gks667 · Cited by 82
Role of microRNAs in glioblastoma
Chen, M., Medarova, Z., & Moore, A. (2021) · Oncotarget · doi:10.18632/oncotarget.28039 · Cited by 84
“Additional targets include P53, TGF-β, and the mitochondrial apoptotic pathways [78, 89, 90].”
BackgroundExosomes as Tools to Suppress Primary Brain Tumor
Katakowski, M., & Chopp, M. (2016) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-015-0280-9 · Cited by 81
“Numerous reports indicate the potential of miRNA for treatment of brain tumor as miRNA-based therapies produce uniquely potent anti-tumor effects due to their actions on multiple oncogenic pathways (Gabriely et al. 2011; Iorio and Croce 2012a; Papagiannakopoulos et al. 2008).”
BackgroundmicroRNAs in Gliomas: Small Regulators of a Big Problem
Silber, J., James, C. D., & Hodgson, J. (2009) · NeuroMolecular Medicine · doi:10.1007/s12017-009-8087-9 · Cited by 80
“In one study, a network of predicted miR-21 key tumor-suppressive targets was constructed in silico leading to the identification of three distinct tumorsuppressive networks regulated by p53, TGF-beta, and the mitochondria apoptosis pathways (Papagiannakopoulos et al. 2008).”
BackgroundCosta, P. M., Cardoso, A. L., Nóbrega, C., Pereira de Almeida, L. F., Bruce, J. N., Canoll, P., & Pedroso de Lima, M. C. (2013) · Human Molecular Genetics · doi:10.1093/hmg/dds496 · Cited by 80
“MiR-21 has also been shown to target multiple components of important apoptosis-related pathways, including p53, TGF-b and mitochondrial apoptosis (29).”
BackgroundmicroRNA-21 Governs TORC1 Activation in Renal Cancer Cell Proliferation and Invasion
Dey, N., Das, F., Ghosh‐Choudhury, N., Mandal, C. C., Parekh, D. J., Block, K. L., Kasinath, B. S., Abboud, H. E., & Choudhury, G. G. (2012) · PLoS ONE · doi:10.1371/journal.pone.0037366 · Cited by 81
Rapid fluorescence imaging of miRNAs in human cells using templated Staudinger reaction
Gorska, K. I., Keklikoglou, I., Tschulena, U., & Winssinger, N. (2011) · Chemical Science · doi:10.1039/c1sc00216c · Cited by 79
The evolving understanding of microRNA in bladder cancer
Guancial, E. A., Joaquim Bellmunt, B., Yeh, S., et al. (2013) · Urologic Oncology Seminars and Original Investigations · doi:10.1016/j.urolonc.2013.04.014 · Cited by 78
“[17] also discovered that miR-21, which down-regulates the p53 pathway in glioblastoma cells [18], and miR-373, which promotes prometastatic pathways in multiple tumor types [19], were among the most up-regulated in MIBC.”
Nedaeinia, R., Sharifi, M., Avan, A., Kazemi, M., Rafiee, L., Ghayour‐Mobarhan, M., & Salehi, R. (2016) · Cancer Gene Therapy · doi:10.1038/cgt.2016.25 · Cited by 78
MicroRNAs and head and neck cancer: Reviewing the first decade of research
Sethi, N., Wright, A. I., Wood, H. M., & Rabbitts, P. H. (2014) · European Journal of Cancer · doi:10.1016/j.ejca.2014.07.012 · Cited by 82
Ou, H., Li, Y., & Kang, M. (2014) · PLoS ONE · doi:10.1371/journal.pone.0109929 · Cited by 79
MicroRNA-21: a ubiquitously expressed pro-survival factor in cancer and other diseases
Li, S., Liang, Z., Liu, X., & Zou, F. (2011) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-011-1052-6 · Cited by 78
“Laryngeal carcinoma [ 69 ] MARCKS Regulator of cell adhesion , cell spreading , membrane trafficking and cell motility Prostate cancer [ 70 ] TIAM Suppression of migration and invasion Colorectal cancer [ 71 ] LRRFIP1 Suppression of cell survival and proliferation Glioblastoma [ 72 ] RhoB Suppression of cell prolifera…”
InfluentialEvaluation of Plasma miR-21 and miR-152 as Diagnostic Biomarkers for Common Types of Human Cancers
Chen, H., Liu, H., Zou, H., Chen, R., Dou, Y., Sheng, S., Dai, S., Ai, J., Melson, J. E., Kittles, R. A., et al. (2016) · Journal of Cancer · doi:10.7150/jca.12351 · Cited by 76
MicroRNA-21 Identified as Predictor of Cancer Outcome: A Meta-Analysis
Zhu, W., & Xu, B. (2014) · PLoS ONE · doi:10.1371/journal.pone.0103373 · Cited by 75
“Altogether, the vital cellular pathways regulating cell proliferation, apoptosis and cell cycle such as Ras [47], p53 [48], PI3K-Akt-mTOR pathway [49], as well as target genes compose an intricate network of mir-21 modulation.”
BackgroundMomen‐Heravi, F., & Bala, S. (2018) · Oncotarget · doi:10.18632/oncotarget.26208 · Cited by 74
“In accordance with in silico analyses, miR-21 is shown to modulate various genes involved in p53/TGFβ/apoptotic/ SMAD pathways [31] and in immunity [32].”
MethodWang, J., Li, Y., Wang, X., et al. (2012) · Basic & Clinical Pharmacology & Toxicology · doi:10.1111/j.1742-7843.2012.00870.x · Cited by 75
Interaction of the oncogenic miR-21 microRNA and the p53 tumor suppressor pathway
Ma, X., Choudhury, S. N., Xiang, H., Dai, Z., & Li, Y. (2013) · Carcinogenesis · doi:10.1093/carcin/bgt044 · Cited by 76
“Downregulation of miR-21 in glioblastoma cells leads to elevated expression of p63 and activators of the p53 pathway, including JMY, TOPORS, TP53BP2 and DAXX, causing cell cycle arrest and increasing apoptosis (27).”
BackgroundKrishnan, P., Ghosh, S., Wang, B., Heyns, M., Graham, K., Mackey, J. R., Kovalchuk, O., & Damaraju, S. (2016) · PLoS ONE · doi:10.1371/journal.pone.0162622 · Cited by 75
LINC00470 Coordinates the Epigenetic Regulation of ELFN2 to Distract GBM Cell Autophagy
Liu, C., Fu, H., Liu, X., Lei, Q., Zhang, Y., She, X., Liu, Q., Liu, Q., Sun, Y., Li, G., et al. (2018) · Molecular Therapy · doi:10.1016/j.ymthe.2018.06.019 · Cited by 75
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“Regarding the mechanism of action, miR-21 could effect a variety of cellular and molecular pathways such as insulin-like growth factor (IGF)-binding protein-3 (IGFBP3) RECK, TIMP3, MMP, and PDCD4 [46,47,49].”
BackgroundThe Role of microRNA-21 in the Onset and Progression of Cancer
Singh, A. K., Singh, A. K., Giri, R., Kumar, D., Sharma, R., Vališ, M., Kuča, K., & Garg, N. (2021) · Future Medicinal Chemistry · doi:10.4155/fmc-2021-0096 · Cited by 81
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“miR-21 is thought to act as an oncogene in part by repressing expression of a range of tumor suppressor genes related to metastasis, proliferation, and apoptosis (8, 9).”
BackgroundBenigni, M., Ricci, C., Jones, A. R., Giannini, F., Al‐Chalabi, A., & Battistini, S. (2016) · NeuroMolecular Medicine · doi:10.1007/s12017-016-8396-8 · Cited by 78
“In particular, miR21-5p and miR-15b have been described as oncomirs, since they work as oncogenes and their overexpression leads to tumour growth, inhibiting the expression of tumour suppressor genes (Papagiannakopoulos et al. 2008; Pang et al. 2015).”
BackgroundMicroRNAs regulate mitochondrial apoptotic pathway in myocardial ischemia-reperfusion-injury
Makhdoumi, P., Roohbakhsh, A., & Karimi, G. (2016) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2016.10.073 · Cited by 72
The role of microRNA in the pathogenesis of glial brain tumors
Beylerli, O., Фанилевич, Г. И., Sufianov, A. A., Ilyasova, T., & Zhang, F. (2022) · Non-coding RNA Research · doi:10.1016/j.ncrna.2022.02.005 · Cited by 72
“These effects are partially mediated by a decrease in target repression, including heterogeneous nuclear ribonucleoprotein K (HNRPK), TAP63 and PDCD4 (Programmed cell death 4) [9,10].”
BackgroundAnanta, J. S., Paulmurugan, R., & Massoud, T. F. (2015) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.5b00694 · Cited by 74
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miRNA Multiplayers in glioma. From bench to bedside
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“In addition, miR-21 also confers survival and cell cycle arrest via p53-mediated and mitochondrial apoptotic pathways in part via direct regulation of HNRPK and Tap63, a p53 homologue (Papagiannakopoulos et al., 2008).”
BackgroundInvolvement of miRNAs in the Differentiation of Human Glioblastoma Multiforme Stem-Like Cells
Aldaz, B., Sagardoy, A., Nogueira, L., Guruceaga, E., Grande, L., Huse, J. T., Aznar, M. A., Díez-Valle, R., Tejada-Solís, S., Alonso, M. M., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0077098 · Cited by 71
“Indeed, miR-21 has shown a widespread involvement in the inhibition of tumor suppressor genes in GBM cells, targeting multiple components of the p53, transforming growth factor-β (TGF-β) and mitochondrial apoptosis pathways [44].”
BackgroundMalhotra, M., Sekar, T. V., Ananta, J. S., Devulapally, R., Afjei, R., Babikir, H. A., Paulmurugan, R., & Massoud, T. F. (2018) · Oncotarget · doi:10.18632/oncotarget.25135 · Cited by 71
“The endogenous levels of miR-21 and miR-10b are elevated in GBM cells [12], and studies that have targeted these miRNAs using antisense oligonucleotides have disrupted the oncogenic properties of these cells [15, 26, 27].”
BackgroundMicro RNA s and lymphomagenesis: a functional review
Lawrie, C. H. (2012) · British Journal of Haematology · doi:10.1111/bjh.12157 · Cited by 71
Expression and clinical significance of microRNA-326 in human glioma miR-326 expression in glioma
Wang, S., Lu, S., Geng, S., Ma, S., Liang, Z., & Jiao, B. (2013) · Medical Oncology · doi:10.1007/s12032-012-0373-y · Cited by 70
“[8] in 2005 both identified miR-21 as an antiapoptotic factor that targeted a network of p53, transforming growth factor (TGF)b, and mitochondrial apoptosis tumor suppressor genes in glioblastoma cells; Godlesski et al.”
BackgroundPaolini, A., Curti, V., Pasi, F., Mazzini, G., Nano, R., & Capelli, E. (2015) · International Journal of Oncology · doi:10.3892/ijo.2015.2864 · Cited by 68
“hsa-miR-21-5p negatively regulates the expression of p21 protein in the p53 network (30), and hsa-miR-421, is a miRNA that downregulates the ataxia telangiectasia mutated (aTM) gene expression inducing changes at S-phase level of cell cycle checkpoint and an increasing of sensitivity to ionizing radiation (31,32).”
BackgroundThe role of MiRNA-21 in gliomas: Hope for a novel therapeutic intervention?
Aloizou, A.-M., Pateraki, G., Siokas, V., Mentis, A.-F. A., Liampas, I., Lazopoulos, G., Kovatsi, L., Mitsias, P. D., Bogdanos, D. P., Paterakis, K., et al. (2020) · Toxicology Reports · doi:10.1016/j.toxrep.2020.11.001 · Cited by 69
“also exposed cells either with or without miR-21 overexpression, to different concentrations of DOX and reported that cells expressing miR-21 did not respond to treatment, even at higher doses [130].”
BackgroundInfluential
Metadata
- Authors
- Papagiannakopoulos, T., Shapiro, A., & Kosik, K. S.
- Affiliations
- University of California, Santa Barbara (US)
- 1Neuroscience Research Institute and
- Venue
- Cancer Research
- Published
- 2008-09-30
- Volume
- 68
- Issue
- 19
- Pages
- 8164-8172
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2111990378
- Semantic Scholar
- 85ace315e035f7501d4a149af358dd774fa2d616
- Cited by
- 705
- References
- 45
- Citations by year
- 2026: 13 · 2025: 13 · 2024: 18 · 2023: 14 · 2022: 24 · 2021: 29 · 2020: 31 · 2019: 32 · 2018: 36 · 2017: 30 · 2016: 53 · 2015: 55 · 2014: 52 · 2013: 72 · 2012: 79
- FWCI
- 15.56
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- W. M. Keck Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- miR-21, glioblastoma, miRNA target genes, p53 pathway, TGF-beta signaling, mitochondrial apoptosis, tumor suppressor pathways, TAp63, cell proliferation, apoptosis, cell cycle arrest, oncogenes
- MeSH terms
- Cell Cycle, Glioblastoma, HeLa Cells, Humans, Models, Biological, Tumor Cells, Cultured, Signal Transduction, Genes, Tumor Suppressor, Genes, p53, Transforming Growth Factor beta, Apoptosis, Gene Targeting, RNA, Small Interfering, MicroRNAs, Cell Proliferation, Genes, Mitochondrial, Gene Regulatory Networks
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