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]
AI snapshot
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.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
5 of 26 cited sources checked · 2 supported · 0 flagged · accuracy not yet measured
- Premisecitation
In glioblastomas, significant effects of miRNAs occur indirectly rather than by direct targeting.
“These data are also consistent with findings in glioblastomas that significant effects of miRNAs occur indirectly rather than by direct targeting (24,43).”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [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. source
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)
Experimental — accuracy not yet measured - cites [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. source
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)
Experimental — accuracy not yet measured
- Premisecitation
SERPINB5 is a transcriptional target of the functional convergence of p53 and TGF-h pathways.
“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).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [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
- Findingreasoning
Down-regulation of miR-21 in glioblastoma cells causes repression of growth.
“Down-regulation of miR-21 in glioblastoma cells leads to derepression of these pathways, causing repression of growth, increased apoptosis, and cell cycle arrest.”
Quote in the paperSubstantial claim - Findingown data
Upon down-regulation of miR-21 with LNA in U251 cells, mRNA levels of major components of the p53/TGF-B/apoptotic pathways increase significantly, ranging from 2-fold to 16-fold.
“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).”
Quote in the paperSubstantial claim - Findingcitation
p53 pathway predicted targets of miR-21 include TP73L (TAp63) and activating cofactors JMY, TOPORS, HNRPK, and TP53BP2.
“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).”
Quote in the paperSubstantial claim
- Findingcitation
PDCD4 increases approximately 8-fold upon miR-21 knockdown.
“In addition, PDCD4, which is involved in mediating TGFh-induced apoptosis, increased f8-fold (35).”
Quote in the paperSubstantial claim - Findingown data
Mitochondrial apoptosis genes APAF1, PPIF, and caspase-3 (CASP3) are up-regulated in response to miR-21 down-regulation.
“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).”
Quote in the paperSubstantial claim - Findingreasoning
Transactivation targets of p53, including IGFBP3, TNSFRSF10B, NOXA, p21 (CDKN1A), and GADD45A, are increased upon miR-21 knockdown.
“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).”
Quote in the paperSubstantial claim - Findingown data
The p53 pathway is derepressed to a great extent in response to miR-21 knockdown.
“The p53 pathway was derepressed to a great extent in response to miR-21 knockdown.”
Quote in the paperSubstantial claim - Findingown data
The phenotypes caused by miR-21 down-regulation are dependent on HNRPK and TAp63.
“These phenotypes are dependent on two of the miR-21 targets validated in this study, HNRPK and TAp63.”
Quote in the paperSubstantial claim - Findingown data
Several genes within the TGF-B pathway, including TGFBR2, TGFBR3, and DAXX, are predicted targets of miR-21.
“Several genes within this TGF-h pathway were predicted targets of miR-21, including TGFBR2, TGFBR3, and DAXX.”
Quote in the paperSubstantial claim - Findingcitation
Mitochondrial-apoptotic pathway genes predicted as miR-21 targets include APAF1, caspase-8, VDAC1, and PPIF.
“The mitochondrial-apoptotic pathway genes included important apoptotic inducers, such as APAF1, caspase-8, and proteins that control mitochondria permeability and cytochrome c release, such as VDAC1 and PPIF (29).”
Quote in the paperSubstantial claim - Findingown data
TGF-B pathway genes, including receptors TGFBR2/TGFBR3, ligands TGFB1/TGFB2, DAXX, and SMAD3, show significant changes in levels upon miR-21 knockdown.
“We observed significant changes in the levels of many TGF-h pathway genes, including receptors TGFBR2/TGFBR3, their ligands TGFB1/TGFB2, DAXX, and the transcription factor SMAD3, which is activated in response to TGFB1/2 binding to the receptors (Fig. 2B).”
Quote in the paperSubstantial claim - Findingreasoning
Down-regulation of miR-21 in glioblastoma cells causes cell cycle arrest.
“Down-regulation of miR-21 in glioblastoma cells leads to derepression of these pathways, causing repression of growth, increased apoptosis, and cell cycle arrest.”
Quote in the paperSubstantial claim - Findingown data
miR-21 targets multiple important components of the p53, TGF-B, and mitochondrial apoptosis tumor-suppressive pathways.
“In this study, we show for the first time that miR-21 targets multiple important components of the p53, transforming growth factor-B (TGF-B), and mitochondrial apoptosis tumor-suppressive pathways.”
Quote in the paperSubstantial claim - Findingown data
Several p53 cofactors and activators (JMY, TP53BP2, HNRPK, TOPORS) and p53 and its homologues TP73L (TAp63) and TP73 are up-regulated upon miR-21 knockdown.
“Several p53 cofactors and activators, JMY, TP53BP2, HNRPK, and TOPORS, which are predicted targets of miR-21, increased significantly in addition to up-regulation of p53 and its other two homologues, TP73L (TAp63) and TP73.”
Quote in the paperSubstantial claim - Findingown data
miR-21 predicted targets form three distinct networks in the interactome, including genes from the TGF-B, p53, and mitochondrial apoptotic pathways.
“Interestingly, we observed that there were three distinct networks in the interactome, which included genes from the TGF-h, p53, and mitochondrial apoptotic pathway (Fig. 1).”
Quote in the paperSubstantial claim - Findingreasoning
Down-regulation of miR-21 in glioblastoma cells causes increased apoptosis.
“Down-regulation of miR-21 in glioblastoma cells leads to derepression of these pathways, causing repression of growth, increased apoptosis, and cell cycle arrest.”
Quote in the paperSubstantial claim - Findingown data
Among the TGF-B pathway transcripts, only TGFBR2, TGFBR3, and DAXX are predicted targets of miR-21.
“From these transcripts, only the two receptors and DAXX are predicted targets of miR-21.”
Quote in the paperNot a substantial claim - Findingown data
Down-regulation of miR-21 in glioblastoma cells leads to derepression of the p53, TGF-B, and mitochondrial apoptosis 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.”
Quote in the paperSubstantial claim - Findingown data
On transfection of LNA-miR-21 into U251 cells, protein levels of each target examined increased 2-fold to 3-fold.
“On transfection of LNA-miR-21 into U251 cells, we observed the expected 2-fold to 3-fold increase in protein level of each target examined (Fig. 4A).”
Quote in the paperSubstantial claim - Findingown data
SERPINB5 is the transcript most highly up-regulated in response to miR-21 knockdown.
“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).”
Quote in the paperNot a substantial claim - Findingown data
The miR-21 targets identified included p63, JMY, TOPORS, TP53BP2, DAXX, and HNRPK.
“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).”
Quote in the paperSubstantial claim - Findingown data
The study identified miR-21 targets in p53, TGF-h, and mitochondrial apoptosis pathways in glioblastoma cells.
“In this study, we have addressed the mechanisms by which miR-21 contributes to the transformed state of glioblastoma cells by identifying targets in important tumor-suppressive pathways, such as p53, TGF-h, and mitochondrial apoptosis.”
Quote in the paperSubstantial claim - Findingown data
Transfection of LNA-miR-21 in U251 and U87 cells increases Annexin V levels 1.5-fold to 2-fold after 24 and 48 hours, respectively, compared with LNA-scrambled.
“On transfection of LNA-miR-21 in U251 and U87 cells, we observed 1.5-fold to 2-fold increase in the levels of an early marker of apoptosis, Annexin V, after 24 and 48 hours, respectively, compared with the negative control LNA-scrambled (Fig. 5A).”
Quote in the paperSubstantial claim - Findingown data
siRNA against TAp63 or HNRPK decreases Annexin V induction by approximately 25% in LNA-miR-21-treated U251 cells.
“There was f25% decrease in Annexin V induction in siRNA-TAp63 and siRNA-HNRPK-treated cells (Fig. 5B).”
Quote in the paperSubstantial claim - Findingown data
Negative control LNA-scrambled and mock did not show any significant growth difference.
“The negative control LNA-scrambled and mock did not show any significant growth difference, suggesting that the LNA treatment itself does not affect growth.”
Quote in the paperSubstantial claim - Findingown data
Ectopic overexpression of miR-21 in HeLa cells significantly decreases the levels of APAF1, DAXX, TAp63 (TP73L), and TGFBR2 compared with empty vector.
“Upon ectopic overexpression of miR-21 by a lentiviral system, we observed significant decreases in the levels of APAF1, DAXX, TAp63 (TP73L), and TGFBR2 compared with the empty vector negative control.”
Quote in the paperSubstantial claim - Findingown data
In U251 cells, miR-21 knockdown increased cells arrested at G0-G1 by 21% with nocodazole synchronization and 25% with doxorubicin synchronization.
“For U251 cells, we observed a 21% and 25% increase in cells arrested at G 0 -G 1 with nocodazole and doxorubicin synchronization, respectively, in the cells where miR-21 was knocked down (Fig. 6B and Supplementary Fig. S2B).”
Quote in the paperSubstantial claim - Findingcitation
No changes in p53 or p21 levels were detected upon miR-21 overexpression in HeLa cells.
“However, we did not detect any changes in p53 or its downstream target p21, which could potentially be explained due to the effect of HPV-E6, a viral antigen that inhibits p53 dissociation from MDM2 (37).”
Quote in the paperNot a substantial claim - Findingown data
2'-O-Me-miR-21 treatment causes a significantly smaller increase in apoptotic cells compared with LNA-miR-21.
“Additionally, we looked at the effect of 2 ¶-O-Me-mir-21 treatments on the levels of Annexin V; however, the increase of apoptotic cells in this case was significantly less when compared with the effect of LNA-miR-21 (Supplementary Fig. S2A).”
Quote in the paperSubstantial claim - Findingown data
miR-21 knockdown increases protein levels of p53 (Ser15).
“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).”
Quote in the paperSubstantial claim - Findingown data
The paper's mRNA, protein, and luciferase data indicate broad dysregulation of many important tumor-suppressive genes with known effects on cellular growth.
“Our mRNA, protein, and luciferase data indicate a broad dysregulation of many important tumor-suppressive genes with known effects on cellular growth.”
Quote in the paperSubstantial claim - Findingown data
miR-21 knockdown significantly suppressed growth of U251 and U87 cells compared with negative controls, LNA-scrambled, and mock.
“Interestingly, we observed a significant suppression in growth of cells in which miR-21 was knocked down compared with negative controls, LNA-scrambled, and the mock (Fig. 6A).”
Quote in the paperSubstantial claim - Findingown data
Addition of LNA-miR-21 (50 nmol/L) caused a significant increase in the population of cells in G0-G1 phase compared with LNA-scr treatments in both U251 and U87 cells.
“Addition of LNA-miR-21 (50 nmol/L) caused a significant increase in the population of cells in G 0 -G 1 phase compared with LNA-scr treatments in both U251 and U87 cells (Fig. 6B).”
Quote in the paperSubstantial claim - Findingcitation
miR-21 knockdown significantly increased apoptotic cells.
“When miR-21 levels were decreased, we observed a significant increase in apoptotic cells, as has been previously reported (6).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [6] Chan JA, Krichevsky AM, Kosik KS. MicroRNA-21 Is an antiapoptotic factor in human glioblastoma cells. Cancer Res 2005; 65: 6029–33. source
- Findingown data
Cotransfection with pre-miR-21, but not prescrambled sequence, specifically decreased luciferase levels of reporters containing 60-bp 3'UTR sequences of JMY, TGFBR2, TGFBR3, HNRPK, TP73L (TAp63), APAF1, BMPR2, TOPORS, DAXX, TP53BP2, and PPIF.
“Cotransfection with pre-miR-21, but not prescrambled sequence, specifically decreased luciferase levels of the reporter of JMY, TGFBR2, TGFBR3, HNRPK, TP73L (TAp63), APAF1, BMPR2, TOPORS, DAXX, TP53BP2, and PPIF (Fig. 3A-C).”
Quote in the paperSubstantial claim - Findingown data
The apoptotic and cell cycle phenotypes observed in the absence of miR-21 are partly dependent on HNRPK and TAp63.
“Both the apoptotic and cell cycle phenotypes, which we observed in the absence of miR-21, are partly dependent on two miR-21 targets, HNRPK and TAp63.”
Quote in the paperSubstantial claim- Rests on an assumption: 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.
- Findingown data
No change in luciferase levels was observed for IGFBP3.
“On the other hand, we did not observe a change in luciferase levels for IGFBP3.”
Quote in the paperNot a substantial claim - Findingown data
In the presence of siRNA-HNRPK and siRNA-TAp63, there was a 2-fold decrease in the proportion of cells arrested in G0-G1 in response to miR-21 down-regulation.
“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.”
Quote in the paperSubstantial claim- Rests on an assumption: 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.
- Premisecitation
PTEN is inactive in a large number of cancers where miR-21 is upregulated, including glioblastomas.
“PTEN, a well-studied tumor suppressor gene is inactive in a large number of cancers where miR-21 is upregulated, including glioblastomas (17,18).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [17] Li J, Yen C, Liaw D, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 1997; 275: 1943–7. source
- cites [18] Wang SI, Puc J, Li J, et al. Somatic mutations of PTEN in glioblastoma multiforme. Cancer Res 1997; 57: 4183–6.
- Premisecitation
miR-21 knockdown in glioblastoma cells significantly repressed tumor formation in vivo.
“Recently, a study determined that miR-21 knockdown in glioblastoma cells significantly repressed tumor formation in vivo (12).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [12] Corsten MF, Miranda R, Kasmieh R, Krichevsky AM, Weissleder R, Shah K. MicroRNA-21 knockdown disrupts glioma growth in vivo and displays synergistic cytotoxicity with neural precursor cell delivered S-TRAIL in human gliomas. Cancer Res 2007; 67: 8994–9000. source
- Interpretationown data
miR-21 is an important oncogene that targets a network of p53, TGF-B, and mitochondrial apoptosis tumor suppressor genes in glioblastoma cells.
“These findings establish miR-21 as an important oncogene that targets a network of p53, TGF-B, and mitochondrial apoptosis tumor suppressor genes in glioblastoma cells.”
Quote in the paperSubstantial claim - Interpretationown data
miR-21 is required for progression through the G0-G1 phase of the cell cycle in glioblastoma cells.
“These experiments show that miR-21 is required for progression through the G 0 -G 1 phase of the cell cycle in glioblastomas cells.”
Quote in the paperSubstantial claim- Rests on an assumption: U251 and U87 cell lines are representative models of glioblastoma for generalizing miR-21 function to glioblastoma.
- Interpretationown data
miR-21 plays an essential role in the proliferative capacity of glioblastoma cells.
“These results suggest that miR-21 plays an essential role in the proliferative capacity of glioblastoma cells.”
Quote in the paperSubstantial claim- Rests on an assumption: U251 and U87 cell lines are representative models of glioblastoma for generalizing miR-21 function to glioblastoma.
- Interpretationreasoning
By targeting p53-related genes, miR-21 can impair p53 response to stimuli such as DNA damage.
“These targets are required for p53 tumor-suppressive activity; therefore, by targeting these genes, miR-21 can impair p53 response to stimuli, such as DNA damage.”
Quote in the paperSubstantial claim - Interpretationown data
miR-21 acts as a suppressor of cell death in glioblastoma cells.
“The increased apoptosis confirmed that miR-21 is acting as a suppressor of cell death in glioblastoma cells.”
Quote in the paperSubstantial claim - Interpretationown data
The observed increase in TGF-h pathway components, in addition to p53, p21, and GADD45A, suggests potential modulation of cell growth in addition to apoptosis.
“The observed increase in TGF-h pathway components in addition to p53, p21, and GADD45A suggests a potential modulation of cell growth in addition to apoptosis (Figs. 2 and 4A).”
Quote in the paperSubstantial claim - Interpretationreasoning
Derepression of the p53 pathway in response to miR-21 downregulation may assist in derepression of the cytostatic response of TGF-h signaling, leading to cell cycle arrest and apoptosis.
“Derepression of the p53 pathway in response to miR-21 downregulation may assist in the derepression of the cytostatic response of TGF-h signaling, leading to cell cycle arrest and apoptosis.”
Quote in the paperSubstantial claim - Interpretationown data
A sufficient magnitude of decrease in miR-21 levels is necessary to cause significant phenotypic effects.
“Furthermore, the differential effect of 2 ¶O-Me-miR-21 and LNA-miR-21 indicated the necessity for a sufficient magnitude of decrease in miR-21 levels to cause significant phenotypic effects.”
Quote in the paperSubstantial claim - Interpretationown data
The phenotypic effects observed upon down-regulation of miR-21 in glioblastoma cells reflect significant repression of multiple components of the p53, TGF-h, and apoptotic pathways by miR-21.
“The phenotypic effects observed upon down-regulation of miR-21 in glioblastoma cells reflect the significant repression of multiple components of the p53, TGF-h, and apoptotic pathways by miR-21.”
Quote in the paperSubstantial claim - Interpretationcitation
Many of the transcripts identified may also be regulated by miR-21 in other types of cancer.
“This confirms that many of the transcripts we identified may also be regulated by miR-21 in other types of cancer.”
Quote in the paperNot a substantial claim - Interpretationreasoning
Regulation of p53-related targets by miR-21 may explain previous observations in breast cancer cells where p53-transactivated genes were up-regulated in response to miR-21 down-regulation.
“Regulation of these p53-related targets by miR-21 may potentially explain previous observations in breast cancer cells, where p53-transactivated genes were up-regulated in response to miR-21 down-regulation (15).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [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
- Interpretationown data
HNRPK and TAp63 are important targets for miR-21-mediated cell cycle progression.
“Therefore, HNRPK and TAp63 are important targets for miR-21-mediated cell cycle progression.”
Quote in the paperSubstantial claim- Rests on an assumption: 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.
- Interpretationown data
miR-21 dysregulation significantly changes the protein levels of its targets in both glioblastoma and cervical cancer cells.
“Taken together, miR-21 dysregulation significantly changes the protein levels of its targets in both glioblastoma and cervical cancer cells.”
Quote in the paperSubstantial claim - Interpretationreasoning
HNRPK and TAp63 play an essential role in the oncogenic function of miR-21.
“Both of these targets play an essential role in the oncogenic function of miR-21.”
Quote in the paperSubstantial claim- Rests on an assumption: 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.
- Interpretationown data
HNRPK and TAp63 are essential for the antiapoptotic function of miR-21.
“These results indicate that HNRPK and TAp63 are essential for the antiapoptotic function of miR-21.”
Quote in the paperSubstantial claim - Premisecitation
HNRPK is a coactivator of p53 in response to DNA damage, assisting in transactivation of p21 and GADD45A.
“HNRPK is a known coactivator of p53 in response to DNA damage, assisting in the transactivation of p21 and GADD45A (22).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [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
- Interpretationown data
The growth repression and cell cycle arrest caused by miR-21 down-regulation can be explained by up-regulation of p21.
“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.”
Quote in the paperSubstantial claim - Interpretationown data
LNA treatment itself does not affect growth.
“The negative control LNA-scrambled and mock did not show any significant growth difference, suggesting that the LNA treatment itself does not affect growth.”
Quote in the paperSubstantial claim - Interpretationreasoning
The inability of HNRPK and TAp63 knockdown to completely rescue the proapoptotic and cell cycle arrest phenotypes observed in the absence of miR-21 suggests that other critical miR-21 targets are involved in mediating miR-21 oncogenic phenotypes.
“However, the inability of their knockdown to completely rescue the proapoptotic and cell cycle arrest phenotypes, which are observed in the absence of miR-21, suggests that there are other critical miR-21 targets involved in mediating miR-21 oncogenic phenotypes.”
Quote in the paperSubstantial claim- Rests on an assumption: 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.
- Interpretationreasoning
miR-21 up-regulation may be a key step leading to oncogenesis in glioblastoma and other types of cancer.
“Our data suggest that miR-21 up-regulation may be a key step leading to oncogenesis in glioblastoma and other types of cancer.”
Quote in the paperSubstantial claim- Rests on an assumption: U251 and U87 cell lines are representative models of glioblastoma for generalizing miR-21 function to glioblastoma.
- Classified as probably not a substantial claim. 6
- May combine two claims. 21
Classified as probably not a substantial claim.
PremisecitationThree miR-21 targets have been described: PTEN, PDCD4, and TPM1.
“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].”
Quote in the paperSubstantial claim1 of 3 sources checked- cites [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. source
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)
Experimental — accuracy not yet measured - cites [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
- cites [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
Classified as probably not a substantial claim. May combine two claims.
PremisecitationTAp63 is a homologue of p53 and mediates both cell cycle arrest and apoptosis.
“TAp63 is a homologue of p53 and is known to mediate both cell cycle arrest and apoptosis (19,38).”
Quote in the paperSubstantial claim1 of 2 sources checkedMay combine two claims.
Findingown dataAPAF1 and PPIF are predicted targets of miR-21.
“APAF1 and PPIF are both predicted targets of miR-21 (Fig. 2C).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown datap53, DNA damage-activated p53 (Ser15), and p21 proteins increase upon miR-21 down-regulation, although they are not direct targets.
“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).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataIn U251 and U87 cells, miR-21 overexpression abolished the dose-dependent increase in caspase-3/7 activity in response to doxorubicin, whereas scrambled controls showed a dose-dependent increase.
“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).”
Quote in the paperSubstantial claim- Rests on an assumption: The p53 pathway is functional and can mediate apoptosis in the U251 and U87 cell lines used.
May combine two claims.
Findingown datamiR-21 regulates sets of genes, directly through targeting certain transcripts and indirectly in other cases.
“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.”
Quote in the paperSubstantial claimMay combine two claims.
FindingreasoningmiR-21 down-regulation significantly represses growth and leads to cell cycle arrest at G0-G1.
“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.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe growth suppression continued throughout the 4 days, with the most significant difference observed on day 3.
“This retarded growth continued throughout the 4 days with the most significant difference observed on day 3.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationHigh levels of miR-21 were first reported in glioblastoma tumors and cell lines.
“High levels of miR-21 were first reported in glioblastoma tumors and cell lines (6).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [6] Chan JA, Krichevsky AM, Kosik KS. MicroRNA-21 Is an antiapoptotic factor in human glioblastoma cells. Cancer Res 2005; 65: 6029–33. source
May combine two claims.
PremisecitationInhibition of miR-21 by LNA or 2'-O-Me-miR-21 led to increased caspase-dependent apoptosis in glioblastoma cells, suggesting miR-21 acts as an oncogene to inhibit apoptosis.
“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).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [6] Chan JA, Krichevsky AM, Kosik KS. MicroRNA-21 Is an antiapoptotic factor in human glioblastoma cells. Cancer Res 2005; 65: 6029–33. source
May combine two claims.
PremisecitationAPAF1, BMPR2, PDCD4, and p21 are up-regulated in MCF-7 breast cancer cells with LNA-miR-21 treatment.
“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).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [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
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationmiR-21 is up-regulated in the majority of human cancers profiled to date.
“The majority of these profiling studies have reported increased levels of miR-21 in most human cancers (6,(8)(9)(10).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [6] Chan JA, Krichevsky AM, Kosik KS. MicroRNA-21 Is an antiapoptotic factor in human glioblastoma cells. Cancer Res 2005; 65: 6029–33. source
- cites [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
- cites [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
May combine two claims.
InterpretationreasoningDAXX plays a role in both p53 and TGF-h pathways and may be a key target in disrupting crosstalk between the two pathways.
“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).”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown datamiR-21 repressed p53-mediated apoptosis in response to doxorubicin-induced DNA damage, thereby contributing to drug resistance in glioblastoma cells.
“MiR-21 repressed p53-mediated apoptosis in response to chemotherapeutic (doxorubicin)-induced DNA damage, therefore contributing to drug resistance in glioblastoma cells.”
Quote in the paperSubstantial claim- Rests on an assumption: The p53 pathway is functional and can mediate apoptosis in the U251 and U87 cell lines used.
May combine two claims.
Interpretationown datamiR-21 up-regulation in cancer cells is sufficient to inhibit p53-mediated apoptosis and protect cells from p53-mediated apoptosis in response to DNA damage induced by a chemotherapeutic agent.
“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.”
Quote in the paperSubstantial claim- Rests on an assumption: The p53 pathway is functional and can mediate apoptosis in the U251 and U87 cell lines used.
Classified as probably not a substantial claim. May combine two claims.
Premisecitationp53 phosphorylated at Ser15 occurs in response to DNA damage and can mediate cell cycle arrest at G0-G1 by transactivation of p21.
“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).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [19] Stiewe T. The p53 family in differentiation and tumorigenesis. Nat Rev Cancer 2007; 7: 165–7. source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationMany miRNAs have evolved to regulate multiple components of certain pathways, thereby mediating more effective negative regulation on those pathways.
“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).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [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
May combine two claims.
Premisecitationp53 activators JMY, TOPORS, TP53BP2, DAXX, and HNRPK can stabilize p53 protein levels by interfering with MDM2 and/or act as p53 transcriptional cofactors, assisting p53 in transactivating genes that induce apoptosis and growth arrest.
“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).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [21] Coutts AS, La Thangue NB. The p53 response: emerging levels of co-factor complexity. Biochem Biophys Res Commun 2005; 331: 778–85. source
- cites [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
- cites [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
May combine two claims.
InterpretationreasoningThe approach links putative targets around a function and identifies multiple targets and an entire network under miRNA control.
“Our approach links putative targets around a function and succeeds in identifying not only multiple targets but uncover an entire network under miRNA control.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningmiR-21 suppression of the p53 response may occur in most cancers where miR-21 is up-regulated, and this oncogenic mechanism may be a more significant contributor to malignancy in tumors with wild-type p53.
“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.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataResistance of gliomas to TGF-h may be partly due to miR-21 negative regulation of multiple TGF-h pathway components, including indirect regulation of TGFB1/2 and direct targeting of TGFBR2/3 and DAXX.
“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.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningmiR-21 acts as a key oncogene modulating cell growth, desensitizing cells to apoptosis and cell cycle arrest.
“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).”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningChanges in the level of miR-21 are likely to dampen the robustness of a highly interconnected tumor-suppressive network and result in global regulation or dysregulation of network functions.
“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.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown datamiR-21 is embedded in a nexus of tumor suppression genes and has multiple specific targets in the network that lead to the observed phenotypes.
“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.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationCancer cells survive only if the apoptotic response is dampened or disrupted, cell cycle checkpoints are evaded, and unrestricted cell proliferation occurs.
“Cancer cells therefore only survive if the apoptotic response is dampened or disrupted, cell cycle checkpoints are evaded, and unrestricted cell proliferation occurs (44).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [44] Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100: 57–70. source
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?
miR-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 [19]
The Introduction identifies PDCD4 as a miR-21 target, and the target-validation section calls it a known target; the results also link PDCD4 to TGF-β-induced apoptosis. Our copy does not identify TIMP3 or RECK as miR-21 targets or establish their roles in metastatic pathways. (LLM, conf=0.88)
Experimental — accuracy not yet measuredmiR-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 [19]
The Introduction (page unavailable) reports increased miR-21 in most human cancers, while the Abstract and miR-21 target validation section (pages unavailable) support a role in glioblastoma cell growth. The claim's stronger “almost all cancer types” wording is not established, and this paper does not report that miR-21 promotes invasion or metastatic behavior. (LLM, conf=0.88)
Experimental — accuracy not yet measuredOverexpressed 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 [19]
The MiR-21 target validation section reports that knocking down miR-21 suppressed growth in U251 and U87 glioblastoma cells, while overexpressing it protected those cells from drug-induced apoptosis. These findings support a role in proliferation and malignant behavior, but the paper does not show that overexpression itself increased the proliferation rate. (LLM, conf=0.85)
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 [13]
The MiR-21 target validation section reports direct-target evidence for HNRPK (the paper’s abbreviation for HNRNPK) and identifies PDCD4 as a known miR-21 target. The Discussion links HNRPK to tumor-suppressive activity, and the References identify PDCD4 as a tumor suppressor. Our copy does not establish RECK as a target or specifically identify the targets as miR-21-5p targets; no page numbers are available. (LLM, conf=0.87)
Experimental — accuracy not yet measuredmiR-21 has been shown to be a strong antiapoptotic factor.
“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]
miR-21 has been reported to be associated with GBM aggressiveness in previous studies.
“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.
Doxorubicin treatment starts at different times after transduction
MinorThe apoptosis assay methods say doxorubicin was added 24 hours after transduction, while the Figure 5 caption says it was added 48 hours after transduction.
“At 24 h later, three different concentrations 0/12.5/25/50Amol/L of doxorubicin were added to the cells.”
“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.”
Figure 6C cell-cycle assay timing conflicts with the methods
MinorThe results say nocodazole was added 24 hours after transfection and cells were harvested another 16 to 20 hours later. The Figure 6C caption instead says PI staining was performed 24 hours after transfection.
“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.”
“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.
Cites a retracted work: 10.1016/j.cell.2005.09.032
InfoThe cited work was retracted on 2024-10-31 (notice 10.1016/j.cell.2024.10.008), not before this paper was published (2008-09-30).
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
“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.”
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Convergence of p53 and TGF-beta signaling networks
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The p53 response: Emerging levels of co-factor complexity
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miRNAs as Biomarkers in Disease: Latest Findings Regarding Their Role in Diagnosis and Prognosis
Condrat, C. E., Thompson, D. C., Barbu, M. G., Bugnar, O. L., Boboc, A. E., Crețoiu, D., Suciu, N., Creţoiu, S. M., & Voinea, S. C. (2020) · Cells · doi:10.3390/cells9020276 · Cited by 1,357 · see citing works
MicroRNAs in Development and Disease
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“In agreement, knockdown of miR-21 results in activation of these pathways, cell cycle arrest, and apoptosis, plausibly through its validated targets, which include heterogeneous nuclear ribonucleoprotein K (HNRK), p53-related TAp63 (469), and PDCD4 (FIGURE 6), in glioblastoma cell lines (98).”
BackgroundMohr, A. M., & Mott, J. L. (2015) · Seminars in Liver Disease · doi:10.1055/s-0034-1397344 · Cited by 1,076 · see citing works
Therapeutic targeting of microRNAs: current status and future challenges
Li, Z., & Rana, T. M. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4359 · Cited by 1,028 · see citing works
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“miR-21 is upregulated in gliomas, as inhibition of miR-21 leads to apoptosis, limits invasion, represses cell growth, and is associated with chemosensitization (59,60).”
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
“also suggest the regulation of the TGF- pathway by miR-21 [97].”
BackgroundEpigenetic Alterations in Colorectal Cancer: Emerging Biomarkers
Okugawa, Y., Grady, W. M., & Goel, A. (2015) · Gastroenterology · doi:10.1053/j.gastro.2015.07.011 · Cited by 782 · see citing works
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“Furthermore, in glioblastoma cells, knockdown of miR-21 induced the activation of caspase-3, transforming growth factor–b, p53, and mitochondrial apoptotic pathways mainly through upregulation of its validated targets, heterogeneous nuclear ribonucleoprotein K, p53related TAp63, and PDCD4, acting in synergy with the a…”
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MicroRNA in Prostate, Bladder, and Kidney Cancer: A Systematic Review
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miR-21 as a key regulator of oncogenic processes
Selçuklu, S. D., Donoghue, M. T. A., & Spillane, C. (2009) · Biochemical Society Transactions · doi:10.1042/bst0370918 · Cited by 446 · see citing works
Cancer Development, Progression, and Therapy: An Epigenetic Overview
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“A knockdown study of glioblastoma cells exhibiting high miR-21 levels demonstrated that miR-21 controls p53-mediated apoptosis and cell growth and leads to cell cycle arrest [79].”
BackgroundApoptosis 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
Kim, Y. J., Hwang, S. J., Bae, Y. C., & Jung, J. S. (2009) · Stem Cells · doi:10.1002/stem.235 · Cited by 373 · see citing works
Garofano, L., Migliozzi, S., Oh, Y. T., D’Angelo, F., Najac, R. D., Ko, A., Frangaj, B., Caruso, F. P., Yu, K., Yuan, J., et al. (2021) · Nature Cancer · doi:10.1038/s43018-020-00159-4 · Cited by 363 · 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
“Our studies are consistent with a previous observation that showed a 21–25% increase in G1 phase in the U251 cell line by miR-21 knockdown.(30)”
BackgroundResultMalzkorn, B., Wolter, M., Liesenberg, F., Grzendowski, M., Stühler, K., Meyer, H. E., & Reifenberger, G. (2010) · Brain Pathology · doi:10.1111/j.1750-3639.2009.00328.x · Cited by 284 · see citing works
“Functional analyses of miR-21 revealed oncogenic properties caused by inhibition of the p53, transforming growth factor-b and mitochondrial apoptosis pathways (44).”
BackgroundShi, 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
“MiR-21, which was significantly elevated in glioblastoma and regulated multiple genes associated with cancer cell proliferation, apoptosis, and invasiveness, functioned as an antiapoptotic factor in cultured glioblastoma multiforme cells (Papagiannakopoulos et al., 2008).”
BackgroundDistinct MicroRNA Alterations Characterize High- and Low-Grade Bladder Cancer
Catto, J. W. F., Miah, S., Owen, H. C., Bryant, H. E., Myers, K. N., Dudziec, E., Larré, S., Milo, M., Rehman, I., Rosario, D. J., et al. (2009) · Cancer Research · doi:10.1158/0008-5472.can-09-0744 · Cited by 327 · see citing works
“Recent data reveal that miR-21 negatively regulates the p53 tumor suppressor pathway, leading to a loss of cellular control (25).”
Tomar, M. S., Kumar, A., Srivastava, C., & Shrivastava, A. (2021) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2021.188616 · Cited by 328 · see citing works
Bollati, V., Marinelli, B., Apostoli, P., Bonzini, M., Nordio, F., Hoxha, M., Pegoraro, V., Motta, V., Tarantini, L., Cantone, L., et al. (2010) · Environmental Health Perspectives · doi:10.1289/ehp.0901300 · Cited by 347 · see citing works
Zhang, Y., Wei, W., Cheng, N., Wang, K., Li, B., Jiang, X., & Sun, S. (2012) · Hepatology · doi:10.1002/hep.25849 · Cited by 300 · see citing works
MicroRNAs in resolution of acute inflammation: identification of novel resolvin Dl‐miRNA circuits
Recchiuti, A., Krishnamoorthy, S., Fredman, G., Chiang, N., & Serhan, C. N. (2011) · The FASEB Journal · doi:10.1096/fj.10-169599 · Cited by 292 · see citing works
Møller, 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
“ANP32Ad, SMARCA4, Caspases, PTEN, Cdc25A, HNRPK, TAp63, Spry2d, LRRFIP1, PDCD4 1:Invasiveness↑ [21–28, 30, 31, 35–55] 2: Invasiveness↓, Apoptosis↑, Viability↓, Proliferation↓, In vivo tumor volume↓, Chemosensitivity↑ Hsa-mir-23a [22–25, 35, 37, 52] Hsa-mir-25c Mdm2, TSC1 1:In vivo tumor volume↓ [22–26, 30, 101] Hsa-mi…”
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
Zhang, J., Yao, T., Wang, Y., Yu, J., Liu, Y., & Lin, Z. (2016) · Cancer Biology & Therapy · doi:10.1080/15384047.2015.1108496 · Cited by 305 · see citing works
The Warburg effect: Insights from the past decade
Upadhyay, M., Samal, J., Kandpal, M., Singh, O. V., & Vivekanandan, P. (2012) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2012.11.003 · Cited by 245 · see citing works
MicroRNA‐21 protects neurons from ischemic death
Buller, B., Liu, X., Wang, X., Zhang, R. L., Zhang, L., Hozeska‐Solgot, A., Chopp, M., & Zhang, Z. G. (2010) · The FEBS Journal · doi:10.1111/j.1742-4658.2010.07818.x · Cited by 242 · see citing works
Li, M., Lee, K. F., Lu, Y., Clarke, I. D., Shih, D. J. H., Eberhart, C. G., Collins, V. P., Meter, T. E. V., Picard, D. J., Zhou, L., et al. (2009) · Cancer Cell · doi:10.1016/j.ccr.2009.10.025 · Cited by 235 · see citing works
“Although miRNAs have been implicated in malignant gliomas (Papagiannakopoulos et al., 2008), their role in malignant pediatric brain tumors remains largely unexplored.”
BackgroundDevulapally, R., Sekar, N. M., Sekar, T. V., Foygel, K., Massoud, T. F., Willmann, J. K., & Paulmurugan, R. (2015) · ACS Nano · doi:10.1021/nn507465d · Cited by 260 · see citing works
New 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
“miR-21 targets multiple components of TP53, TGFB1, and mitochondrial apoptosis tumor suppressive pathways (including HNRPK and TP63) [306].”
BackgroundMicroRNA 21 Blocks Apoptosis in Mouse Periovulatory Granulosa Cells1
Carletti, M. Z., Fiedler, S. D., & Christenson, L. K. (2010) · Biology of Reproduction · doi:10.1095/biolreprod.109.081448 · Cited by 236 · see citing works
“Although many different cell types undergo apoptosis in response to inhibition of Mir21 action, the Mir21 targets implicated vary widely for different cells [34, 36].”
BackgroundResultInfluentialZhang, P., Cheng, F.-F., Zhou, R., Cao, J., Li, J., Burda, C., Min, Q., & Zhu, J. (2014) · Angewandte Chemie International Edition · doi:10.1002/anie.201308920 · Cited by 231 · see citing works
miR-21: an oncomir on strike in prostate cancer
Folini, M., Gandellini, P., Longoni, N., Profumo, V., Callari, M., Pennati, M., Colecchia, M., Supino, R., Veneroni, S., Salvioni, R., et al. (2010) · Molecular Cancer · doi:10.1186/1476-4598-9-12 · Cited by 229 · see citing works
“In several cancer cell lines highly expressing miR-21, its down-regulation by antisense oligomers resulted in growth suppression, induction of apoptosis and impairment of migration and invasion [5,10,20-27].”
BackgroundRen, 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.”
BackgroundCrosstalk between TGF-β signaling and the microRNA machinery
Butz, H., Rácz, K., Hunyady, L., & Patócs, A. (2012) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2012.04.003 · Cited by 215 · see citing works
The oncogenic and tumour suppressive roles of microRNAs in cancer and apoptosis
Babashah, S., & Soleimani, M. (2011) · European Journal of Cancer · doi:10.1016/j.ejca.2011.02.008 · Cited by 215 · see citing works
MicroRNA-21 targets LRRFIP1 and contributes to VM-26 resistance in glioblastoma multiforme
Li, Y., Li, W., Yang, Y., Lu, Y., He, C., Hu, G., Liu, H., Chen, J., He, J., & Yu, H. (2009) · Brain Research · doi:10.1016/j.brainres.2009.06.053 · Cited by 208 · see citing works
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Long 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
Yin, G., Chen, R., Alvero, A. B., Fu, H., Holmberg, J. C., Glackin, C. A., Rutherford, T., & Mor, G. (2010) · Oncogene · doi:10.1038/onc.2010.111 · Cited by 210 · see citing works
The role of microRNA in modulating myocardial ischemia-reperfusion injury
Ye, Y., Perez-Polo, J. R., Qian, J., & Birnbaum, Y. (2010) · Physiological Genomics · doi:10.1152/physiolgenomics.00130.2010 · Cited by 206 · see citing works
MicroRNAs 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
“AP- 1 induces miR- 21, which downregulates tumor suppressors PDCD4 and PTEN.”
BackgroundInfluentialA 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
Micro RNA s play a central role in molecular dysfunctions linking inflammation with cancer
Tili, E., Michaille, J., & Croce, C. M. (2013) · Immunological Reviews · doi:10.1111/imr.12050 · Cited by 207 · see citing works
“miR-21 oncogenicity comes from its targeting of tumor suppressors such as PTEN, PDCD4, components of the p53 pathway, or by modulating transforming growth factor-b (TGF-b) signaling, thus promoting cell proliferation, survival, and migration/invasion (2, 33).”
BackgroundXiong, 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
“…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 et al. 2009, 2011; Sabatel et al. 2011; Sheedy, 2015; Shi et al. 2013; Van Wynsberghe et al. 2011;…”
Identification 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
The TGF-β Paradox in Human Cancer: An Update
Tian, M., & Schiemann, W. P. (2009) · Future Oncology · doi:10.2217/14796694.5.2.259 · Cited by 196 · see citing works
“, Smad3, Daxx and programmed cell death 4 [PDCD4]) [135,136].”
BackgroundGuan, Y., Mizoguchi, M., Yoshimoto, K., Hata, N., Shono, T., Suzuki, S. O., Araki, Y., Kuga, D., Nakamizo, A., Amano, T., et al. (2010) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-10-0207 · Cited by 195 · see citing works
“MiR-21 is also a component in a network of key tumor-suppressive pathways in glioblastoma cells (40).”
BackgroundLi, Y., Kong, D., Wang, Z., & Sarkar, F. H. (2010) · Pharmaceutical Research · doi:10.1007/s11095-010-0105-y · Cited by 191 · see citing works
Costa, P. M., Cardoso, A. L., Custódia, C., Cunha, P. P., de Almeida, L. P., & de Lima, M. C. P. (2015) · Journal of Controlled Release · doi:10.1016/j.jconrel.2015.04.002 · Cited by 189 · see citing works
Synthetic circular RNA functions as a miR-21 sponge to suppress gastric carcinoma cell proliferation
Liu, X., Abraham, J. M., Cheng, Y., Wang, Z., Wang, Z., Zhang, G., Ashktorab, H., Smoot, D. T., Cole, R. N., Boronina, T. N., et al. (2018) · Molecular Therapy Nucleic Acids · doi:10.1016/j.omtn.2018.09.010 · Cited by 212 · see citing works
MicroRNAs: molecular features and role in cancer
Lages, E. (2012) · Frontiers in bioscience · doi:10.2741/4068 · Cited by 187 · see citing works
Pro-neural miR-128 is a glioma tumor suppressor that targets mitogenic kinases
Papagiannakopoulos, T. Y., Friedmann‐Morvinski, D., Neveu, P. A., Dugas, J. C., Gill, R. M., Huillard, E., Liu, C., Zong, H., Rowitch, D. H., Barres, B. A., et al. (2011) · Oncogene · doi:10.1038/onc.2011.380 · Cited by 188 · see citing works
“Cell lysis, protein quantitation and western blotting were performed as previously described (Papagiannakopoulos et al., 2008; Xu et al., 2009).”
MethodSelf-citationThe 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
“TGF-b, EGF, BMP2 and BMP4 induce the expression of miR-21 in a posttranscriptional step (Davis et al., 2008; Gabriely et al., 2008; Papagiannakopoulos et al., 2008); nevertheless, BMP6 inhibits miRNA-21 expression in breast cancer by repressing ZEB1 and AP-1 (Du et al.”
BackgroundMicroRNA-21 Modulates the Levels of Reactive Oxygen Species by Targeting SOD3 and TNF α
Zhang, X., Ng, W. L., Wang, P., Tian, L., Werner, E., Wang, H., Doetsch, P. W., & Wang, Y. (2012) · Cancer Research · doi:10.1158/0008-5472.can-12-0639 · Cited by 181 · see citing works
“The role of mir-21 in carcinogenesis is believed to be linked to the multiple targets of miR-21 such as PTEN, PDCD4 and TPM1 (5-9), however, the whole picture for miR-21-induced tumorigenesis remains unclear.”
InfluentialDownregulation 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
Genome-wide expression profiling identifies deregulated miRNAs in malignant astrocytoma
Rao, S. A., Santosh, V., & Somasundaram, K. (2010) · Modern Pathology · doi:10.1038/modpathol.2010.135 · Cited by 179 · see citing works
The Tumor Suppressors p53, p63, and p73 Are Regulators of MicroRNA Processing Complex
Boominathan, L. (2010) · PLoS ONE · doi:10.1371/journal.pone.0010615 · Cited by 178 · see citing works
“Interestingly, miR-21 has been shown to suppress the expression of TA-p63/p53 [5], indicating a feedback loop between DNp63/ p53/TA-p63/p73 and miR-21[Figure 1].”
BackgroundRippe, C., Blimline, M., Magerko, K. A., Lawson, B. R., LaRocca, T. J., Donato, A. J., & Seals, D. R. (2011) · Experimental Gerontology · doi:10.1016/j.exger.2011.10.004 · Cited by 176 · see citing works
“The decrease in miR-21, a miRNA with anti-apoptotic effects acting through caspase-3 (Papagiannakopoulos et al., 2008), likely contributed to the associated increases in apoptosis and caspase-3 observed in our senescent HAEC.”
Ren, Y. T., Kang, C., Yuan, X.-B., Zhou, X., Xu, P., Han, L., Wang, G. X., Jia, Z., Zhong, Y., Yu, S., et al. (2010) · Journal of Biomaterials Science Polymer Edition · doi:10.1163/156856209x415828 · Cited by 175 · see citing works
Munker, R., & Calin, G. A. (2011) · Clinical Science · doi:10.1042/cs20110005 · Cited by 174 · see citing works
MicroRNAs and the cancer phenotype: profiling, signatures and clinical implications
Stahlhut, C. E., & Slack, F. J. (2013) · Genome Medicine · doi:10.1186/gm516 · Cited by 174 · see citing works
“miR-21 has been identified as being upregulated in glioblastomas, and miR-21 knockdown in glioblastoma cell lines results in caspase activation and elevated apoptotic rates, indicating a pro-survival function for miR-21 [44-48].”
BackgroundMicroRNA signature in diabetic wound healing: promotive role of miR‐21 in fibroblast migration
Madhyastha, R., Madhyastha, H., Nakajima, Y., Omura, S., & Maruyama, M. (2012) · International Wound Journal · doi:10.1111/j.1742-481x.2011.00890.x · Cited by 168 · see citing works
Delayed ischemic preconditioning contributes to renal protection by upregulation of miR-21
Xu, X., Kriegel, A. J., Liu, Y., Usa, K., Mladinov, D., Liu, H., Fang, Y., Ding, X., & Liang, M. (2012) · Kidney International · doi:10.1038/ki.2012.241 · Cited by 171 · see citing works
Linnstaedt, S. D., Gottwein, E., Skalsky, R. L., Luftig, M. A., & Cullen, B. R. (2010) · Journal of Virology · doi:10.1128/jvi.01248-10 · Cited by 189 · see citing works
“at high levels in LCLs (Table 1) and has previously been associated with tumorigenesis (1, 29, 34).”
BackgroundMicroRNAs as gatekeepers of apoptosis
Subramanian, S., & Steer, C. J. (2010) · Journal of Cellular Physiology · doi:10.1002/jcp.22066 · Cited by 168 · see citing works
miR-145-mediated suppression of cell growth, invasion and metastasis.
Sachdeva, M., & Mo, Y. (2010) · PubMed Central · Cited by 169 · see citing works
MicroRNA in Glioblastoma: An Overview
Banelli, B., Forlani, A., Allemanni, G., Morabito, A., Pistillo, M. P., & Romani, M. (2017) · International Journal of Genomics · doi:10.1155/2017/7639084 · Cited by 167 · see citing works
MicroRNA-21 is involved in osteosarcoma cell invasion and migration
Wu, Z., Shuhua, Y., Xiufang, W., et al. (2010) · Medical Oncology · doi:10.1007/s12032-010-9563-7 · Cited by 165 · see citing works
“[25] confirmed that miR-21 targeted a network of p53, TGF-b, and mitochondrial apoptosis tumor suppressor gene and caused repression of growth, increased apoptosis, and cell cycle arrest in glioblastoma cells.”
BackgroundHuang, G., Nishimoto, K., Zhou, Z., Hughes, D. P. M., & Kleinerman, E. S. (2011) · Cancer Research · doi:10.1158/0008-5472.can-11-1460 · Cited by 164 · see citing works
“Different miRNAs have also been implicated in regulating the expression of Fas, including miR-21 in glioblastoma, miR-200c in NCI60 cells, and miR-146a in mesenchymal cells (18-20).”
BackgroundDysregulation of MicroRNAs in cancer
Chen, P., Su, J.-L., & Hung, M. (2012) · Journal of Biomedical Science · doi:10.1186/1423-0127-19-90 · Cited by 163 · see citing works
“indicated that knockdown of miR-21 activates the p53 pathway, mediates the induction of TGF-β signaling, and eventually suppresses cell growth, increases apoptosis, and induces cell cycle arrest in glioblastoma cells [20].”
BackgroundMicroRNAs and cancer stem cells: the sword and the shield
Sun, X., Jiao, X., Pestell, T. G., Fan, C., Qin, S., Mirabelli, E., Ren, H., & Pestell, R. G. (2013) · Oncogene · doi:10.1038/onc.2013.492 · Cited by 162 · see citing works
Gwak, H., Kim, T. H., Jo, G. H., Kim, Y., Kwak, H., Kim, J. H., Yin, J., Yoo, H., Lee, S. H., & Park, J. B. (2012) · PLoS ONE · doi:10.1371/journal.pone.0047449 · Cited by 155 · see citing works
“miR-21 has been demonstrated to target a network of key tumor-suppressor molecules [14].”
BackgroundLakomý, R., Šáňa, J., Hankeová, S., Fadrus, P., Křen, L., Lžičařová, E., Svoboda, M., Doleželová, H., Smrčka, M., Vyzula, R., et al. (2011) · Cancer Science · doi:10.1111/j.1349-7006.2011.02092.x · Cited by 155 · see citing works
MicroRNA-21 targets tumor suppressor genes ANP32A and SMARCA4
Schramedei, K., Mörbt, N., Pfeifer, G., Läuter, J., Rosołowski, M., Tomm, J. M., von Bergen�, M., Horn, F., & Brocke-Heidrich, K. (2011) · Oncogene · doi:10.1038/onc.2011.15 · Cited by 155 · see citing works
“To date, experimentally confirmed targets include multiple tumor suppressive components of the p53, TGF-b and mitochondrial apoptosis pathways (Papagiannakopoulos et al., 2008), as well as tumor suppressors PDCD4 (Asangani et al.”
BackgroundMelkamu, T., Zhang, X., Tan, J., Zeng, Y., & Kassie, F. (2009) · Carcinogenesis · doi:10.1093/carcin/bgp208 · Cited by 152 · see citing works
miRNAs and cancer: An epigenetics view
Malumbres, M. (2012) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2012.06.005 · Cited by 152 · see citing works
“…cells, miR-21 functions as an anti-apoptotic factor and this role is at least partially due to the repression of a highly interconnected tumor suppressor network that includes multiple components of the p53, TGFβ and apoptotic pathways (Chan et al., 2005; Papagiannakopoulos et al., 2008).”
BackgroundCurrent Progress on Understanding MicroRNAs in Glioblastoma Multiforme
Karsy, M., Arslan, E., & Moy, F. (2012) · Genes & Cancer · doi:10.1177/1947601912448068 · Cited by 151 · see citing works
“miR-21 has been shown to target multiple proteins of the p53, transforming growth factor-β (TGF-β), and mitochondrial apoptosis pathways.(50) This study also showed that miR-21 downregulation increased GBM apoptosis, reduced chemotherapeutic resistance to doxorubicin, decreased cell proliferation, and increased G0/G1…”
BackgroundDai, X., & Tan, C. (2014) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2014.09.010 · Cited by 148 · see citing works
Aigner, A. M. (2011) · Journal of Molecular Medicine · doi:10.1007/s00109-010-0716-0 · Cited by 146 · see citing works
Loss of miR-204 Expression Enhances Glioma Migration and Stem Cell-like Phenotype
Ying, Z., Li, Y., Wu, J., Zhu, X., Yang, Y., Tian, H., Li, W., Hu, B., Cheng, S., & Li, M. (2012) · Cancer Research · doi:10.1158/0008-5472.can-12-2895 · Cited by 146 · see citing works
“As documented previously, miRNAs up-regulated in gliomas, including miR-21 (17-19), miR-9 (20, 21) and miR-10b, were also screened out.”
BackgroundErnst, A., Campos, B., Meier, J., Devens, F., Liesenberg, F., Wolter, M., Reifenberger, G., Herold-Mende, C., Lichter, P., & Radlwimmer, B. (2010) · Oncogene · doi:10.1038/onc.2010.83 · Cited by 126 · see citing works
microRNA Replacement Therapy for Cancer
Henry, J. C., Azevedo‐Pouly, A. C. P., & Schmittgen, T. D. (2011) · Pharmaceutical Research · doi:10.1007/s11095-011-0548-9 · Cited by 144 · see citing works
“growth factor-β (TGF-β) pathways in glioblastoma cells (38).”
BackgroundMicroRNA involvement in glioblastoma pathogenesis
Nováková, J., Slabý, O., Vyzula, R., & Michálek, J. (2009) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2009.06.034 · Cited by 141 · see citing works
“This way, miR-21 regulates apoptosis, cell cycle and translation miR-21 can impair p53 response to stimuli such as DNA damage [14].”
BackgroundInfluentialMicroRNA in Cervical Cancer: OncomiRs and Tumor Suppressor miRs in Diagnosis and Treatment
Banno, K., Iida, M., Yanokura, M., Kisu, I., Iwata, T., Tominaga, E., Tanaka, K., & Aoki, D. (2014) · The Scientific World JOURNAL · doi:10.1155/2014/178075 · Cited by 143 · see citing works
Uncovering MicroRNA and Transcription Factor Mediated Regulatory Networks in Glioblastoma
Sun, J., Gong, X. Q., Purow, B. W., & Zhao, Z. (2012) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1002488 · Cited by 142 · see citing works
Modulation of microRNA editing, expression and processing by ADAR2 deaminase in glioblastoma
Tomaselli, S., Galeano, F., Alon, S., Raho, S., Galardi, S., Polito, V. A., Presutti, C., Vincenti, S., Eisenberg, E., Locatelli, F., et al. (2015) · Genome biology · doi:10.1186/s13059-014-0575-z · Cited by 144 · see citing works
“miR-21 is involved in cell proliferation and cell migration [36].”
BackgroundMicroenvironmental regulation of cancer metastasis by miRNAs
Zhang, Y., Yang, P., & Wang, X. (2013) · Trends in Cell Biology · doi:10.1016/j.tcb.2013.09.007 · Cited by 138 · see citing works
MicroRNA-21 in Glomerular Injury
Lai, J. Y., Luo, J., O'Connor, C. L., Jing, X., Nair, V., Ju, W., Randolph, A. E., Ben‐Dov, I. Z., Matar-Ujvary, R., Briskin, D., et al. (2014) · Journal of the American Society of Nephrology · doi:10.1681/asn.2013121274 · Cited by 139 · see citing works
How theTP53Family ProteinsTP63andTP73Contribute to Tumorigenesis: Regulators and Effectors
Candi, E., Agostini, M., Melino, G., & Bernassola, F. (2014) · Human Mutation · doi:10.1002/humu.22523 · Cited by 137 · see citing works
“Remarkably, the cell cycle arrest phenotype elicited by miR-21 downregulation in glioblastoma cells, is, at least partially, dependent on TATP63 [Papagiannakopoulos et al., 2008].”
BackgroundRynkeviciene, R., Simiene, J., Strainiene, E., Stankevicius, V., Usinskiene, J., Miseikyte Kaubriene, E., Meskinyte, I., Cicenas, J., & Suziedelis, K. (2018) · Cancers · doi:10.3390/cancers11010017 · Cited by 136 · see citing works
“Another study showed that CASC2 is a target of miR-21 [43], which is frequently overexpressed in tumor cells [135] and takes part in stimulation of proliferation, migration and invasion processes possibly through p53 pathway [136].”
BackgroundLet-7 microRNA inhibits the proliferation of human glioblastoma cells
Lee, S.-T., Chu, K., Oh, H.-J., Im, W., Lim, J., Kim, S.-K., Park, C.-K., Jung, K.-H., Lee, S.-K., Kim, M., et al. (2011) · Journal of Neuro-Oncology · doi:10.1007/s11060-010-0286-6 · Cited by 138 · see citing works
Radiation-Induced Micro-RNA Modulation in Glioblastoma Cells Differing in DNA-Repair Pathways
Chaudhry, M. A., Sachdeva, H., & Omaruddin, R. A. (2010) · DNA and Cell Biology · doi:10.1089/dna.2009.0978 · Cited by 131 · see citing works
“It is suggested that miR-21 acts as an oncogene that targets a network of p53, transforming growth factor-b, and mitochondrial apoptosis tumor suppressor genes in glioblastoma cells (Papagiannakopoulos et al., 2008).”
MiR-21: an environmental driver of malignant melanoma?
Melnik, B. C. (2015) · Journal of Translational Medicine · doi:10.1186/s12967-015-0570-5 · Cited by 129 · see citing works
“Noteworthy, STAT3 stimulates the expression of miR-21 [30, 40, 117].”
BackgroundFeedback regulation of TGF-β signaling
Yan, X., Xiong, X., & Chen, Y. (2017) · Acta Biochimica et Biophysica Sinica · doi:10.1093/abbs/gmx129 · Cited by 127 · see citing works
“TβRII Human glioblastoma cells [172] miR-23a Up Smad2 Human hepatocellular carcinoma [178] Smad3 Smad4 miR-26a Down Smad4 Mouse lung fibroblasts and MRC-5 cells [179] miR-98 Down TβRI Human cardiac fibroblasts [180] miR-132 Up Smad7 Human Glioma cells [181] miR-143 Up Smad3 Human NSCLC A549 cells [182] miR-146a Down S…”
BackgroundMicroRNAs and Cellular Phenotypy
Kosik, K. S. (2010) · Cell · doi:10.1016/j.cell.2010.09.008 · Cited by 123 · see citing works
“…diverse mRNAs that collectively control apoptosis and proliferation, and the dysregulation of miR-21 is associated with many types of cancer (Papagiannakopoulos et al., 2008). miRNAs, including nonhomologous miRNAs, are often physically clustered in the genome, and these sets of miRNAs may…”
BackgroundSelf-citation
- 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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