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Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo
Open accessAbstract
MicroRNAs (miRNAs) are small, noncoding RNAs that play a critical role in developmental and physiological processes and are implicated in the pathogenesis of several human diseases, including cancer. They function by regulating target gene expression post-transcriptionally. In this study, we examined the role of oncogenic mir-21 in the pathogenesis of glioblastoma, the most aggressive form of primary brain tumor. We have previously reported that mir-21 is expressed at higher levels in primary glioblastoma-tissue and glioblastoma-derived cell lines than in normal brain tissue. We demonstrate that downregulation of mir-21 in glioblastoma-derived cell lines results in increased expression of its target, programmed cell death 4 (Pdcd4), a known tumor-suppressor gene. In addition, our data indicate that either downregulation of mir-21 or overexpression of its target, Pdcd4, in glioblastoma-derived cell lines leads to decreased proliferation, increased apoptosis, and decreased colony formation in soft agar. Using a glioblastoma xenograft model in immune-deficient nude mice, we observe that glioblastoma-derived cell lines in which mir-21 levels are downregulated or Pdcd4 is over-expressed exhibit decreased tumor formation and growth. Significantly, tumors grow when the glioblastoma-derived cell lines are transfected with anti-mir-21 and siRNA to Pdcd4, confirming that the tumor growth is specifically regulated by Pdcd4. These critical in vivo findings demonstrate an important functional linkage between mir-21 and Pdcd4 and further elucidate the molecular mechanisms by which the known high level of mir-21 expression in glioblastoma can attribute to tumorigenesis--namely, inhibition of Pdcd4 and its tumor-suppressive functions.
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TL;DR
In glioblastoma-derived cell lines and primary tumors, high miR-21 is inversely associated with the tumor suppressor Pdcd4; inhibiting miR-21 or overexpressing Pdcd4 reduces proliferation, increases apoptosis, and suppresses anchorage-independent growth. In nude-mouse xenografts, anti-miR-21 or Pdcd4 overexpression reduces tumor growth, and siRNA against Pdcd4 reverses the anti-miR-21 effect, supporting Pdcd4 as a key mediator.
Key findings
- miR-21 was elevated in all 7 glioblastoma-derived cell lines and all 13 glioblastoma tumors examined, while Pdcd4 protein was undetectable in primary glioblastoma tissues and cell lines compared with normal brain. Anti-miR-21 transfection increased Pdcd4 protein at 24, 48, and 72 hours.
- Anti-miR-21 treatment decreased proliferation, increased TUNEL-positive apoptosis, increased G0/G1 and decreased S-phase fraction, and reduced soft-agar colony formation by 65% (10 mM anti-miR-21) and 75% (30 mM anti-miR-21) in 3 independent experiments; U251 and U87 cells treated with anti-miR-21 formed 70% and 60% fewer colonies, respectively.
- Pdcd4 overexpression increased apoptosis and decreased colony formation. Anti-miR-21 plus Pdcd4 siRNA restored colony numbers similar to untreated controls; cells treated with anti-miR-21 and Pdcd4 siRNA produced 85% of the colonies seen with anti-miR-21 alone.
- In xenografts, anti-miR-21 reduced tumor growth by 30% at day 30 (P = .01); Pdcd4 overexpression produced a 90% decrease (P = .001) or complete lack of tumor growth. In 5 independent xenograft experiments, only 5 of 24 U251 GFP+Pdcd4 and 6 of 24 U87 GFP+Pdcd4 mice developed detectable tumors by day 30, and these were on average 90% smaller. Anti-miR-21 plus Pdcd4 siRNA tumors grew comparably to controls, reaching 1.5 cm³ by day 30. Pdcd4 was undetectable in 4 individual tumors arising from Pdcd4-overexpressing lines.
Methods
- Glioblastoma-derived cell lines SNB19, U251, U87, and SF767 were used with primary glioblastoma and normal brain samples. Stable Pdcd4-expressing polyclonal and monoclonal cultures were derived; transient transfections used anti-miR-21, negative/toxicity control, and Pdcd4 siRNA. Assays included Northern blot, Western blot, stem-loop real-time PCR, proliferation counts, TUNEL apoptosis, cell-cycle flow cytometry, and soft-agar colony formation.
- Xenografts used female 4–6-week-old Nude-Foxn1 nu mice injected subcutaneously in the flank with 5 × 10⁶ cells. Tumor size was measured in 3 dimensions, volume calculated as ellipsoid, and tumors imaged with the IVIS 200 Xenogen system. Data were from 5 independent xenograft experiments (total n = 24 animals per condition); statistics used unpaired two-tailed Student t test with P < .05, and experiments were performed at least 3 times.
Limitations
- Stated: xenografts were not of sufficient size to analyze DNA, RNA, and protein, so only Pdcd4 protein was measured. The authors note that rare cells may escape Pdcd4 inhibition through altered transgene integration or epigenetic inactivation, and small tumors from anti-miR-21-treated cells may arise from untransfected cells. They also note miR-21 can target several genes; anti-miR-21 plus Pdcd4 siRNA still produced 85% of colonies compared with anti-miR-21 alone, suggesting additional miR-21 targets.
- Evident: the in vivo work uses subcutaneous xenografts in immune-deficient nude mice rather than orthotopic or patient-derived models, and no survival or clinical outcome data are reported. Transfection efficiency was 80%–90%, leaving potential untransfected cells in treated populations.
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51 Own result · 32 Sources not found · 13 Own interpretation · 3 Own method · 1 No basis given
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In the paper
“Also, TUNEL staining revealed enhanced apoptosis in U251 (Fig. 3B) and U87 cells (data not shown) treated with anti-mir-21, compared with cells cultured in either medium alone or with NS control.”
§ Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo > Inhibiting mir-21 expression in glioblastoma-derived cell lines results in decreased proliferation, increased apoptosis, and diminished anchorage-independent growth
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Western blot analyses of nuclear proteins isolated from these same U251 and U87 cultures exhibited increased Pdcd4 protein levels 24, 48, and 72 h after anti-mir-21 treatment (Fig. 2B, lanes 3 -5 and 8-10, respectively).”
§ Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo > Down Regulation of mir-21 Expression in Glioblastoma-Derived Cell Lines Results in Enhanced Pdcd4 Expression
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Increased apoptosis in U87 cells treated with anti-mir-21 or stably over expressing Pdcd4 (U87 Pdcd4 ) was also observed (data not shown).”
§ Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo > Inhibiting mir-21 expression in glioblastoma-derived cell lines results in decreased proliferation, increased apoptosis, and diminished anchorage-independent growth
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
“The U251 Pdcd4 polyclonal cell culture showed a decrease in colony number compared to cells that did not have elevated Pdcd-4 levels.”
§ Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo > Inhibiting mir-21 expression in glioblastoma-derived cell lines results in decreased proliferation, increased apoptosis, and diminished anchorage-independent growth
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
“In addition, our data indicate that either downregulation of mir-21 or overexpression of its target, Pdcd4, in glioblastomaderived cell lines leads to decreased proliferation, increased apoptosis, and decreased colony formation in soft agar.”
- Also stated in: § Inhibiting mir-21 expression in glioblastoma-derived cell lines results in decreased proliferation, increased apoptosis, and diminished anchorage-independent growth · plain
“Also, TUNEL staining revealed enhanced apoptosis in U251 (Fig. 3B) and U87 cells (data not shown) treated with anti-mir-21, compared with cells cultured in either medium alone or with NS control.”
§ Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo > Abstract
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.
- Also stated in: § Inhibiting mir-21 expression in glioblastoma-derived cell lines results in decreased proliferation, increased apoptosis, and diminished anchorage-independent growth · plain
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 demonstrate that downregulation of mir-21 in glioblastoma-derived cell lines results in increased expression of its target, programmed cell death 4 (Pdcd4), a known tumor-suppressor gene.”
- Also stated in: § Down Regulation of mir-21 Expression in Glioblastoma-Derived Cell Lines Results in Enhanced Pdcd4 Expression · plain
“Western blot analyses of nuclear proteins isolated from these same U251 and U87 cultures exhibited increased Pdcd4 protein levels 24, 48, and 72 h after anti-mir-21 treatment (Fig. 2B, lanes 3 -5 and 8-10, respectively).”
§ Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo > Abstract
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Down Regulation of mir-21 Expression in Glioblastoma-Derived Cell Lines Results in Enhanced Pdcd4 Expression · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In addition, our data indicate that either downregulation of mir-21 or overexpression of its target, Pdcd4, in glioblastomaderived cell lines leads to decreased proliferation, increased apoptosis, and decreased colony formation in soft agar.”
- Also stated in: § Inhibiting mir-21 expression in glioblastoma-derived cell lines results in decreased proliferation, increased apoptosis, and diminished anchorage-independent growth · plain
“We observed decreased cell numbers in cultures treated with anti-mir-21, compared with cultures that were incubated in regular media or transfected with a nonspecific negative toxicity control (Fig. 3A).”
§ Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo > Abstract
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.
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- Also stated in: § Inhibiting mir-21 expression in glioblastoma-derived cell lines results in decreased proliferation, increased apoptosis, and diminished anchorage-independent growth · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In addition, our data indicate that either downregulation of mir-21 or overexpression of its target, Pdcd4, in glioblastomaderived cell lines leads to decreased proliferation, increased apoptosis, and decreased colony formation in soft agar.”
- Also stated in: § Inhibiting mir-21 expression in glioblastoma-derived cell lines results in decreased proliferation, increased apoptosis, and diminished anchorage-independent growth · plain
“The U251 Pdcd4 polyclonal cell culture showed a decrease in colony number compared to cells that did not have elevated Pdcd-4 levels.”
§ Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo > Abstract
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.
- Also stated in: § Inhibiting mir-21 expression in glioblastoma-derived cell lines results in decreased proliferation, increased apoptosis, and diminished anchorage-independent growth · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In addition, our data indicate that either downregulation of mir-21 or overexpression of its target, Pdcd4, in glioblastomaderived cell lines leads to decreased proliferation, increased apoptosis, and decreased colony formation in soft agar.”
§ Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo > Abstract
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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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
“Clonal isolates and a polyclonal culture of U251 overexpressing Pdcd-4, U251 Pdcd4 demonstrated increased spontaneous apoptosis, as determined by TUNEL staining, compared with the parental cells from which they were derived (Fig. 3B and C).”
§ Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo > Inhibiting mir-21 expression in glioblastoma-derived cell lines results in decreased proliferation, increased apoptosis, and diminished anchorage-independent growth
plaindirect- Asserted: passes — The authors put it forward as true.
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- It may state two separate claims as one. 15
- Probably not a substantial claim. 19
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 decreased numbers of colonies formed by U87 cells that were treated with anti-mir-21 or stably over-expressed Pdcd4 (U87 Pdcd4 ) (Fig. 4B).”
§ Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo > Inhibiting mir-21 expression in glioblastoma-derived cell lines results in decreased proliferation, increased apoptosis, and diminished anchorage-independent growth
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
“Subcutaneous injection of 5 × 10 6 cells from U251 GFP or U87 GFP in the flank of immunosuppressed mice gave rise to tumors that were first palpable by day 7 after injection and that developed to 1.5 cm 3 in size by day 30.”
§ Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo > Downregulation of mir-21 or Overexpression of Pdcd4 Results in Reduction of Glioblastoma Xenograft Growth that is Reversed by siRNA to Pdcd4
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
“High cellularity and microvascular prolifer- ation (Supplemental Fig. S1) and the presence of necrosis (Supplemental Fig. S2), all of which are defining features of glioblastoma, are evident in these tumors.”
§ Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo > Downregulation of mir-21 or Overexpression of Pdcd4 Results in Reduction of Glioblastoma Xenograft Growth that is Reversed by siRNA to Pdcd4
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In these in vivo experiments mice that received cell lines overexpressing Pdcd4 showed a substantial decrease in tumor size and/or complete ablation of tumor growth (Fig. 5A).”
§ Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo > Discussion
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In the paper
“In addition to being a pro-apoptotic gene, Pdcd4 is a suppressor of malignant transformation and tumor progression and has been shown to inhibit invasion and intravasation by tumor cells.16,22 -25”
§ Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo > Downregulation of mir-21 or Overexpression of Pdcd4 Results in Reduction of Glioblastoma Xenograft Growth that is Reversed by siRNA to Pdcd4
What the sources say
- Not matchedcites [16]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [22]
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boosteddirect- Asserted: passes — The authors put it forward as true.
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- Not matched
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“We routinely achieved 80% -90% transfection efficiency.”
§ Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo > Down Regulation of mir-21 Expression in Glioblastoma-Derived Cell Lines Results in Enhanced Pdcd4 Expression
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“MiR-21 has been identified as one of the most commonly overexpressed miRNAs in solid tumors.9,10”
§ Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo > M
What the sources say
- Not matchedcites [9]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [10]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Glioblastomas are the most malignant brain tumors of glial origin.21,28”
§ Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo > Discussion
What the sources say
- Not matchedcites [21]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [28]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“Previous work in our laboratory 8 and by others 9 -14 has demonstrated that miR-21 is a member of a class of miRNAs that are frequently overexpressed in solid tumors and may contribute to oncogenesis.”
§ Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo > Discussion
What the sources say
- Not matchedcites [8]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [9]
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- Not matchedcites [13]
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- Not matchedcites [14]
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hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Not matched
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“Low levels of mir-21 are expressed in grade II and grade III gliomas, whereas higher levels are observed in glioblastoma.13,15”
§ Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo > M
What the sources say
- Not matchedcites [13]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [15]
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plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Not matched
In the paper
“because mir-21 can potentially target several genes, 11”
§ Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo > Inhibiting mir-21 expression in glioblastoma-derived cell lines results in decreased proliferation, increased apoptosis, and diminished anchorage-independent growth
What the sources say
- Not matchedcites [11]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
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What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All of the experiments were performed at least 3 times.”
§ Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo > Statistical Analysis
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“They are also among the most resistant of all human tumors to available modalities of treatment, perhaps because of their genetic heterogeneity and invasiveness.28”
§ Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo > Discussion
What the sources say
- Not matchedcites [28]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
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In the paper
“In glioblastoma, mir-21 is overexpressed, and its expression correlates with glioma grade.8,10 -15”
§ Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo > M
What the sources say
- Not matchedcites [8]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [10]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [11]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [12]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [13]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [14]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [15]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Not matched
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
“Mice that received U251 GFP or U87 GFP lines after transfection with anti-mir-21 and siRNA to PDCD4 significantly gave rise to tumors that were comparable to the untreated controls (Fig. 5A and 5C), confirming that the tumor growth is specifically regulated by PDCD4 and represents a crucial functional linkage between mir-21 and PDCD4 in vivo.”
§ Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo > Discussion
boosteddirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“Negative regulation of Pdcd4 by mir-21 has recently been demonstrated in glioblastoma and in several other tumors.41 -44”
§ Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo > Discussion
What the sources say
- Not matchedcites [41]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [42]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [43]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [44]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
boosteddirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
- Not matched
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“Pdcd4, a described target of mir-21, 16 -18 has been characterized as both a tumor suppressor 16,21 -25 and a pro-apoptotic gene that may function by binding eukaryotic initiation factor 4A (eIF4A) and inhibiting translation initiation.38 -40”
§ Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo > Discussion
What the sources say
- Not matchedcites [38]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [39]
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- Not matchedcites [40]
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hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Not matched
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“Elevated expression of miR-21 has been documented in several different types of cancer including those arising in breast, 9,16 brain, 11 -15 prostate, 29 ovaries, 30,31 colon, 32 and pancreas, 33 as well as cervical carcinoma, 34 hepatocellular carcinoma, 35 chronic lymphocytic leukemia, 36 and acute myeloid leukemia.37”
§ Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo > Discussion
What the sources say
- Not matchedcites [9]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [16]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [11]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [12]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [13]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [14]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [15]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [29]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
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.
- Not matched
In the paper
“Although an additional major pathway of Pdcd4 inactivation is the increased proteasomal degradation of Pdcd4 due to its phosphorylation by Akt and p70(S6K), 46 our findings provide strong evidence that, by inhibition of Pdcd4 by mir-21, over-expression contributes to glioblastoma growth.”
§ Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo > Discussion
What the sources say
- Not matchedcites [46]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“This is similar to the antiapoptotic activity of mir-21 in hepatocellular carcinoma where mir-21 has been shown to downregulate PTEN, initiate caspase activity, and lead to decreased apoptosis.35,45”
§ Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo > Discussion
What the sources say
- Not matchedcites [35]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [45]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Not matched
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
“However, our data suggest that, along with suppression of Pdcd4's pro-apoptotic function, downregulation of its tumor-suppressive activity also contributes to the oncogenic role of mir-21.”
§ Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“The anti-apoptotic activity for mir-21 in glioblastoma lines that we observed is consistent with previously published data.11,12”
§ Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo > Discussion
What the sources say
- Not matchedcites [11]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [12]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
In the paper
“For example, miR-21 has been shown to inhibit apoptosis by regulating Bcl-2 in murine breast cancer model 49,50 and to inhibit gemcitabine-induced apoptosis by modulating PTEN and the PI3K pathway.51”
§ Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo > Discussion
What the sources say
- Not matchedcites [51]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Data are representative of 5 independent xenograft experiments (total n ¼ 24 animals per condition).”
- Also stated in: § Discussion · plain
“Data are averages of 5 independent xenograft experiments (total n ¼ 24 animals per condition) + SEM.”
§ Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo > Discussion
plainn = 24- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Also stated in: § Discussion · plain
In the paper
“Consistent with this idea is the observation that mir-21 regulation of 2 important matrix metalloproteinase inhibitors, RECK and TIMP3, may be of importance in vivo.13”
§ Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo > Discussion
What the sources say
- Not matchedcites [13]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgedconditional- 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.
- Not matched
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 finding that high levels of Pdcd4 expression inhibited tumor growth suggests that inhibiting Pdcd4 degradation or enhancing its expression may be a therapeutic strategy of importance for glioblastoma.”
§ Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“For example, miR-21 has been shown to inhibit apoptosis by regulating Bcl-2 in murine breast cancer model 49,50 and to inhibit gemcitabine-induced apoptosis by modulating PTEN and the PI3K pathway.51”
§ Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo > Discussion
What the sources say
- Not matchedcites [49]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [50]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
The paper relies on this without support.
The effect of mir-21 regulation of Pdcd4 on specific biological activities (apoptosis, proliferation, anchorage-independent growth, or in vivo growth of glioblastoma xenografts) has not been studied.
“However, the effect of mir-21 regulation of Pdcd4 on specific biological activities of pathologic potential (eg, apoptosis, proliferation, anchorage-independent growth, or more significantly, in vivo growth of glioblastoma xenografts) has, to our knowledge, not been studied.”
The paper relies on this without support.
Anchorage-independent growth in soft agar correlates closely with tumorigenicity of transformed cells.
“Anchorage-independent growth assayed in soft agar is a characteristic of transformed cells that correlates closely with their tumorigenicity.”
The paper relies on this without support.
The effect of mir-21/Pdcd4 regulation on specific biological activities, such as apoptosis, proliferation, or anchorage-independent growth, has not been studied.
“Although mir-21 has been shown to regulate Pdcd4 in glioblastoma, 18 the effect of mir-21/Pdcd4 regulation on specific biological activities, such as apoptosis, proliferation, or anchorageindependent growth, has not been studied.”
The paper relies on this without support.
The effect on in vivo growth of glioblastoma cells of mir-21/Pdcd4 has not been explored.
“More significantly, the effect on in vivo growth of glioblastoma cells of mir-21/Pdcd4 has not been explored.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“miR-21 is a well-known miRNA, found to be overexpressed in almost all cancer types, where its upregulation promotes cell proliferation, invasion, and metastatic behavior.”
From Potential Therapeutic Effects of Exosomes Packed With a miR-21-Sponge Construct in a Rat Model of Glioblastoma (2019) · cites this paper as [18]
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 [18]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“miR-21 targets several genes such as PDCD4, TIMP3, and RECK, which are key regulators of apoptotic and metastatic pathways (17–23).”
From Potential Therapeutic Effects of Exosomes Packed With a miR-21-Sponge Construct in a Rat Model of Glioblastoma (2019) · cites this paper as [18]
The cited source says what the claim attributes to it.
In the citing paper
“Previously, we showed that overexpression of PDCD4 leads to decreased anchorage-independent growth in glioblastoma (GBM)-derived cell lines and decreased tumor growth in a GBM xenograft model.”
From Tumor suppressor PDCD4 inhibits NF-κB-dependent transcription in human glioblastoma cells by direct interaction with p65 (2014) · cites this paper as [13]
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
§ Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo > Inhibiting mir-21 expression in glioblastoma-derived cell lines results in decreased proliferation, increased apoptosis, and diminished anchorage-independent growth
“Compared with cells that were treated with anti-mir-21 only, U251 or U87 that were treated with anti-mir-21 and siRNA to Pdcd4 produced higher number of colonies, similar to those formed by untreated U251 or U87 (Fig. 4A and B).”
§ Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo > Discussion
“Interestingly, cells treated with anti-mir-21 and siRNA to Pdcd4 produced 85% of the colonies compared to cells treated with anti-mir-21 only.”
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
§ Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo > Inhibiting mir-21 expression in glioblastoma-derived cell lines results in decreased proliferation, increased apoptosis, and diminished anchorage-independent growth
“Also, TUNEL staining revealed enhanced apoptosis in U251 (Fig. 3B) and U87 cells (data not shown) treated with anti-mir-21, compared with cells cultured in either medium alone or with NS control.”
§ Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo > Discussion
“(B) Cell-cycle analyses of U251 and U87 cells and cells transfected with non-specific negative/toxicity anti-mir (NS) control (30 mM) or anti-mir-21 (30 mM) as well as U251 Pdcd4 and U87 Pdcd4 cells.”
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
§ Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo > Discussion
“(B) Western blot analysis of mir-21 in primary tissues (2H, 4A10, 35A28, and 52A28) and GBM-derived cell lines (SNB19, U251, U87, and SF767), compared with normal human brain samples (NB4330 and NB4126).”
§ Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo > Discussion
“Forty micrograms of protein from whole-cell lysates were loaded in each well for quantifying Pdcd4 protein levels by Western blot analysis using an anti-Pdcd4 antibody.”
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
“Kutay, 2006, Journal of cellular biochemistry, 99, 671, 10.1002/jcb.20982”
Cited work 10.1002/jcb.20982 · retracted 2025-04-28 · notice 10.1002/jcb.70023 · this paper published 2011-06-01
Citations
Cites
1 retracted
RETRACTED: Downregulation of miR‐122 in the rodent and human hepatocellular carcinomas
Kutay, H., Bai, S., Datta, J., Motiwala, T., Pogribny, I., Frankel, W., Jacob, S. T., & Ghoshal, K. (2006) · Journal of Cellular Biochemistry · doi:10.1002/jcb.20982 · Cited by 608
RetractedMicroRNA signatures in human cancers
Calin, G. A., & Croce, C. M. (2006) · Nature reviews. Cancer · doi:10.1038/nrc1997 · Cited by 7,668
Oncomirs—MicroRNAs with a role in cancer
Esquela-Kerscher, A., & Slack, F. J. (2006) · Nature Reviews Cancer · doi:10.1038/nrc1840 · Cited by 5,884
A microRNA expression signature of human solid tumors defines cancer gene targets
Volinia, S., Calin, G. A., Liu, C.-G., Ambs, S., Cimmino, A., Petrocca, F., Visone, R., Iorio, M., Roldo, C., Ferracin, M., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0510565103 · Cited by 5,697
Real-time quantification of microRNAs by stem-loop RT-PCR
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MicroRNA-21 Regulates Expression of the PTEN Tumor Suppressor Gene in Human Hepatocellular Cancer
Meng, F., Henson, R., Wehbe–Janek, H., Ghoshal, K., Jacob, S. T., & Patel, T. (2007) · Gastroenterology · doi:10.1053/j.gastro.2007.05.022 · Cited by 2,773
MicroRNA-21 Is an Antiapoptotic Factor in Human Glioblastoma Cells
Chan, J. A., Krichevsky, A. M., & Kosik, K. S. (2005) · Cancer Research · doi:10.1158/0008-5472.can-05-0137 · Cited by 2,557
Asangani, I. A., Rasheed, S. A. K., Nikolova, D. A., Leupold, J. H., Colburn, N. H., Post, S., & Allgayer, H. (2008) · Oncogene · doi:10.1038/sj.onc.1210856 · Cited by 1,882
Self-citationSi, M.-L., Zhu, S., Wu, H., Lu, Z., Wu, F., & Mo, Y.-Y. (2007) · Oncogene · doi:10.1038/sj.onc.1210083 · Cited by 1,600
MicroRNA Signatures in Human Ovarian Cancer
Iorio, M. V., Visone, R., Leva, G. D., Donati, V. L., Petrocca, F., Casalini, P., Taccioli, C., Volinia, S., Liu, C.-G., Alder, H., et al. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-1936 · Cited by 1,396
Research works printed but not linked: 3
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Cited by
Sorted by citations
Teplyuk, N. M., Mollenhauer, B., Gabriely, G., Giese, A., Kim, E. L., Smolsky, M., Kim, R. Y., Saria, M. G., Pastorino, S., Kesari, S. P., et al. (2012) · Neuro-Oncology · doi:10.1093/neuonc/nos074 · Cited by 304
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 273
“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…”
BackgroundResultInfluentialmiR-124 Inhibits STAT3 Signaling to Enhance T Cell–Mediated Immune Clearance of Glioma
Wei, J., Wang, F., Kong, L.-Y., Xu, S., Doucette, T. A., Ferguson, S. D., Yang, Y., McEnery, K., Jethwa, K. R., Gjyshi, O., et al. (2013) · Cancer Research · doi:10.1158/0008-5472.can-12-4318 · Cited by 253
“In addition, oncogenic miR inhibition in murine glioma models has resulted in in vivo growth inhibition (16).”
BackgroundMicroRNAs in glioblastoma multiforme pathogenesis and therapeutics
Shea, A. A., Harish, V., Afzal, Z., Chijioke, J., Kedir, H., Dusmatova, S., Roy, A., Ramalinga, M., Harris, B. T., Blancato, J. K., et al. (2016) · Cancer Medicine · doi:10.1002/cam4.775 · Cited by 211
“AP- 1 induces miR- 21, which downregulates tumor suppressors PDCD4 and PTEN.”
BackgroundInfluentialLi, B., Ren, S., Li, X., Wang, Y., Garfield, D. H., Zhou, S., Chen, X., Su, C., Chen, M., Kuang, P., et al. (2013) · Lung Cancer · doi:10.1016/j.lungcan.2013.11.003 · Cited by 179
Fang, H., Xie, J., Zhang, M., Zhao, Z., Wan, Y., & Yao, Y. (2017) · PubMed Central · Cited by 164
Bhome, R., Goh, R. W., Bullock, M. D., Pillar, N., Thirdborough, S. M., Mellone, M., Mirnezami, R., Galea, D., Veselkov, K., Gu, Q., et al. (2017) · Aging · doi:10.18632/aging.101355 · Cited by 155
RNA Nanoparticle-Based Targeted Therapy for Glioblastoma through Inhibition of Oncogenic miR-21
Lee, T. J., Yoo, J. Y., Shu, D., Li, H., Zhang, J., Yu, J.-G., Jaime‐Ramirez, A. C., Acunzo, M., Romano, G., Cui, R., et al. (2017) · Molecular Therapy · doi:10.1016/j.ymthe.2016.11.016 · Cited by 148
Dissecting Tumor Growth: The Role of Cancer Stem Cells in Drug Resistance and Recurrence
Aramini, B., Masciale, V., Grisendi, G., Bertolini, F., Maur, M., Guaitoli, G., Isca, C., Morandi, U., Stella, F., Dominici, M., et al. (2022) · Cancers · doi:10.3390/cancers14040976 · Cited by 154
“A study of engineered exosomes containing miRNA (particularly miR-21) show they effectively downregulated target genes PDCD4 and RECK of the miR-21 in glioma cell lines [274].”
BackgroundThe inhibition of miR-21 promotes apoptosis and chemosensitivity in ovarian cancer
Chan, J. K., Blansit, K., Kiet, T. K., Sherman, A. E., Wong, G., Earle, C., & Bourguignon, L. (2014) · Gynecologic Oncology · doi:10.1016/j.ygyno.2014.01.034 · Cited by 145
“Previous studies have shown that tumor suppressor protein, PDCD4 (Programmed Cell Death Protein 4) serves as one of the target proteins for miR-21 [21, 22].”
InfluentialBullock, M. D., Pickard, K., Nielsen, B. S., Sayan, E., Jenei, V., Mellone, M., Mitter, R., Primrose, J. M., Thomas, G. J., Packham, G., et al. (2013) · Cell Death and Disease · doi:10.1038/cddis.2013.213 · Cited by 133
Park, Y. M., Hwang, S. J., Masuda, K., Choi, K.-M., Jeong, M., Nam, D., Gorospe, M., & Kim, H. H. (2012) · Molecular and Cellular Biology · doi:10.1128/mcb.00443-12 · Cited by 127
“The results showing that hnRNPC-regulated PDCD4 expression influenced the proliferation and apoptosis of T98G cells were consistent with previous reports that overexpression of PDCD4 decreased proliferation and increased apoptosis (18).”
BackgroundResultMonfared, H., Jahangard, Y., Nikkhah, M., Mirnajafi-Zadeh, J., & Mowla, S. J. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.00782 · Cited by 123
Costa, P. M., Cardoso, A. L., Mendonça, L. S., Serani, A., Custódia, C., Conceição, M., Simões, S., Moreira, J. N., de Almeida, L. P., & de Lima, M. C. P. (2013) · Molecular Therapy — Nucleic Acids · doi:10.1038/mtna.2013.30 · Cited by 126
MicroRNAs in glioblastoma pathogenesis and therapy: A comprehensive review
Ahir, B. K., Ozer, H., Engelhard, H. H., & Lakka, S. S. (2017) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2017.10.003 · Cited by 120
MicroRNAs as pharmacological targets in endothelial cell function and dysfunction
Chamorro-Jorganes, A., Araldi, E., & Suárez, Y. (2013) · Pharmacological Research · doi:10.1016/j.phrs.2013.04.002 · Cited by 115
“However, other studies reported a pro-angiogenic role f miR-21 in ECs [148] and tumors [149,150].”
Regulation of microRNA expression and function by nuclear receptor signaling
Yang, Z., & Wang, L. (2011) · Cell & Bioscience · doi:10.1186/2045-3701-1-31 · Cited by 111
“Pdcd4;PTEN;PPARa; [28,97-101]”
Role of exosomes in malignant glioma: microRNAs and proteins in pathogenesis and diagnosis
Ghaemmaghami, A. B., Mahjoubin‐Tehran, M., Movahedpour, A., Morshedi, K., Sheida, A., Taghavi, S. P., Mirzaei, H., & Hamblin, M. R. (2020) · Cell Communication and Signaling · doi:10.1186/s12964-020-00623-9 · Cited by 108
Effect of miR-21 and miR-30b/c on TRAIL-induced apoptosis in glioma cells
Quintavalle, C., Donnarumma, E., Iaboni, M., Roscigno, G., Garofalo, M., Romano, G., Fiore, D., Marinis, P. D., Croce, C. M., & Condorelli, G. (2012) · Oncogene · doi:10.1038/onc.2012.410 · Cited by 106
Lee, H. K., Bier, A., Cazacu, S., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0054652 · Cited by 105
“In GBM, various miRNAs such as miR-21 [14], miR221/222 [15], miR-125 [16] and miR-10b [17], have been”
BackgroundFu, J., Rodova, M., Nanta, R., Meeker, D., Veldhuizen, P. J. V., Srivastava, R. K., & Shankar, S. (2013) · Neuro-Oncology · doi:10.1093/neuonc/not011 · Cited by 106
“It has been shown that miR-21 is expressed at higher levels in primary glioblastoma-tissue and glioblastomaderived cell lines than in normal brain tissue.(50) Since NVP-LDE-225 induced the expression of PdCD4, we hypothesized that this expression was regulated by miR-21.”
BackgroundInfluentialCai, N., Wang, Y., & Zheng, P. (2012) · RNA · doi:10.1261/rna.035295.112 · Cited by 103
“…in many solid tumors and has been reported to be associated with tumor progression, poor survival, and drug resistance through its interactions with PDCD4, PTEN, and CCL20 (Connolly et al. 2008; Yamamichi et al. 2009; Bao et al. 2011; Gaur et al. 2011; Gong et al. 2011; Yao and Lin 2012).”
BackgroundThe Role of MicroRNAs in Chemoresistance
Bahreini, F., & Rezaei, N. (2023) · Springer eBooks · doi:10.1007/978-3-030-80962-1_336-1 · Cited by 100
Yang, Y., Meng, H., Peng, Q., Yang, X., Gan, R., Zhao, L., Chen, Z., Lu, J., & Meng, Q. H. (2014) · Cancer Gene Therapy · doi:10.1038/cgt.2014.66 · Cited by 96
Damania, P., Sen, B., Dar, S. B., Kumar, S., Kumari, A., Gupta, E., Sarin, S. K., & Venugopal, S. K. (2014) · PLoS ONE · doi:10.1371/journal.pone.0091745 · Cited by 91
“Since PDCD4 and PTEN are pro-apoptotic proteins, our data is in agreement with the previous data that HBx inhibits apoptosis and enhances cellular proliferation in hepatoma cells [26,28].”
BackgroundResultBlockage of a miR-21/EGFR regulatory feedback loop augments anti-EGFR therapy in glioblastomas
Zhang, K.-L., Han, L., Chen, L., Shi, Z., Yang, M., Ren, Y., Chen, L., Zhang, J., Pu, P., & Kang, C. (2013) · Cancer Letters · doi:10.1016/j.canlet.2013.08.043 · Cited by 87
Role of microRNAs in glioblastoma
Chen, M., Medarova, Z., & Moore, A. (2021) · Oncotarget · doi:10.18632/oncotarget.28039 · Cited by 84
“Other oncogenic effects of miR-21, such as proliferation, invasiveness, and chemoresistance in a variety of GBM cell lines have also been reported [79, 81, 84].”
BackgroundMa, Y., Liang, A., Fan, Y., Huang, Y., Zhao, X., Sun, Y. W., & Chen, X. (2016) · Oncotarget · doi:10.18632/oncotarget.8715 · Cited by 81
“As a typical tumor suppressor gene (TSG), PDCD4 can inhibit eukaryotic translation initiation factor 4A1 (EIF4A1) and NF-κB-dependent transcriptional factors via direct interaction with p65, to induce apoptosis in glioblastoma cells [82].”
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
“Here, and in accordance with previous studies (42,44), we provide evidence that oligonucleotide-mediated miR-21 silencing increases the expression levels of the Figure 7.”
ResultDikshit, B., Irshad, K., Madan, E., Aggarwal, N., Sarkar, C., Chandra, P. S., Gupta, D. K., Chattopadhyay, P., Sinha, S., & Chosdol, K. (2012) · Oncogene · doi:10.1038/onc.2012.393 · Cited by 79
Strategies to Modulate MicroRNA Functions for the Treatment of Cancer or Organ Injury
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“It is one of the most extensively studied miRNAs, with several known targets, including phosphatase and tensin homolog (Meng et al., 2007), programmed cell death 4 (Gaur et al., 2011), and BTG antiproliferation factor 2 (Liu et al., 2009).”
BackgroundZhou, X., Ren, Y., Liu, A., Han, L., Zhang, K., Li, S., Li, P., Li, P., Kang, C., Wang, X., et al. (2014) · Oncology Reports · doi:10.3892/or.2014.3114 · Cited by 76
The Role of microRNA-21 in the Onset and Progression of Cancer
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Guduric‐Fuchs, J., O’Connor, A., Cullen, A., Harwood, L., Medina, R. J., O’Neill, C. L., Stitt, A. W., Curtis, T. M., & Simpson, D. A. C. (2012) · Journal of Cellular Biochemistry · doi:10.1002/jcb.24084 · Cited by 74
“The proangiogenic role for miR-21 in RMECs suggested by the decreased proliferation, migration and tube formation observed after its inhibition is in agreement with its reported effects in, for example, glioblastoma [Gaur et al., 2011] and bladder cancer cells [Tao et al.”
ResultThe 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].”
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
“Downregulation of miR-21 is known to enhance PTEN and PDCD4 tumor suppressor gene expression, and lead to decreased proliferation, increased apoptosis and decreased colony formation [35].”
BackgroundWang, N., Zhang, C., He, J. H., Duan, X.-F., Wang, Y., Ji, X., Zang, W., Li, M., Ma, Y., Wang, T., et al. (2013) · Digestive Diseases and Sciences · doi:10.1007/s10620-013-2612-2 · Cited by 70
The role of MiRNA-21 in gliomas: Hope for a novel therapeutic intervention?
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“When both miR-21 and PDCD4 were inhibited, the tumors regained their growth potential, highlighting the role of PDCD4 inhibition, as a downstream target of miR-21, in glioma proliferation [23].”
BackgroundMafi, A., Rahmati, A., Babaei Aghdam, Z., Salami, R., Salami, M., Vakili, O., & Aghadavod, E. (2022) · Cellular & Molecular Biology Letters · doi:10.1186/s11658-022-00354-4 · Cited by 56
“miR-21 targets several tumor suppressor genes known to be critical regulators of apoptosis or cell proliferation, including programmed cell death 4 (PDCD4) [92], acidic nuclear phosphoprotein 32 family member A (ANP32A) [91], PTEN [90], and Sprouty 2 (SPRY2) [94].”
BackgroundTargeting strategies on miRNA-21 and PDCD4 for glioblastoma
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Biomarkers of Cancer Stem Cells for Experimental Research and Clinical Application
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“For example, exosomes containing miR-21 produced an effective downregulation of the PDCD4 and RECK genes in glioma cell lines [112].”
BackgroundmiRNA-183 Suppresses Apoptosis and Promotes Proliferation in Esophageal Cancer by Targeting PDCD4
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“Furthermore, results of previous studies confirmed that PDCD4 is an important tumor suppressor gene (Gaur et al., 2011; Wei et al., 2012; Zhang et al., 2010).”
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“…et al., 2007), autophagy (Kroemer and Levine, 2008), pyroptosis (Brennan and Cookson, 2000), parthanatos (Andrabi et al., 2008), or autoschizis (Gilloteaux et al., 1998) are being used by the scientific community, most often they refer to cell deathmodes that are executed (at least in part) by…”
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The critical roles of miR-21 in anti-cancer effects of curcumin.
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“MiR-21 mediated PDCD4 degradation has also been demonstrated in breast cancer (76), cervical cancer (77), Glioblastoma (78,79) and hepatocellular carcinoma (80).”
BackgroundHenriksen, M., Johnsen, K. B., Andersen, H. H., Pilgaard, L., & Duroux, M. C. (2014) · Molecular Neurobiology · doi:10.1007/s12035-014-8668-y · Cited by 57
Extracellular Vesicles and MicroRNAs: Their Role in Tumorigenicity and Therapy for Brain Tumors
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“It was also shown that downregulation of miR-21 diminished tumor growth in immunodeficient mice (Corsten et al. 2007; Gaur et al. 2011; Zhou et al. 2010).”
BackgroundChang, C., Wang, H., Liu, J., Pan, C., Zhang, D., Li, X., & Pan, Y. (2019) · ACS Infectious Diseases · doi:10.1021/acsinfecdis.9b00032 · Cited by 53
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“It is commonly upregulated in several types of malignancies, included HCC (19-22).”
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Upregulation of miR-107 Inhibits Glioma Angiogenesis and VEGF Expression
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“In particular, several miRNAs are involved in glioma progression events, such as growth, invasion, angiogenesis, and resistance to chemotherapy (Li et al. 2009; Ren et al. 2010; Gaur et al. 2011; Sun et al. 2011).”
Hwang, S.-K., Baker, A. R., Young, M. R., & Colburn, N. H. (2014) · Carcinogenesis · doi:10.1093/carcin/bgu008 · Cited by 49
“We recently reported that PDCD4 leads to decreased anchorage-independent growth in glioblastoma (GBM)-derived cell lines as well as decreased tumor growth in a GBM xenograft model (13).”
BackgroundSelf-citationNoncoding RNAs in Glioblastoma: Emerging Biological Concepts and Potential Therapeutic Implications
Shahzad, U., Krumholtz, S. L., Rutka, J. T., & Das, S. (2021) · Cancers · doi:10.3390/cancers13071555 · Cited by 50
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Overexpressed miRNA-137 Inhibits Human Glioma Cells Growth by Targeting Rac1
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Nutrient-Gene Interaction in Colon Cancer, from the Membrane to Cellular Physiology
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“Elevated expression of miR-21 has been reported in breast (223), glioblastoma (67), pancreatic (140), and colon (9, 45, 216) cancers.”
BackgroundXiong, Y., Tang, Y., Fan, F., Zeng, Y., Li, C., Zhou, G., Hu, Z., Zhang, L., & Liu, Z. (2019) · Translational research · doi:10.1016/j.trsl.2019.07.013 · Cited by 50
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Altering β-cell number through stable alteration of miR-21 and miR-34a expression
Backe, M. B., Novotny, G. W., Christensen, D. P., Grunnet, L. G., & Mandrup-Poulsen, T. R. (2014) · Islets · doi:10.4161/isl.27754 · Cited by 43
HBx-induced miR-21 suppresses cell apoptosis in hepatocellular carcinoma by targeting interleukin-12
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“Previous studies have shown that HBx inhibits apoptosis and enhances cellular proliferation in hepatoma cells (34,35), while the mechanism is unknown.”
BackgroundZhang, J., Yang, Y., Liu, Y., Fan, Y., Liu, Z., Wang, X., Yuan, Q., Yin, Y., Yu, J., Zhu, M., et al. (2014) · Journal of Surgical Research · doi:10.1016/j.jss.2014.02.012 · Cited by 41
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“On the other hand, over-expression of PDCD4 leads to decreased proliferation and increased apoptosis in glioblastoma-derived cell lines, while its down-regulation by miR-21 facilitates glioblastoma proliferation in vivo [92].”
MicroRNA–target cross-talks: Key players in glioblastoma multiforme
Toraih, E. A., Aly, N. M., Abdallah, H. Y., Alqahtani, S. A. M., Shaalan, A. A. M., Hussein, M. H., & Fawzy, M. S. (2017) · Tumor Biology · doi:10.1177/1010428317726842 · Cited by 41
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Mechanistic insights into the role of microRNAs in cancer: influence of nutrient crosstalk
Shah, M. S., Davidson, L. A., & Chapkin, R. S. (2012) · Frontiers in Genetics · doi:10.3389/fgene.2012.00305 · Cited by 41
“…et al., 2009), colon (Asangani et al., 2008; Davidson et al., 2009b; Wang et al., 2009a), and glioblastoma (Chan et al., 2005; Ciafre et al., 2005; Gaur et al., 2011). miR-21 exhibits anti-apoptotic properties by targeting several tumor suppressors such as PTEN, PDCD4, BCL2, TIMP3, TGFβR2, SPRY3,…”
BackgroundCurrent Progress for the Use of miRNAs in Glioblastoma Treatment
Tivnan, A., & McDonald, K. L. (2013) · Molecular Neurobiology · doi:10.1007/s12035-013-8464-0 · Cited by 40
“Conversely, miR-21 has been extensively studied due to its significant upregulation in glioblastoma and the noted observation that miR-21 inhibition induced apoptosis in glioblastoma cells in vitro [32, 54–56] and in vivo [40, 57, 58].”
BackgroundZhang, S., Han, L., WEI, J., et al. (2015) · International Journal of Oncology · doi:10.3892/ijo.2015.2841 · Cited by 39
“Through targeting of PTEN, PDCD4, RECK and other signal transduction pathways, miR-21 regulates the proliferation, apoptosis, and invasion of hepatocellular cancer, colorectal cancer, breast cancer (15-19).”
BackgroundNovotny, G. W., Lundh, M., Backe, M. B., Christensen, D. P., Hansen, J. B., Dahllöf, M. S., Pallesen, E. M. H., & Mandrup-Poulsen, T. R. (2012) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2012.09.014 · Cited by 37
Kwak, G., Kim, H., Park, J., Kim, E. H., Jang, H., Han, G., Wang, S. Y., Yang, Y., Kwon, I. C., & Kim, S. H. (2021) · ACS Nano · doi:10.1021/acsnano.1c00799 · Cited by 38
Unraveling the impact of miR-21 on apoptosis regulation in glioblastoma
Shaikh, M. A. J., Altamimi, A. S. A., Afzal, M., Gupta, G., Singla, N., Gilhotra, R., almalki, W. H., Kazmi, I., Alzarea, S. I., Prasher, P., et al. (2024) · Pathology - Research and Practice · doi:10.1016/j.prp.2024.155121 · Cited by 37
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“MiR-21 upregulation also enhances proliferation and invasion in pancreatic, glioblastoma and CRC cell lines [40–42].”
BackgroundInhibition of miR-21 in glioma cells using catalytic nucleic acids
Belter, A., Rolle, K., Piwecka, M., Fedoruk-Wyszomirska, A., Naskręt-Barciszewska, M. Z., & Barciszewski, J. (2016) · Scientific Reports · doi:10.1038/srep24516 · Cited by 36
Noncoding RNAs in Glioblastoma
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Dissimilar microRNA-21 functions and targets in trophoblastic cell lines of different origin
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Anti-cancer Therapies in High Grade Gliomas
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“Other animal studies also reported tumor reduction following inhibition of oncogenic miR-21 in GBM [116].”
BackgroundEngineered smart materials for RNA based molecular therapy to treat Glioblastoma
Singh, R. R., Mondal, I., Janjua, T. I., Popat, A., & Kulshreshtha, R. (2023) · Bioactive Materials · doi:10.1016/j.bioactmat.2023.11.007 · Cited by 36
“The major targets of miR-21 that regulate different hallmarks of GBM include HNRNPK, PDCD4, p53, TAp63, TGF-β , Ras/Raf, ERKs, MMPs, PTEN, Spry2, SMARCA4, ANP32A and LRRFIP1 [103,105,106,137,141 – 145].”
BackgroundXIAO, B., Zhou, X., Ye, M., et al. (2015) · Molecular Medicine Reports · doi:10.3892/mmr.2015.4537 · Cited by 34
“In recent years, numerous studies regarding miRNAs have been conducted, and miRNAs have been identified as exhibiting an important role in the initiation and progression of cancer, and thus have been suggested as a target for the treatment of glioblastoma (17,18-20).”
BackgroundDrug-Like Small Molecules That Inhibit Expression of the Oncogenic MicroRNA-21
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“MiR-21 is a negative regulator of Pdcd4, and Pdcd4 likely contributes to miR21-induced tumor cell invasion and anti-apoptosis [18,19].”
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“related to poor prognosis of ovarian tumor patients [98].”
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Host Non-Coding RNA Regulates Influenza A Virus Replication
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“Intriguingly, a previous study reported an important functional linkage between miR-21 and tumor suppressor PDCD4, by which the overexpression of miR-21 can contribute to inhibition of PDCD4 and its tumorsuppressive functions (18).”
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Glioma-Derived Extracellular Vesicles – Far More Than Local Mediators
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“In vitro suppression of miR-21 decreased proliferation and increased apoptosis in GBM cells (28).”
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“Tumor suppressor genes, PDCD4 and SERPINB5, have been reported as being miR-21 suppressed genes [21,33].”
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“…Additionally, MiR-98 decreased cell apoptosis by targeting the FAS/FASL gene (Zhang B. Y. et al., 2016), and miR-21 reduced cell apoptosis by targeting programmed cell death 4 (PDCD4) (He et al., 2013), a well-known apoptosis gene (Gaur et al., 2011; Stagakis et al., 2011; Junker et al., 2015).”
Background
Metadata
- Authors
- Gaur, A. B., Holbeck, S. L., Colburn, N. H., & Israel, M. A.
- Affiliations
- Dartmouth College (US)
- Corresponding author
- Gaur, A. B.
- Venue
- Neuro-Oncology
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-06-01
- Volume
- 13
- Issue
- 6
- Pages
- 580-590
- ISSN
- 1522-8517 (ISSN-L)
- 1523-5866
- PMC
- PMC3107097
- OpenAlex
- W2097617161
- Semantic Scholar
- baf2769011f484edff3d111bdecfc52cb2d992b6
- Cited by
- 180
- References
- 55
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 8 · 2023: 9 · 2022: 11 · 2021: 16 · 2020: 14 · 2019: 9 · 2018: 7 · 2017: 13 · 2016: 13 · 2015: 14 · 2014: 15 · 2013: 19 · 2012: 15
- FWCI
- 5.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Neuro-Oncology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (submittedVersion)
- PubMed Central (submittedVersion)
- Funders
- U.S. Department of Health and Human Services
- National Institutes of Health
- National Cancer Institute
- 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 › Glioma Diagnosis and Treatment
- Keywords
- miR-21, PDCD4, glioblastoma, microRNA, tumor suppressor, cell proliferation, apoptosis, colony formation, xenograft tumor growth, carcinogenesis, post-transcriptional regulation
- MeSH terms
- Animals, Brain, Brain Neoplasms, Cell Adhesion, Cell Movement, Female, Glioblastoma, Humans, Mice, Nude, RNA, Messenger, Blotting, Northern, Blotting, Western, RNA-Binding Proteins, Apoptosis, Reverse Transcriptase Polymerase Chain Reaction, MicroRNAs, Cell Proliferation, Apoptosis Regulatory Proteins, Mice
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