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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- Findingown data
Anti-mir-21 treatment increases apoptosis in U251 and U87 cells compared with medium alone or NS control.
“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.”
Quote in the paperSubstantial claim - Findingown data
Anti-mir-21 treatment increases Pdcd4 protein levels in U251 and U87 cells at 24, 48, and 72 h after transfection.
“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).”
Quote in the paperSubstantial claim - Findingown data
Overexpression of Pdcd4 in U87 cells increases apoptosis.
“Increased apoptosis in U87 cells treated with anti-mir-21 or stably over expressing Pdcd4 (U87 Pdcd4 ) was also observed (data not shown).”
Quote in the paperSubstantial claim - Findingown data
Overexpression of Pdcd4 in U251 cells decreases colony number in soft agar compared with cells without elevated Pdcd4.
“The U251 Pdcd4 polyclonal cell culture showed a decrease in colony number compared to cells that did not have elevated Pdcd-4 levels.”
Quote in the paperSubstantial claim - Findingown data
Downregulation of mir-21 in glioblastoma-derived cell lines leads to increased apoptosis.
“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.”
Quote in the paperSubstantial claim - Also stated in: § Inhibiting mir-21 expression in glioblastoma-derived cell lines results in decreased proliferation, increased apoptosis, and diminished anchorage-independent growth · plain
- Findingown data
Downregulation of mir-21 in glioblastoma-derived cell lines results in increased expression of Pdcd4.
“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).”
Quote in the paperSubstantial claim - Also stated in: § Down Regulation of mir-21 Expression in Glioblastoma-Derived Cell Lines Results in Enhanced Pdcd4 Expression · plain
- Findingown data
Downregulation of mir-21 in glioblastoma-derived cell lines leads to decreased proliferation.
“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).”
Quote in the paperSubstantial claim - Also stated in: § Inhibiting mir-21 expression in glioblastoma-derived cell lines results in decreased proliferation, increased apoptosis, and diminished anchorage-independent growth · plain
- Findingown data
Overexpression of Pdcd4 in glioblastoma-derived cell lines leads to decreased colony formation in soft agar.
“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.”
Quote in the paperSubstantial claim - Also stated in: § Inhibiting mir-21 expression in glioblastoma-derived cell lines results in decreased proliferation, increased apoptosis, and diminished anchorage-independent growth · plain
- Findingown data
Overexpression of Pdcd4 in glioblastoma-derived cell lines leads to decreased proliferation.
“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.”
Quote in the paperSubstantial claim - Findingown data
Overexpression of Pdcd4 in U251 cells increases spontaneous apoptosis compared with parental cells.
“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).”
Quote in the paperSubstantial claim - Findingown data
Anti-mir-21 treatment decreases cell numbers in U251 and U87 cultures compared with regular media or nonspecific negative toxicity control.
“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).”
Quote in the paperSubstantial claim - Findingown data
mir-21 is expressed at higher levels in primary glioblastoma tissue and glioblastoma-derived cell lines than in normal brain tissue.
“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.”
- Also stated in: § Down Regulation of mir-21 Expression in Glioblastoma-Derived Cell Lines Results in Enhanced Pdcd4 Expression · plain
“Elevated levels of mir-21 were observed in all 7 glioblastoma-derived cell lines and in all 13 glioblastoma tumors we examined (Fig. 1) (data not shown).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [8]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [12]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [18]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Also stated in: § Down Regulation of mir-21 Expression in Glioblastoma-Derived Cell Lines Results in Enhanced Pdcd4 Expression · plain
- Findingown data
Overexpression of Pdcd4 in glioblastoma-derived cell lines leads to increased apoptosis.
“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
“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).”
Quote in the paperSubstantial claim - Also stated in: § Inhibiting mir-21 expression in glioblastoma-derived cell lines results in decreased proliferation, increased apoptosis, and diminished anchorage-independent growth · plain
- Findingown data
In 3 independent experiments, anti-mir-21 decreased colony number by 65% at 10 mM and 75% at 30 mM.
“In 3 independent experiments, the number of colonies formed following exposure to anti-mir-21 decreased by 65% (10 mM anti-mir-21) and 75% (30 mM anti-mir-21).”
Quote in the paperSubstantial claim - Findingown data
Downregulation of mir-21 in glioblastoma-derived cell lines leads to decreased tumor formation and growth in a glioblastoma xenograft model in immune-deficient nude mice.
“U251 GFP or U87 GFP lines transfected with anti-mir-21 demonstrated decreased tumor growth in vivo (Fig. 5A).”
Quote in the paperSubstantial claim - Findingown data
Overexpression of Pdcd4 in glioblastoma-derived cell lines leads to decreased tumor formation and growth in a glioblastoma xenograft model in immune-deficient nude mice.
“Mice that received cell lines overexpressing Pdcd4, U251 GFP+Pdcd4 , or U87 GFP+Pdcd4 also had tumors that were reduced in size, compared with tumors arising in animals injected with the same cells bearing only GFP and not overexpressing Pdcd4 (Fig. 5A).”
Quote in the paperSubstantial claim - Findingown data
There is a significant inverse correlation (P = .004) between miR-21 and Pdcd4 protein expression levels in NCI60 glioma-derived cell lines.
“In that analysis we found a significant inverse correlation (P ¼ .004) between miR-21 and Pdcd4 protein expression levels (data not shown) similar to the data described above in Fig. 2A and B that demonstrated undetectable levels of Pdcd4 protein in glioblastoma-derived cell lines that expressed high levels of mir-21 and vice-versa.”
Quote in the paperSubstantial claim - Findingown data
Anti-mir-21 treatment decreases mir-21 levels in U251 and U87 cells at 24, 48, and 72 h after transfection.
“Northern blot analyses demonstrated decreased levels of mir-21 in U251 and U87 cells 24, 48, and 72 h after transfection with anti-mir-21 (Fig. 2A, lanes 3-5 and 8 -10).”
Quote in the paperSubstantial claim - Findingown data
Anti-mir-21 treatment decreases anchorage-independent growth and colony formation in soft agar in U251 cells compared with controls.
“U251 cells treated with anti-mir-21 for 72 h and plated in soft agar displayed decreased anchorage-independent growth and formed fewer colonies (Fig. 4A and B) when compared to controls.”
Quote in the paperSubstantial claim - Findingown data
In glioblastoma xenografts, co-transfection of anti-mir-21 with siRNA to Pdcd4 reverses the decreased tumor growth, producing tumors comparable to controls.
“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.”
- Also stated in: § Downregulation of mir-21 or Overexpression of Pdcd4 Results in Reduction of Glioblastoma Xenograft Growth that is Reversed by siRNA to Pdcd4 · plain
“More importantly, animals that received U251 GFP or U87 GFP lines after transfection with anti-mir-21 and siRNA to PDCD4 gave rise to tumors that developed to 1.5 cm 3 in size by day 30, comparable to the tumors that developed from the control, untreated glioblastoma-derived cell lines (Fig. 5A).”
Quote in the paperSubstantial claim - Also stated in: § Downregulation of mir-21 or Overexpression of Pdcd4 Results in Reduction of Glioblastoma Xenograft Growth that is Reversed by siRNA to Pdcd4 · plain
- Findingown data
There is an inverse correlation between mir-21 and Pdcd4 protein levels in glioblastoma-derived cell lines.
“Having observed an inverse correlation between mir-21 and Pdcd4 protein levels (Fig. 1A and B)”
- Also stated in: § Down Regulation of mir-21 Expression in Glioblastoma-Derived Cell Lines Results in Enhanced Pdcd4 Expression · boosted
“In that analysis we found a significant inverse correlation (P ¼ .004) between miR-21 and Pdcd4 protein expression levels (data not shown) similar to the data described above in Fig. 2A and B that demonstrated undetectable levels of Pdcd4 protein in glioblastoma-derived cell lines that expressed high levels of mir-21 and vice-versa.”
Quote in the paperSubstantial claim - Also stated in: § Down Regulation of mir-21 Expression in Glioblastoma-Derived Cell Lines Results in Enhanced Pdcd4 Expression · boosted
- Findingown data
Downregulation of mir-21 in glioblastoma-derived cell lines leads to decreased colony formation in soft agar.
“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
“U251 cells treated with anti-mir-21 for 72 h and plated in soft agar displayed decreased anchorage-independent growth and formed fewer colonies (Fig. 4A and B) when compared to controls.”
Quote in the paperSubstantial claim - Also stated in: § Inhibiting mir-21 expression in glioblastoma-derived cell lines results in decreased proliferation, increased apoptosis, and diminished anchorage-independent growth · plain
- Findingown data
Pdcd4 protein levels are undetectable in primary glioblastoma tissues and glioblastoma-derived cell lines compared with normal human brain samples.
“By use of Western blot analysis, we observed that Pdcd4 protein levels are undetectable in primary glioblastoma tissues (Fig. 1B, lanes 1 -4) and glioblastoma-derived cell lines (Fig. 1B, lanes 5 -8), compared with normal human brain samples (Fig. 1B, lanes 9 -10).”
Quote in the paperSubstantial claim - Findingown data
Treatment with anti-mir-21 plus siRNA to Pdcd4 increases colony number compared with anti-mir-21 alone, to levels similar to untreated U251 or U87 cells.
“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).”
Quote in the paperSubstantial claim - Findingown data
In 5 independent xenograft experiments, only 5 of 24 mice receiving U251 GFP+Pdcd4 and 6 of 24 mice receiving U87 GFP+Pdcd4 developed tumors detectable by day 30.
“In the 5 independent xenograft experiments we performed examining U251 GFP+Pdcd4 or U87 GFP+Pdcd4 , only 5 of 24 and 6 of 24 mice, respectively, developed tumors detectable by day 30.”
Quote in the paperSubstantial claim - Findingown data
Animals receiving U251 GFP or U87 GFP cells transfected with anti-mir-21 and siRNA to PDCD4 develop tumors comparable to control untreated cells by day 30.
“More importantly, animals that received U251 GFP or U87 GFP lines after transfection with anti-mir-21 and siRNA to PDCD4 gave rise to tumors that developed to 1.5 cm 3 in size by day 30, comparable to the tumors that developed from the control, untreated glioblastoma-derived cell lines (Fig. 5A).”
Quote in the paperSubstantial claim - Findingown data
U251 or U87 cells treated for 72 h with anti-mir-21 form 70% and 60% fewer colonies, respectively, than control cells.
“U251 or U87 cells treated for 72 h with anti-mir-21 formed 70% and 60% fewer colonies, respectively, than did control cells.”
Quote in the paperSubstantial claim - Findingown data
Pdcd4 protein levels were undetectable by Western blot analysis of 4 individual tumors that arose from animals injected with U251 GFP+Pdcd4 or U87 GFP+Pdcd4 lines.
“we were able to measure Pdcd4 protein levels and found that Pdcd4 levels were undetectable by Western blot analysis of 4 individual tumors that arose from animals injected with U251 GFP+Pdcd4 or U87 GFP+Pdcd4 lines (Fig. 5D).”
Quote in the paperSubstantial claim - Findingown data
Mice receiving Pdcd4-overexpressing U251 GFP+Pdcd4 or U87 GFP+Pdcd4 cells have reduced tumor size compared with mice receiving the same cells bearing only GFP.
“Mice that received cell lines overexpressing Pdcd4, U251 GFP+Pdcd4 , or U87 GFP+Pdcd4 also had tumors that were reduced in size, compared with tumors arising in animals injected with the same cells bearing only GFP and not overexpressing Pdcd4 (Fig. 5A).”
Quote in the paperSubstantial claim - Findingown data
U251 Pdcd4 and U87 Pdcd4 cell lines form fewer colonies in soft agar than cells without elevated Pdcd4.
“In addition, U251 Pdcd4 and U87 Pdcd4 cell lines were also examined and demonstrated a decrease in number of colonies formed in soft agar, compared with cells that did not have elevated Pdcd-4 levels (Fig. 4A and 4B).”
Quote in the paperSubstantial claim - Findingown data
Tumor growth was reduced by 30% at day 30 (P = .01) in mice injected with anti-mir-21-transfected U251 GFP or U87 GFP cells.
“In all of these experiments, tumor growth was reduced by 30% at day 30 (P ¼ .01) in mice that were injected with anti-mir-21-transfected U251 GFP or U87 GFP cells.”
Quote in the paperSubstantial claim - Findingown data
Tumors arising from untreated U251 or U87 or U251 or U87 cell lines transfected with NS control or anti-mir-21 or with anti-mir-21 and siRNA to PDCD4 show similar morphological features of glioblastoma and are indistinguishable from one another.
“Furthermore, hematoxylin and eoisin staining of tumors (Supplemental Fig. S1) that arose from untreated U251 or U87 or U251 or U87 cell lines transfected with NS control or anti-mir-21 or with anti-mir-21 and siRNA to PDCD4 show similar morphological features of glioblastoma and are indistinguishable from one another.”
Quote in the paperNot a substantial claim - Findingown data
Tumors that developed from U251 GFP+Pdcd4 or U87 GFP+Pdcd4 xenografts were on average 90% smaller than tumors from untreated or nonspecific negative/toxicity control treated U251 GFP or U87 GFP cells.
“These tumors were, on average, 90% smaller than the tumors that arose after injection with untreated or nonspecific negative/toxicity control treated U251 GFP or U87 GFP cells (data not shown).”
Quote in the paperSubstantial claim - Findingown data
U251 GFP or U87 GFP cells transfected with anti-mir-21 show decreased tumor growth in vivo.
“U251 GFP or U87 GFP lines transfected with anti-mir-21 demonstrated decreased tumor growth in vivo (Fig. 5A).”
Quote in the paperSubstantial claim - Findingown data
Some tumors, albeit much smaller than controls, did develop in U251 GFP+Pdcd4- or U87 GFP+Pdcd4-derived xenografts.
“However, the fact that some tumors, albeit much smaller than those formed in the control groups, did develop in U251 GFP+Pdcd4 -or U87 GFP+Pdcd4 -derived xenografts provided an opportunity to examine Pdcd4 levels in such tumors (Fig. 5D).”
Quote in the paperSubstantial claim - Findingown data
There was a 90% (P = .001) decrease in tumor size or complete lack of tumor growth in mice injected with Pdcd4 over-expressing U251 GFP+Pdcd4 or U87 GFP+Pdcd4 cells.
“Similarly, we saw an 90% (P ¼ .001)decrease in tumor size or complete lack of tumor growth in mice that were injected with Pdcd4 over-expressing U251 GFP+Pdcd4 or U87 GFP+Pdcd4 cells.”
Quote in the paperSubstantial claim - Findingown data
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.
“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.”
Quote in the paperSubstantial claim - Findingown data
Inhibition of mir-21 in glioblastoma-derived cell lines resulted in enhanced Pdcd4 expression.
“Furthermore, by assessing endogenous Pdcd4 protein levels in glioblastoma-derived cell lines (Fig. 1B) and in lines in which endogenous mir-21 expression had been inhibited (Fig. 2A and B), we determined that inhibition of mir-21 in glioblastoma-derived cell lines resulted in enhanced Pdcd4 expression.”
Quote in the paperSubstantial claim - Findingown data
Glioblastoma-derived cell lines expressing Pdcd4 showed diminished anchorage-independent growth.
“In addition, glioblastoma-derived cell lines in which mir-21 levels were inhibited displayed decreased anchorage-independent growth (Fig. 4A and B), whereas glioblastoma-derived cell lines expressing Pdcd4 showed increased apoptosis and diminished anchorage-independent growth (Fig. 4A and B).”
Quote in the paperSubstantial claim - Findingreasoning
Cells treated with anti-mir-21 and siRNA to Pdcd4 produced 85% of the colonies compared to cells treated with anti-mir-21 only.
“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.”
Quote in the paperSubstantial claim - Findingown data
Cells treated with anti-mir-21 had decreased proliferation compared with untreated cells.
“We observed that cells treated with anti-mir-21 had decreased proliferation (Fig. 3A) and also exhibited enhanced apoptosis, compared with untreated cells (Fig. 3B).”
Quote in the paperSubstantial claim - Findingown data
Glioblastoma-derived cell lines in which mir-21 levels were inhibited displayed decreased anchorage-independent growth.
“In addition, glioblastoma-derived cell lines in which mir-21 levels were inhibited displayed decreased anchorage-independent growth (Fig. 4A and B), whereas glioblastoma-derived cell lines expressing Pdcd4 showed increased apoptosis and diminished anchorage-independent growth (Fig. 4A and B).”
Quote in the paperSubstantial claim - Findingown data
Cells treated with anti-mir-21 and siRNA to Pdcd4 produced an increased number of colonies similar to those formed by untreated controls, compared with cells treated with anti-mir-21 only.
“Compared with cells treated with anti-mir-21 only, cells that were treated with anti-mir-21 and siRNA to Pdcd4 produced an increased number of colonies similar to those formed by untreated controls (Fig. 4A and B).”
Quote in the paperSubstantial claim - Findingown data
Cells treated with anti-mir-21 exhibited enhanced apoptosis compared with untreated cells.
“We observed that cells treated with anti-mir-21 had decreased proliferation (Fig. 3A) and also exhibited enhanced apoptosis, compared with untreated cells (Fig. 3B).”
Quote in the paperSubstantial claim - Findingown data
Pdcd4 was undetectable in the few, small tumors that did develop from the Pdcd4 overexpressing lines.
“Importantly, Pdcd4 was undetectable in the few, small tumors that did develop from the Pdcd4 overexpressing lines.”
Quote in the paperSubstantial claim - Findingown data
Glioblastoma-derived cell lines in which mir-21 expression had been inhibited formed smaller tumors than those that arose after injection of untreated control cell lines.
“We observed that glioblastomaderived cell lines in which mir-21 expression had been inhibited formed fewer tumors and smaller tumors (Fig. 5A) than those that arose after injection of untreated control cell lines.”
Quote in the paperSubstantial claim - Findingown data
mir-21 expression is high in human glioblastoma-derived cell lines and glioblastoma primary tumors compared with normal brain tissue.
“The high level of mir-21 expression in human glioblastoma-derived cell lines and glioblastoma primary tumors, compared with that observed in normal brain tissue, suggested its potential in contributing to the malignant behavior of glioblastoma (Fig. 1A and C).”
Quote in the paperSubstantial claim - Findingown data
Glioblastoma-derived cell lines expressing Pdcd4 showed increased apoptosis.
“In addition, glioblastoma-derived cell lines in which mir-21 levels were inhibited displayed decreased anchorage-independent growth (Fig. 4A and B), whereas glioblastoma-derived cell lines expressing Pdcd4 showed increased apoptosis and diminished anchorage-independent growth (Fig. 4A and B).”
Quote in the paperSubstantial claim - Findingown data
Glioblastoma-derived cell lines in which mir-21 expression had been inhibited formed fewer tumors than those that arose after injection of untreated control cell lines.
“We observed that glioblastomaderived cell lines in which mir-21 expression had been inhibited formed fewer tumors and smaller tumors (Fig. 5A) than those that arose after injection of untreated control cell lines.”
Quote in the paperSubstantial claim - Interpretationown data
High mir-21 expression in glioblastoma contributes to tumorigenesis by inhibiting Pdcd4 and its tumor-suppressive functions.
“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.”
Quote in the paperSubstantial claim - Interpretationown data
Tumor growth in glioblastoma xenografts is specifically regulated by Pdcd4.
“confirming that the tumor growth is specifically regulated by Pdcd4.”
Quote in the paperSubstantial claim - Interpretationown data
The data are consistent with regulation of Pdcd4 by mir-21.
“These data are consistent with the regulation of Pdcd-4 by mir-21.”
Quote in the paperSubstantial claim - Interpretationown data
mir-21 regulates Pdcd4.
“the inverse correlation between mir-21/Pdcd4 levels (Fig. 2A and B) strongly suggests that mir-21 regulates Pdcd4.”
Quote in the paperSubstantial claim - Interpretationown data
There is an important functional linkage between mir-21 and Pdcd4 in glioblastoma.
“These critical in vivo findings demonstrate an important functional linkage between mir-21 and Pdcd4”
Quote in the paperSubstantial claim - Premisecitation
Pdcd4 has a binding site for mir-21.
“Pdcd4 has a binding site for mir-21 11,12”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [11]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [12]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Premisecitation
Most glioblastomas examined to date have high levels of mir-21 expression.
“Although glioblastomas harbor diverse oncogenes and mutated tumor-suppressor genes whose pattern of alteration and expression varies considerably from tumor to tumor, 20 most glioblastomas examined to date have high levels of mir-21 expression.11 -14,18”
Quote in the paperNot a substantial claim0 of 5 sources checked- cites [11]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [12]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [13]
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- cites [14]
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- cites [18]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Premisecitation
mir-21 was shown to regulate Pdcd4 in glioblastoma.
“Recently, mir-21 was shown to regulate Pdcd4 in glioblastoma.18”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [18]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Premisecitation
Normal brain tissue expresses Pdcd4.
“Normal brain tissue expresses Pdcd4.19,26,27”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [19]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [26]
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- Premisecitation
Pdcd4 is pro-apoptotic.
“conversely, Pdcd4 has been shown to be pro-apoptotic.24”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [24]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Premisecitation
Pdcd4 is a functional target of mir-21.
“Pdcd4, a known tumor suppressor gene, has been identified as a functional target of mir-21.16,17”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [16]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [17]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Premisecitation
Pdcd4 is a known tumor suppressor gene.
“Pdcd4, a known tumor suppressor gene, has been identified as a functional target of mir-21.16,17”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [16]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [17]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Premisecitation
Mir-21 acts as an anti-apoptotic factor in glioblastoma-derived cell lines.
“Mir-21 has been shown to act as an anti-apoptotic factor in glioblastoma-derived cell lines, 11,12”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [11]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [12]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationown data
Our findings provide strong evidence that, by inhibition of Pdcd4 by mir-21, over-expression contributes to glioblastoma growth.
“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.”
Quote in the paperSubstantial claim - Interpretationreasoning
The small tumors formed by anti-mir-21-treated cells were probably formed by a fraction of glioblastoma-derived cells that had not been transfected in vitro by synthetic anti-mir-21 prior to their injection into mice.
“Similarly, the small tumors formed by anti-mir-21-treated cells were probably formed by a fraction of glioblastoma-derived cells that had not been transfected in vitro by synthetic anti-mir-21 prior to their injection into mice.”
Quote in the paperNot a substantial claim - Interpretationown data
The finding that Pdcd4 protein levels were not detectable is strong evidence that these tumors were formed by cells not expressing Pdcd4.
“The finding that Pdcd4 protein levels were not detectable (Fig. 5D) is strong evidence that these tumors were formed by cells not expressing Pdcd4.”
Quote in the paperNot a substantial claim - Interpretationown data
The high level of mir-21 expression in glioblastoma suggests its potential in contributing to the malignant behavior of glioblastoma.
“The high level of mir-21 expression in human glioblastoma-derived cell lines and glioblastoma primary tumors, compared with that observed in normal brain tissue, suggested its potential in contributing to the malignant behavior of glioblastoma (Fig. 1A and C).”
Quote in the paperSubstantial claim - Interpretationown data
The decreased tumor growth was predominantly a result of Pdcd4 being downregulated by mir-21.
“More importantly, we verified that the decreased tumor growth was predominantly a result of Pdcd4 being downregulated by mir-21.”
Quote in the paperSubstantial claim - Premisecitation
Pdcd4 has been characterized as a tumor suppressor.
“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”
Quote in the paperSubstantial claim0 of 6 sources checked- cites [16]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [21]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [22]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [23]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [24]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [25]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Premisecitation
mir-21 can target several genes.
“More importantly, because mir-21 can target several genes, 10,11 we sought to determine whether the biologic effects we observed following mir-21 inhibition were a consequence of Pdcd4 inhibition.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [10]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [11]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationown data
A possible explanation for this finding is that mir-21 also inhibits other genes contributing to the malignant characteristics of glioblastoma-derived cells.
“A possible explanation for this finding is that mir-21 also inhibits other genes contributing to the malignant characteristics of glioblastoma-derived cells 47,48 .”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [47]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [48]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Premisecitation
Pdcd4 is a described target of mir-21.
“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”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [16]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [17]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [18]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Premisecitation
mir-21 may play an oncogenic role in glioblastoma acting as an antiapoptotic factor.
“Also, mir-21 may play an oncogenic role in glioblastoma acting as an antiapoptotic factor.11 -15”
Quote in the paperSubstantial claim0 of 5 sources checked- cites [11]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [12]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [13]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [14]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [15]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Premisecitation
The combined treatment of glioblastoma with an miR-21 antagonist and pathotropic neural precursor cell-mediated delivery of TRAIL to glioblastoma in vivo resulted in a significant reduction in tumor xenograft growth in mice.
“The combined treatment of glioblastoma with an miR-21 antagonist and pathotropic neural precursor cell -mediated delivery of tumor necrosis factor-related apoptosis -inducing ligand (TRAIL) to glioblastoma in vivo resulted in a significant reduction in tumor xenograft growth in mice.14”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [14]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- May combine two claims. 15
- Classified as probably not a substantial claim. 19
May combine two claims.
Findingown dataAnti-mir-21 treatment or stable overexpression of Pdcd4 in U87 cells decreases colony formation in soft agar.
“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).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataSubcutaneous injection of 5 × 10^6 U251 GFP or U87 GFP cells into immunosuppressed mice gives rise to tumors first palpable by day 7 and reaching 1.5 cm^3 by day 30.
“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.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Findingown dataHigh cellularity and microvascular proliferation and the presence of necrosis, all defining features of glioblastoma, are evident in these tumors.
“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.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataMice that received cell lines overexpressing Pdcd4 showed a substantial decrease in tumor size and/or complete ablation of tumor growth.
“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).”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationPdcd4 is a suppressor of malignant transformation and tumor progression and inhibits invasion and intravasation by tumor cells.
“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”
Quote in the paperSubstantial claim0 of 5 sources checked- cites [16]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [22]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [23]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [24]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [25]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataTransfection efficiency was routinely 80%-90%.
“We routinely achieved 80% -90% transfection efficiency.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationmiR-21 is one of the most commonly overexpressed miRNAs in solid tumors.
“MiR-21 has been identified as one of the most commonly overexpressed miRNAs in solid tumors.9,10”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [9]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [10]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationGlioblastomas are the most malignant brain tumors of glial origin.
“Glioblastomas are the most malignant brain tumors of glial origin.21,28”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [21]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [28]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationmiR-21 is a member of a class of miRNAs that are frequently overexpressed in solid tumors and may contribute to oncogenesis.
“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.”
Quote in the paperNot a substantial claim0 of 7 sources checked- cites [8]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [9]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [10]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [11]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [12]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [13]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [14]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
PremisecitationLow levels of mir-21 are expressed in grade II and grade III gliomas, whereas higher levels are observed in glioblastoma.
“Low levels of mir-21 are expressed in grade II and grade III gliomas, whereas higher levels are observed in glioblastoma.13,15”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [13]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [15]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Classified as probably not a substantial claim.
Premisecitationmir-21 can potentially target several genes.
“because mir-21 can potentially target several genes, 11”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAll experiments were performed at least 3 times.
“All of the experiments were performed at least 3 times.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationGlioblastomas are among the most resistant of all human tumors to available modalities of treatment, perhaps because of their genetic heterogeneity and invasiveness.
“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”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [28]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
PremisecitationIn glioblastoma, mir-21 is overexpressed and its expression correlates with glioma grade.
“In glioblastoma, mir-21 is overexpressed, and its expression correlates with glioma grade.8,10 -15”
Quote in the paperSubstantial claim0 of 7 sources checked- cites [8]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [10]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [11]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [12]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [13]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [14]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [15]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Interpretationown dataTumor growth is specifically regulated by PDCD4 and represents a crucial functional linkage between mir-21 and PDCD4 in vivo.
“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.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationNegative regulation of Pdcd4 by mir-21 has recently been demonstrated in glioblastoma and in several other tumors.
“Negative regulation of Pdcd4 by mir-21 has recently been demonstrated in glioblastoma and in several other tumors.41 -44”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [41]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [42]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [43]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [44]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationPdcd4 is a pro-apoptotic gene that may function by binding eIF4A and inhibiting translation initiation.
“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”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [38]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [39]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [40]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationElevated expression of miR-21 has been documented in several different types of cancer including breast, brain, prostate, ovaries, colon, pancreas, cervical carcinoma, hepatocellular carcinoma, chronic lymphocytic leukemia, and acute myeloid leukemia.
“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”
Quote in the paperNot a substantial claim0 of 8 sources checked- cites [9]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [16]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [11]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [12]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [13]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [14]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [15]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [29]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAn additional major pathway of Pdcd4 inactivation is the increased proteasomal degradation of Pdcd4 due to its phosphorylation by Akt and p70(S6K).
“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.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [46]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitationmir-21 has been shown to downregulate PTEN, initiate caspase activity, and lead to decreased apoptosis in hepatocellular carcinoma.
“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”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [35]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [45]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Interpretationown dataOur 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.
“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.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
InterpretationcitationThe anti-apoptotic activity for mir-21 in glioblastoma lines that we observed is consistent with previously published data.
“The anti-apoptotic activity for mir-21 in glioblastoma lines that we observed is consistent with previously published data.11,12”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [11]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [12]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationmiR-21 has been shown to inhibit gemcitabine-induced apoptosis by modulating PTEN and the PI3K pathway.
“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”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [51]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown dataThe xenograft experiments were performed with 5 independent experiments and total n=24 animals per condition.
“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.”
Quote in the paperNot a substantial claim- Also stated in: § Discussion · plain
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitationmir-21 regulation of 2 important matrix metalloproteinase inhibitors, RECK and TIMP3, may be of importance in vivo.
“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”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [13]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Classified as probably not a substantial claim. May combine two claims.
Interpretationown dataInhibiting Pdcd4 degradation or enhancing its expression may be a therapeutic strategy of importance for glioblastoma.
“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.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationmiR-21 has been shown to inhibit apoptosis by regulating Bcl-2 in murine breast cancer model.
“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”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [49]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [50]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
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?
miR-21 is overexpressed in almost all cancer types, and its upregulation promotes cell proliferation, invasion, and metastatic behavior.
“miR-21 is a well-known miRNA, found to be overexpressed in almost all cancer types, where its upregulation promotes cell proliferation, invasion, and metastatic behavior.”
From Potential Therapeutic Effects of Exosomes Packed With a miR-21-Sponge Construct in a Rat Model of Glioblastoma (2019) · cites this paper as [18]
The Discussion (page unavailable) reports elevated miR-21 in several cancer types, not almost all cancer types. The Abstract (page unavailable) reports that reducing miR-21 decreases proliferation in glioblastoma-derived cells, but this study does not establish that miR-21 upregulation promotes invasion or metastasis; those topics appear in titles of cited works in the References. (LLM, conf=0.87)
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 [18]
The Results section on inhibiting miR-21 reports that reducing it in glioblastoma-derived cell lines decreased proliferation and anchorage-independent growth; the Discussion also links high miR-21 expression to malignant behavior. The paper does not report experimentally overexpressing miR-21 to show an increased proliferation rate, and its findings concern glioblastoma-derived cell lines rather than cell lines generally. Page numbers are unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredmiR-21 targets several genes such as PDCD4, TIMP3, and RECK, which are key regulators of apoptotic and metastatic pathways.
“miR-21 targets several genes such as PDCD4, TIMP3, and RECK, which are key regulators of apoptotic and metastatic pathways (17–23).”
From Potential Therapeutic Effects of Exosomes Packed With a miR-21-Sponge Construct in a Rat Model of Glioblastoma (2019) · cites this paper as [18]
Overexpression of PDCD4 leads to decreased anchorage-independent growth in GBM-derived cell lines and decreased tumor growth in a GBM xenograft model.
“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.
Colony-count rescue is described in opposite directions
MinorThe results say that adding siRNA to Pdcd4 increases colony formation relative to anti-mir-21 alone. The discussion instead says the combined treatment produces 85% as many colonies as anti-mir-21 alone, which would be a decrease.
“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).”
“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.”
TUNEL results are assigned to the cell-cycle figure panel
MinorThe results cite Fig. 3B for TUNEL staining, but the figure caption identifies panel B as cell-cycle analysis; it identifies panel C as TUNEL staining.
“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.”
“(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.”
Figure 1B identifies different Western blot targets
MinorThe caption calls panel B a Western blot of mir-21, then says the blot quantifies Pdcd4 protein using an anti-Pdcd4 antibody.
“(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).”
“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.
Cites a retracted work: 10.1002/jcb.20982
InfoThe cited work was retracted on 2025-04-28 (notice 10.1002/jcb.70023), not before this paper was published (2011-06-01).
Cited work 10.1002/jcb.20982 · retracted 2025-04-28 · notice 10.1002/jcb.70023 · this paper published 2011-06-01
“Kutay, 2006, Journal of cellular biochemistry, 99, 671, 10.1002/jcb.20982”
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 · see citing works
RetractedMicroRNA signatures in human cancers
Calin, G. A., & Croce, C. M. (2006) · Nature reviews. Cancer · doi:10.1038/nrc1997 · Cited by 7,592 · see citing works
Oncomirs — microRNAs with a role in cancer
Esquela‐Kerscher, A., & Slack, F. J. (2006) · Nature reviews. Cancer · doi:10.1038/nrc1840 · Cited by 7,038 · see citing works
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 · see citing works
Real-time quantification of microRNAs by stem-loop RT-PCR
Chen, C. (2005) · Nucleic Acids Research · doi:10.1093/nar/gni178 · Cited by 4,931 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
Frankel, L. B., Christoffersen, N. R., Jacobsen, A., Lindow, M., Krogh, A., & Lund, A. H. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m707224200 · Cited by 1,141 · see citing works
MicroRNA-21 Targets the Tumor Suppressor Gene Tropomyosin 1 (TPM1)
Zhu, S., Si, M.-L., Wu, H., & Mo, Y.-Y. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m611393200 · Cited by 1,090 · see citing works
MicroRNA-21 targets tumor suppressor genes in invasion and metastasis
Zhu, S., Wu, H., Wu, F., Nie, D., Sheng, S., & Mo, Y.-Y. (2008) · Cell Research · doi:10.1038/cr.2008.24 · Cited by 1,051 · see citing works
miR‐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
MicroRNA 21 Promotes Glioma Invasion by Targeting Matrix Metalloproteinase Regulators
Gabriely, G., Wurdinger, T., Kesari, S., Esau, C. C., Burchard, J., Linsley, P. S., & Krichevsky, A. M. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.00479-08 · Cited by 888 · see citing works
MicroRNA-21 targets tumor suppressor genes in invasion and metastasis
Shuomin, Zhu, Hailong, H., Wu, Fangting, Daotai, Nie, Shijie, Sheng, Yin-Yuan, et al. (2008) · Cell Research · Cited by 831 · see citing works
How microRNAs control cell division, differentiation and death
Miska, E. A. (2005) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2005.08.005 · Cited by 816 · see citing works
MicroRNA Expression Profiles in Serous Ovarian Carcinoma
Nam, E. J., Yoon, H., Kim, S. W., Kim, H., Kim, Y. T., Kim, J., Kim, J. W., & Kim, S. (2008) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-07-1731 · Cited by 735 · see citing works
MicroRNA-21 promotes cell transformation by targeting the programmed cell death 4 gene
Lu, Z., Liu, M., Stribinskis, V, Klinge, C. M., Ramos, K. S., Colburn, N. H., & Li, Y. (2008) · Oncogene · doi:10.1038/onc.2008.72 · Cited by 711 · see citing works
Self-citationMicroRNA-21 Targets a Network of Key Tumor-Suppressive Pathways in Glioblastoma Cells
Papagiannakopoulos, T., Shapiro, A., & Kosik, K. S. (2008) · Cancer Research · doi:10.1158/0008-5472.can-08-1305 · Cited by 705 · see citing works
Gaur, A., Jewell, D. A., Liang, Y., Ridzon, D., Moore, J. H., Chen, C., Ambros, V. R., & Israel, M. A. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-2698 · Cited by 593 · see citing works
Self-citationMicroRNAs and their regulatory roles in animals and plants
Zhang, B., Wang, Q., & Pan, X. (2006) · Journal of Cellular Physiology · doi:10.1002/jcp.20869 · Cited by 553 · see citing works
Quantitative technologies establish a novel microRNA profile of chronic lymphocytic leukemia
Fulci, V., Chiaretti, S., Goldoni, M., Azzalin, G., Carucci, N., Tavolaro, S., Castellano, L., Magrelli, A., Citarella, F., Messina, M., et al. (2007) · Blood · doi:10.1182/blood-2006-12-062398 · Cited by 498 · see citing works
Yang, H.-S., Jansen, A. P., Komar, A. A., Zheng, X., Merrick, W. C., Costes, S., Lockett, S. J., Sonenberg, N., & Colburn, N. H. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.1.26-37.2003 · Cited by 494 · see citing works
Self-citationGliomagenesis: genetic alterations and mouse models
Holland, E. C. (2001) · Nature Reviews Genetics · doi:10.1038/35052535 · Cited by 453 · see citing works
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
Patterns of Known and Novel Small RNAs in Human Cervical Cancer
Lui, W., Pourmand, N., Patterson, B. K., & Fire, A. Z. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-0561 · Cited by 430 · see citing works
MicroRNA-21 is Overexpressed in Pancreatic Cancer and a Potential Predictor of Survival
Dillhoff, M. E., Liu, J., Frankel, W. L., Croce, C. M., & Bloomston, M. (2008) · Journal of Gastrointestinal Surgery · doi:10.1007/s11605-008-0584-x · Cited by 409 · see citing works
Corsten, M. F., Miranda, R., Kasmieh, R., Krichevsky, A. M., Weissleder, R., & Shah, K. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-1045 · Cited by 406 · see citing works
MicroRNA expression profiling in relation to the genetic heterogeneity of acute myeloid leukemia
Jongen‐Lavrencic, M., Sun, S. M., Dijkstra, M. K., Valk, P. J. M., & Löwenberg, B. (2008) · Blood · doi:10.1182/blood-2008-01-133355 · Cited by 401 · see citing works
Wickramasinghe, N. S. M. D., Manavalan, T. T., Dougherty, S. M., Riggs, K. A., Li, Y., & Klinge, C. M. (2009) · Nucleic Acids Research · doi:10.1093/nar/gkp117 · Cited by 391 · see citing works
Li, T., Li, D., Sha, J., Sun, P., & Huang, Y. (2009) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2009.03.077 · Cited by 370 · see citing works
Zhou, X., Ren, Y., Moore, L. M., Mei, M., You, Y., Xu, P., Wang, B., Wang, G., Jia, Z., Pu, P., et al. (2010) · Laboratory Investigation · doi:10.1038/labinvest.2009.126 · Cited by 358 · see citing works
Mammalian microRNAs: a small world for fine-tuning gene expression
Sevignani, C., Calin, G. A., Siracusa, L. D., & Croce, C. M. (2006) · Mammalian Genome · doi:10.1007/s00335-005-0066-3 · Cited by 357 · see citing works
Bourguignon, L., Spevak, C. C., Wong, G., Xia, W., & Gilad, E. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.027466 · Cited by 316 · see citing works
Mechanisms of translational control by the 3′ UTR in development and differentiation
de Moor, C. H., Meijer, H. A., & Lissenden, S. (2005) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2004.11.007 · Cited by 310 · see citing works
The tumour suppressor Pdcd4: recent advances in the elucidation of function and regulation
Lankat–Buttgereit, B., & Göke, R. (2009) · Biology of the Cell · doi:10.1042/bc20080191 · Cited by 307 · see citing works
Selaru, F. M., Olaru, A., Kan, T., David, S., Cheng, Y., Mori, Y., Yang, J. P., Paun, B. C., Jin, Z., Agarwal, R., et al. (2009) · Hepatology · doi:10.1002/hep.22838 · Cited by 286 · see citing works
An autoregulatory loop mediated by miR-21 and PDCD4 controls the AP-1 activity in RAS transformation
Talotta, F., Cimmino, A., Matarazzo, M. R., Casalino, L., De Vita, G., D'Esposito, M., Di Lauro, R., & Verde, P. (2009) · Oncogene · doi:10.1038/onc.2008.370 · Cited by 242 · see citing works
MicroRNA-21 down-regulates the expression of tumor suppressor PDCD4 in human glioblastoma cell T98G
Chen, Y., Liu, W., Chao, T., Zhang, Y., Yan, X., Gong, Y., Qiang, B., Yuan, J., Sun, M., & Peng, X. (2008) · Cancer Letters · doi:10.1016/j.canlet.2008.06.034 · Cited by 217 · see citing works
Yao, Q., Xu, H. M., Zhang, Q.-Q., Zhou, H., & Qu, L. (2009) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2009.08.044 · Cited by 204 · see citing works
Promising molecular targets for cancer prevention: AP-1, NF-κB and Pdcd4
Young, M. R., Yang, H., & Colburn, N. H. (2003) · Trends in Molecular Medicine · doi:10.1016/s1471-4914(02)00009-6 · Cited by 167 · see citing works
Self-citationTranslation Inhibitor Pdcd4 Is Targeted for Degradation during Tumor Promotion
Schmid, T., Jansen, A. P., Baker, A. R., Hegamyer, G., Hagan, J. P., & Colburn, N. H. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-1719 · Cited by 151 · see citing works
Self-citationStandart, N., & Jackson, R. J. (2007) · Genes & Development · doi:10.1101/gad.1591507 · Cited by 127 · see citing works
Pdcd4, a colon cancer prognostic that is regulated by a microRNA
Allgayer, H. (2009) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2009.09.001 · Cited by 123 · see citing works
Crystal structure of the eIF4A–PDCD4 complex
Chang, J. H., Cho, Y. H., Sohn, S. Y., Choi, J. M., Kim, A., Kim, Y. C., Jang, S. K., & Cho, Y. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0808275106 · Cited by 120 · see citing works
Frequent loss of PDCD4 expression in human glioma: Possible role in the tumorigenesis of glioma
Gao, F., Zhang, P., Zhou, C., Li, J., Wang, Q., Zhu, F., Ma, C., Sun, W., & Zhang, L. (2007) · Oncology Reports · doi:10.3892/or.17.1.123 · Cited by 100 · see citing works
Structural Basis for Inhibition of Translation by the Tumor Suppressor Pdcd4
LaRonde-LeBlanc, N. A., Santhanam, A. N., Baker, A. R., Wlodawer, A., & Colburn, N. H. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.00867-06 · Cited by 76 · see citing works
Self-citationGao, F., Wang, X., Zhu, F., Wang, Q., Zhang, X., Guo, C., Zhou, C., Ma, C., Sun, W., Zhang, Y., et al. (2009) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2008.00497.x · Cited by 66 · see citing works
Programmed Cell Death Protein 4 (PDCD4) Acts As a Tumor Suppressor in Neuroendocrine Tumor Cells
Göke, R., Gregel, C. M., Göke, A., Arnold, R., Schmidt, H., & Lankat–Buttgereit, B. (2004) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1294.024 · Cited by 49 · see citing works
Estradiol downregulates miR-21 expression and miR-21 gene targets in MCF-7 breast cancer cells.
Wickramasinghe, N. S. M. D., Manavalan, T. T., Riggs, K., Li, Y., & Klinge, C. M. (2009) · Cancer Research · doi:10.1158/0008-5472.sabcs-3051 · Cited by 45 · see citing works
Molecularly targeted therapies for malignant glioma: rationale for combinatorial strategies
Thaker, N. G., & Pollack, I. F. (2009) · Expert Review of Neurotherapeutics · doi:10.1586/ern.09.116 · Cited by 42 · see citing works
Bourguignon, L. Y. W., Spevak, C. C., & Wong, G. (2010) · Cancer Research · doi:10.1158/1538-7445.am10-2039
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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 302 · 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…”
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 · see citing works
“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 207 · see citing works
“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 176 · see citing works
Fang, H., Xie, J., Zhang, M., et al. (2017) · PubMed · Cited by 165 · see citing works
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 · see citing works
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 · see citing works
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 153 · see citing works
“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 142 · see citing works
“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 · see citing works
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 125 · see citing works
“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 · see citing works
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 120 · see citing works
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 118 · see citing works
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 114 · see citing works
“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 110 · see citing works
“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 107 · see citing works
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 · see citing works
Lee, H. K., Bier, A., Cazacu, S., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0054652 · Cited by 105 · see citing works
“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 104 · see citing works
“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 · see citing works
“…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 · see citing works
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 94 · see citing works
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 · see citing works
“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 · see citing works
Role of microRNAs in glioblastoma
Chen, M., Medarova, Z. O., & Moore, A. V. (2021) · Oncotarget · doi:10.18632/oncotarget.28039 · Cited by 86 · see citing works
“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 · see citing works
“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 · see citing works
“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 · see citing works
Strategies to Modulate MicroRNA Functions for the Treatment of Cancer or Organ Injury
Lee, T. J., Yuan, X., Kerr, K. M., Yoo, J. Y., Kim, D., Kaur, B., & Eltzschig, H. K. (2020) · Pharmacological Reviews · doi:10.1124/pr.119.019026 · Cited by 78 · see citing works
“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 · see citing works
The Role of microRNA-21 in the Onset and Progression of Cancer
Singh, A. K., Singh, A. K., Giri, R., Kumar, D., Sharma, R., Vališ, M., Kuča, K., & Garg, N. (2021) · Future Medicinal Chemistry · doi:10.4155/fmc-2021-0096 · Cited by 77 · see citing works
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 73 · see citing works
“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 71 · see citing works
“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 · see citing works
“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 · see citing works
The role of MiRNA-21 in gliomas: Hope for a novel therapeutic intervention?
Aloizou, A.-M., Pateraki, G., Siokas, V., Mentis, A.-F. A., Liampas, I., Lazopoulos, G., Kovatsi, L., Mitsias, P. D., Bogdanos, D. P., Paterakis, K., et al. (2020) · Toxicology Reports · doi:10.1016/j.toxrep.2020.11.001 · Cited by 69 · see citing works
“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., Aghdam, Z. B., Salami, R., Salami, M., Vakili, O., & Aghadavod, E. (2022) · Cellular & Molecular Biology Letters · doi:10.1186/s11658-022-00354-4 · Cited by 66 · see citing works
“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
Wang, G., Wang, J. J., Tang, H., & To, S. S. T. (2015) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2015.07.001 · Cited by 63 · see citing works
Biomarkers of Cancer Stem Cells for Experimental Research and Clinical Application
Saito, S., Ku, C., Wuputra, K., Pan, J.-B., Lin, C., Lin, Y., Wu, D., & Yokoyama, K. K. (2022) · Journal of Personalized Medicine · doi:10.3390/jpm12050715 · Cited by 66 · see citing works
“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
Yang, M., Liu, R., Li, X., Liao, J., Pu, Y., Pan, E., Yin, L., & Wang, Y. (2014) · Molecules and Cells · doi:10.14348/molcells.2014.0147 · Cited by 60 · see citing works
“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).”
ResultJiang, Z., Liang, L., Hou, Z., Liu, W., Wang, H., Zhou, T., Li, Y., & Chen, S. (2019) · Cellular Signalling · doi:10.1016/j.cellsig.2019.109483 · Cited by 58 · see citing works
Development of targeted therapies in treatment of glioblastoma.
Xu, Y., Gao, P., Sun, Y., et al. (2015) · PubMed · doi:10.7497/j.issn.2095-3941.2015.0020 · Cited by 58 · see citing works
Emerging Roles of microRNA in Modulating Cell‐Death Processes in Malignant Glioma
Palumbo, S., Miracco, C., Pirtoli, L., & Comincini, S. (2013) · Journal of Cellular Physiology · doi:10.1002/jcp.24446 · Cited by 58 · see citing works
“…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…”
Tao, L., Wu, Y., & Zhang, S. (2019) · Neoplasma · doi:10.4149/neo_2018_181207n930 · Cited by 56 · see citing works
The critical roles of miR-21 in anti-cancer effects of curcumin.
Chen, J., TieFeng, X., & Chen, C. (2015) · PubMed Central · doi:10.3978/j.issn.2305-5839.2015.09.20 · Cited by 55 · see citing works
“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 · see citing works
Extracellular Vesicles and MicroRNAs: Their Role in Tumorigenicity and Therapy for Brain Tumors
Bronisz, A., Godlewski, J. A., & Chiocca, E. A. (2016) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-015-0293-4 · Cited by 56 · see citing works
“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 · see citing works
Ananta, J. S., Paulmurugan, R., & Massoud, T. F. (2016) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.6b00388 · Cited by 53 · see citing works
Wang, Y., Wang, S., Wu, Y., Ren, Y., Li, Z., Yao, X., Zhang, C., Ye, N., Jing, C., Dong, J., et al. (2017) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-16-0606 · Cited by 53 · see citing works
Salvi, A., Abeni, E., Portolani, N., Barlati, S., & Petro, G. D. (2012) · International Journal of Oncology · doi:10.3892/ijo.2012.1716 · Cited by 52 · see citing works
“It is commonly upregulated in several types of malignancies, included HCC (19-22).”
BackgroundLi, M., Li, J., Liu, L., Li, W., Yang, Y., & Yuan, J. X. (2013) · Cancers · doi:10.3390/cancers5041306 · Cited by 50 · see citing works
Upregulation of miR-107 Inhibits Glioma Angiogenesis and VEGF Expression
Chen, L., Li, Z., Xu, S.-Y., et al. (2015) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-015-0225-3 · Cited by 50 · see citing works
“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 · see citing works
“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 49 · see citing works
Itani, S., Kunisada, T., Morimoto, Y., Yoshida, A., Sasaki, T., Ito, S., Ouchida, M., Sugihara, S., Shimizu, K., & Ozaki, T. (2012) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-012-1223-1 · Cited by 48 · see citing works
Krichevsky, A. M., & Uhlmann, E. J. (2019) · Neurotherapeutics · doi:10.1007/s13311-018-00702-3 · Cited by 47 · see citing works
Overexpressed miRNA-137 Inhibits Human Glioma Cells Growth by Targeting Rac1
Sun, G., Cao, Y., Shi, L., et al. (2013) · Cancer Biotherapy and Radiopharmaceuticals · doi:10.1089/cbr.2012.1380 · Cited by 46 · see citing works
Nutrient-Gene Interaction in Colon Cancer, from the Membrane to Cellular Physiology
Hou, T. Y., Davidson, L. A., Kim, E., Fan, Y., Fuentes, N. R., Triff, K., & Chapkin, R. S. (2016) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-071715-051039 · Cited by 45 · see citing works
“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 46 · see citing works
Junker, F., Chabloz, A., Koch, U., & Radtke, F. (2015) · Blood · doi:10.1182/blood-2014-12-618892 · Cited by 45 · see citing works
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 44 · see citing works
HBx-induced miR-21 suppresses cell apoptosis in hepatocellular carcinoma by targeting interleukin-12
Yin, D., Wang, Y., Sai, W., et al. (2016) · Oncology Reports · doi:10.3892/or.2016.5026 · Cited by 43 · see citing works
“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 42 · see citing works
Li, Y., Wang, X., Wang, X., Wan, L., Liu, Y., Shi, Y., Zhang, L., Fang, Z., & Wei, Z. (2018) · Biology of Reproduction · doi:10.1093/biolre/ioy052 · Cited by 42 · see citing works
Fawzy, M. S., Toraih, E. A., Ibrahiem, A. T., Abdeldayem, H., Mohamed, A. O., & Abdel‐Daim, M. M. (2017) · PLoS ONE · doi:10.1371/journal.pone.0187310 · Cited by 41 · see citing works
“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 · see citing works
Giunti, L., Ros, M. D., Vinci, S., Gelmini, S., Iorio, A. L., Buccoliero, A. M., Cardellicchio, S., Castiglione, F., Genitori, L., de Martino, M., et al. (2015) · Europe PMC (PubMed Central) · Cited by 41 · see citing works
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 40 · see citing works
“…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 · see citing works
“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 · see citing works
“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 · see citing works
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 · see citing works
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 · see citing works
Bullock, M. D., Pickard, K. M., Mitter, R., Sayan, E., Primrose, J. M., Ivan, C., Călin, G. A., Thomas, G. J., Packham, G., & Mirnezami, A. H. (2015) · Oncotarget · doi:10.18632/oncotarget.3225 · Cited by 37 · see citing works
“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 · see citing works
Noncoding RNAs in Glioblastoma
Zhang, Y., Cruickshanks, N. A., Pahuski, M., Yuan, F., Dutta, A., Schiff, D., Purow, B. W., & Abounader, R. (2017) · Codon Publications eBooks · doi:10.15586/codon.glioblastoma.2017.ch6 · Cited by 38 · see citing works
Dissimilar microRNA-21 functions and targets in trophoblastic cell lines of different origin
Chaiwangyen, W., Ospina‐Prieto, S., Photini, S. M., et al. (2015) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2015.08.018 · Cited by 35 · see citing works
Anti-cancer Therapies in High Grade Gliomas
Tănase, C., Enciu, A., Mihai, S., Neagu, A. I., Calenic, B., & Cruceru, M. L. (2013) · Current Proteomics · doi:10.2174/1570164611310030007 · Cited by 35 · see citing works
“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 35 · see citing works
“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 · see citing works
“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
Shortridge, M. D., Chaubey, B., Zhang, H.-Y., et al. (2023) · ACS Chemical Biology · doi:10.1021/acschembio.2c00502 · Cited by 33 · see citing works
MiRNAs as major players in brain health and disease: current knowledge and future perspectives
Kapplingattu, S. V., Bhattacharya, S., & Adlakha, Y. K. (2025) · Cell Death Discovery · doi:10.1038/s41420-024-02283-x · Cited by 39 · see citing works
Shen, L., Ling, M., Li, Y., Xu, Y., Zhou, Y., Ye, J., Pang, Y., Zhao, Y., Jiang, R., Zhang, J., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0057652 · Cited by 33 · see citing works
“MiR-21 is a negative regulator of Pdcd4, and Pdcd4 likely contributes to miR21-induced tumor cell invasion and anti-apoptosis [18,19].”
BackgroundDou, Y., Jiang, X., Xie, H., He, J., & Xiao, S. (2019) · Journal of Ovarian Research · doi:10.1186/s13048-019-0573-6 · Cited by 33 · see citing works
“related to poor prognosis of ovarian tumor patients [98].”
BackgroundGuo, Y., Hu, G., Xia, Y., Li, H., Ji, Y., Zhang, J., Chen, Y., Guo, H., Yang, Y., Wang, Y., et al. (2022) · Bioactive Materials · doi:10.1016/j.bioactmat.2022.02.013 · Cited by 33 · see citing works
Yeh, W., Lin, H., Huang, C.-Y., Huang, B., Lin, C., Lu, D., & Wei, K. (2015) · Oncotarget · doi:10.18632/oncotarget.6092 · Cited by 32 · see citing works
Shen, Z., & She, Q. (2018) · Cellular Physiology and Biochemistry · doi:10.1159/000493447 · Cited by 32 · see citing works
Host Non-Coding RNA Regulates Influenza A Virus Replication
Liao, Y., Guo, S., Liu, G., Qiu, Z., Wang, J., Yang, D., Tian, X., Qiao, Z., Ma, Z., & Liu, Z. (2021) · Viruses · doi:10.3390/v14010051 · Cited by 32 · see citing works
Hwang, S., Jeong, Y., & Chang, Y. (2020) · PubMed Central · Cited by 31 · see citing works
Jia, X., Nie, Q., Zhang, X., et al. (2016) · Infection and Immunity · doi:10.1128/iai.00688-16 · Cited by 31 · see citing works
RNA–Small-Molecule Interaction: Challenging the “Undruggable” Tag
Kaur, J., Sharma, A., Mundlia, P., Sood, V., Pandey, A., Singh, G., & Barnwal, R. P. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.3c01354 · Cited by 30 · see citing works
Chen, B., Huang, S. G., Ju, L., Li, M., Nie, F. F., Zhang, Y., Zhang, Y. H., Chen, X., & Gao, F. (2016) · Brazilian Journal of Medical and Biological Research · doi:10.1590/1414-431x20155020 · Cited by 30 · see citing works
“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).”
BackgroundWei, X., Ye, M., Jia, H., et al. (2024) · Biosensors and Bioelectronics · doi:10.1016/j.bios.2024.116975 · Cited by 29 · see citing works
Glioma-Derived Extracellular Vesicles – Far More Than Local Mediators
Tankov, S., & Walker, P. R. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.679954 · Cited by 30 · see citing works
“In vitro suppression of miR-21 decreased proliferation and increased apoptosis in GBM cells (28).”
BackgroundZhang, Y., Köllmer, M., Buhrman, J. S., Tang, M. Y., & Gemeinhart, R. A. (2014) · Peptides · doi:10.1016/j.peptides.2014.06.008 · Cited by 29 · see citing works
“Tumor suppressor genes, PDCD4 and SERPINB5, have been reported as being miR-21 suppressed genes [21,33].”
Halle, B., Marcusson, E. G., Aaberg-Jessen, C., et al. (2015) · Journal of Neuro-Oncology · doi:10.1007/s11060-015-1947-2 · Cited by 27 · see citing works
The Role of Non-coding RNAs in Viral Myocarditis
Zhang, C., Xiong, Y., Zeng, L., Peng, Z., Liu, Z., Zhan, H., & Yang, Z. (2020) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2020.00312 · Cited by 27 · see citing works
“…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
- 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 › Genetics › 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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