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120 publications mentioning mmu-mir-22 (showing top 100)

Open access articles that are associated with the species Mus musculus and mention the gene name mir-22. Click the [+] symbols to view sentences that include the gene name, or the word cloud on the right for a summary.

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[+] score: 352
Inhibition of Jun expression or activity decreased HuR expression while overexpression of Jun increased HuR level (Fig.   7a), which is opposite from the alteration of miR-22 expression after the same treatment (Fig. 6b). [score:11]
H&E staining of these tumours showed decreased cell mitosis in the miR-22 -overexpressing group and increased mitosis in the HuR -overexpressing group, whereas xenografts with both miR-22 and HuR overexpression exhibited more cell mitosis than xenografts with miR-22 overexpression alone (Fig. 5f and g). [score:9]
Taken together, these results confirmed that miR-22 functioned as a tumour-suppressive miRNA to inhibit SW480 proliferation and migration by targeting HuR. [score:7]
Similarly, introduction of a JNK (c-Jun N-terminal kinase) specific inhibitor SP600125, which was used to inhibit Jun activity, significantly increased the expression levels of miR-22, pri-miR-22 and C17orf91 (Fig. 6b- d). [score:7]
miR-22 functioned as a tumour-suppressive miRNA in CRC to inhibit CRC proliferation and migration and tumour growth by targeting HuR. [score:7]
As anticipated, mimics of miR-22 and miR-129 both inhibited HuR expression, while inhibitors of them increased HuR levels (Fig. 3j). [score:7]
Thus, this feedback regulation may explain the widespread downregulation of miR-22 and the overexpression of HuR in CRC. [score:7]
Overexpression of miR-22 inhibits HIF-1α and VEGF, thus suppressing CRC cell angiogenesis [38]. [score:7]
As shown in Fig. 6f and g, Jun was successfully recruited by binding site 1, site 2 and site 4. However, Jun could not bind site 3. The results further confirmed that Jun transcriptionally repressed miR-22 by binding directly at site 1, site 2 and site 4 in C17orf91 promoter regions, but not site 3. Finally, we tested if Jun could affect HuR expression by inhibiting miR-22. [score:6]
We found that an important tumour-suppressive miRNA, miR-22, was significantly downregulated in CRC tissues and inversely correlated with HuR in both CRC tissues and CRC cell lines. [score:6]
We also performed Transwell assays and found that overexpression of miR-22 inhibited SW480 cell migration, whereas inhibition of miR-22 promoted migration (Fig. 4g and h). [score:6]
As shown in Fig. 6f and g, Jun was successfully recruited by binding site 1, site 2 and site 4. However, Jun could not bind site 3. The results further confirmed that Jun transcriptionally repressed miR-22 by binding directly at site 1, site 2 and site 4 in C17orf91 promoter regions, but not site 3. Finally, we tested if Jun could affect HuR expression by inhibiting miR-22. [score:6]
In this study, we showed that upregulated HuR functions as a potent oncogene in promoting CRC proliferation and migration and is a target gene of miR-22. [score:6]
In breast cancer, miR-22 inhibits cell invasion and migration by targeting Sp1, CD147 and GLUT1 [32, 33]. [score:5]
HuR showed higher expression levels in CRC cell lines than those in NCM460, whereas miR-22 and miR-129 expression levels were lower in the CRC cell lines (Fig.   3a, b and d). [score:5]
These results revealed the tumour-suppressive role of miR-22 in vivo functioning by targeting HuR. [score:5]
Moreover, the onco-transcription factor Jun was found to suppress miR-22 expression at the transcriptional level. [score:5]
To validate the contribution of miR-22 -induced HuR inhibition on CRC tumourigenesis in vivo, we injected SW480 cells overexpressing miR-22 and/or HuR into the armpits of nude mice to construct a xenograft mo del for CRC. [score:5]
Considering that miR-22 had a greater inhibitory effect on HuR than miR-129, we next focused on miR-22 to explore the consequences of miR-22 -driven HuR suppression in CRC. [score:5]
g and i Recovery experiments indicated that the suppression of SW480 migration by miR-22 was due to its inhibitory effect on HuR. [score:5]
miR-22 inhibits SW480 proliferation and migration in vitro by targeting HuR. [score:5]
Considering our results, this inhibition might be explained by ERK-activated Jun, which could then inhibit miR-22. [score:5]
miR-22 suppresses CRC tumour growth in vivo by targeting HuR. [score:5]
Some studies have reported that Jun can inhibit p53 expression and activity [61, 62], whereas p53 can transcriptionally activate miR-22 [63, 64]. [score:5]
In gastric cancer, miR-22 inhibits both tumour proliferation and metastasis by targeting MMP14 and Snail [34]. [score:5]
b, e and f Recovery experiments indicated that the suppression of SW480 proliferation by miR-22 was due to its inhibitory effect on HuR. [score:5]
Because a double -negative feedback is equal to positive feedback and is known for its ability to amplify a response into a self-sustained mode that is independent of the original stimuli, the feedback loop composed of Jun, miR-22 and HuR may minimize miR-22 expression and amplify HuR expression in CRC cells, thus allowing CRC cells to become more autonomous, for example, to reproduce more rapidly and to metastasize to new microenvironments. [score:5]
We also found that miR-22 inhibits CRC cell proliferation and migration in vitro and decelerates xenografted tumour growth in vivo by targeting HuR. [score:5]
Our findings highlight the critical roles of the Jun/miR-22/HuR regulatory axis in CRC progression and may provide attractive potential targets for CRC prevention and treatment. [score:4]
A similar result was observed after deleting site 2 and site 4 gradually, but this did not occur with site 3, indicating that site 3 had little effect on the expression regulation of miR-22 (Fig. 6e). [score:4]
We demonstrated that miR-22 directly bound to the 3’-UTR of HuR and led to inhibition of HuR protein, which repressed CRC proliferation and migration in vitro and decelerated CRC xenografted tumour growth in vivo. [score:4]
miR-22 and miR-129 can inhibit HuR by binding to its 3’-UTR. [score:3]
It should be noted that Jun might also regulate miR-22 via an indirect mechanism. [score:3]
Restoration of HuR diminished the tumour-suppressive effect of miR-22. [score:3]
Pri-miR-22 is downregulated in CRC tissues compared with that in normal adjacent tissues. [score:3]
Fig. 2HuR is a potential target gene of miR-22 and miR-129. [score:3]
j Western blot analysis of HuR levels in 3 CRC cell lines after treatment with miR-22/miR-129 mimic or inhibitor. [score:3]
We used the mutant plasmids to repeat the luciferase experiments, and miR-22 and miR-129 mimics or inhibitors no longer influenced luciferase activity (Fig. 3k). [score:3]
Pearson correlation analysis revealed a significant negative correlation between the expression of Jun and miR-22 (Fig. 7d), and a positive correlation between Jun and HuR (Fig. 7e), which supported the existence of Jun/miR-22/HuR axis in CRC. [score:3]
Then, we co -transfected SW480 cells with this vector, β-gal vector and miR-22/miR-129 mimics/inhibitors. [score:3]
miR-22 is known as one of the most important tumour-suppressive miRNAs in many different cancer types [29, 30]. [score:3]
As shown in Fig. 4b, restoration of HuR in SW480 completely abolished the proliferation inhibition effect of miR-22. [score:3]
miR-22 is inhibited by Jun at the transcription level. [score:3]
The growth curve of xenografted tumours showed that overexpression of miR-22 delayed tumour growth, whereas HuR markedly promoted it. [score:3]
In another paper, miR-22 could significantly inhibit the DNA -binding ability of AP-1 [60]. [score:3]
To explore the association between HuR or miR-22/miR-129 expression levels and the life expectancy of CRC patients, we downloaded RNA-Seq raw data and survival data of CRC patients from the TCGA data portal (http://cancergenome. [score:3]
miR-22 is significantly downregulated in CRC tissue compared with that in normal adjacent mucosa [35] and improves 5-FU and paclitaxel sensitivity in chemotherapy [36, 37]. [score:3]
For CRC, miR-22 even has a more profound tumour-suppressive effect. [score:3]
Furthermore, we found that the onco-transcription factor Jun could inhibit the transcription of miR-22. [score:3]
HuR is a potential target gene of miR-22 and miR-129. [score:3]
To test the effect of miR-22 on SW480 cell proliferation, a miR-22 mimic or inhibitor was transfected into SW480 cells. [score:3]
Further analysis using Pearson’s correlation analysis of scatter plots revealed that miR-22 and miR-129 were inversely correlated with HuR expression (Fig. 3c and e). [score:3]
Various downstream target genes of miR-22 have been elucidated, including HIF1α, VEGF, TIAM1, MMP-2, COX-2 [38– 40], and HuR here. [score:3]
One study reported that ERK can repress the expression of miR-22 [58]. [score:3]
IHC staining for HuR and Ki-67 showed less HuR and lower percentage of proliferative cells in LV-miR-22 infected tumours, whereas tumours overexpressing HuR showed more proliferative cells than the control group. [score:3]
Our results highlighted the importance of miR-22 and HuR in CRC, and noted the possibility that targeting miR-22 or HuR might be a practical way to treat CRC in clinical environments. [score:3]
The HuR vector effectively restored the HuR protein level suppressed by miR-22 (Fig. 5e). [score:3]
As shown in Fig. 5a and c, miR-22 overexpression attenuated xenografted tumour growth, whereas HuR significantly promoted this process. [score:3]
As presented in Fig. 6b- d, inhibition of Jun increased the levels of mature miR-22, pri-miR-22 and C17orf91, and vice versa. [score:3]
Restoration of HuR reversed the inhibition of tumour growth by miR-22 (Fig.   5b). [score:3]
These results indicated that Jun could suppress the transcription of miR-22. [score:3]
As predicted by Targetscan, miR-22 and miR-129 have 3 conserved binding sites in the 3’-UTR of HuR (Fig. 2e and f). [score:3]
a, c and d miR-22 inhibits SW480 proliferation. [score:3]
k Relative luciferase activities in SW480 treated with a miR-22/miR-129 mimic or inhibitor. [score:3]
In hepatocellular carcinoma, miR-22 suppresses cell proliferation and tumourigenicity and is correlated with patient prognosis [31]. [score:3]
For HuR intervention, besides administration of miR-22, a specific small molecule inhibitor or siRNA [51, 52] should be a practical and efficient treatment. [score:3]
miR-22 is also activated by vitamin D and exerts anti-proliferative and anti-migratory roles in CRC cells by targeting TIAM1, MMP-2 and MMP-9 [39, 40]. [score:3]
Here, miR-22 was found to be markedly reduced in CRC, and lower miR-22 expression predicted a shorter life expectancy. [score:3]
More attention should be payed to the miR-22/HuR regulatory axis in CRC treatment. [score:2]
Next, we used siRNA or overexpression vectors to specifically knock down or raise Jun’s level (the efficiencies of si-Jun and Jun vectors are shown in Additional file 4: Figure S2b) and investigated whether Jun affected mature miR-22, pri-miR-22 and C17orf91 levels. [score:2]
Thus, we speculated that some TFs might regulate miR-22 transcription. [score:2]
These data suggested a double -negative regulatory relationship between miR-22 and Jun. [score:2]
Taken together, this study identified an essential Jun/miR-22/HuR regulatory axis in CRC (the working mo del is summarised in Fig.   8) and highlighted the vital role of HuR and miR-22 in CRC proliferation and migration. [score:2]
Thus, the Jun/miR-22/HuR regulatory axis may contribute to tumourigenesis of colorectal cancer. [score:2]
was used to explore the validity of putative Jun binding sites for miR-22 regulation. [score:2]
g and h Transwell assays revealed that miR-22 could inhibit SW480 migration. [score:2]
CCK-8 and EdU assays revealed that the miR-22 mimic delayed SW480 proliferation, whereas the miR-22 inhibitor accelerated cell proliferation (Fig.   4a, c and d). [score:2]
In this study, we demonstrated that miR-22 was directly repressed at the transcriptional level by the onco-TF Jun, which is a core member of transcription factor complex AP-1 involved in the oncogenesis of various cancers [56, 57]. [score:2]
Combining bioinformatics predictions and in vitro validation, miR-22 and miR-129 were demonstrated to be upstream repressors of HuR by directly binding to its 3’-UTR. [score:2]
After deleting site 1, the increase in fluorescence signal was less than when site 1 was in the promoter, indicating the efficiency of site 1 in miR-22 regulation. [score:2]
Both software packages identified the onco-TF Jun as potential regulator of miR-22. [score:2]
DNA fragments containing the miR-22 or miR-129 binding sites of HuR 3’-UTR were inserted into the pMIR-Report Luciferase vector. [score:1]
Significantly, restoration of HuR expression resulted in a higher percentage of migrant cells compared with that in the miR-22 mimic group in Transwell assays (Fig. 4g and i). [score:1]
b- d The influences of Jun on the levels of mature miR-22, pri-miR-22 and C17orf91, respectively. [score:1]
Hsa-miR-22 is located in the 3rd exon of a non-coding transcript C17orf91 (also called MIR22HG) in chromosome 17, and it is co-transcribed with this host gene [48]. [score:1]
The minimum free energy values of the miR-22-HuR mRNA hybridisations were −22.1, −22.0 and −20.8 kcal/mol, which were lower than that of miR-129-HuR mRNA duplexes (−20.2, −13.2 and −14.6 kcal/mol), indicating that miR-22 has a tighter interaction with HuR mRNA than miR-129 (Fig. 2e and f). [score:1]
This strategy is also applicable to miR-22. [score:1]
JASPAR and SABiosciences were used to predict transcriptional factors that could affect miR-22. [score:1]
We also analysed the relationship among Jun, miR-22 and HuR in CRC tissue samples. [score:1]
We also analysed the correlation between the levels of miR-22/miR-129 and HuR in the CRC tissues mentioned above. [score:1]
There is the possibility that Jun/p53/miR-22 axis exists in CRC also. [score:1]
d Pearson’s correlation scatter plot of the fold changes of Jun protein and miR-22 levels in CRC tissue pairs. [score:1]
We then constructed two mutant luciferase vectors on which the binding sites of miR-22/miR-129 in the HuR 3’-UTR were mutated to abolish the interaction between miR-22/miR-129 and HuR mRNA. [score:1]
Although miR-22 shows vital significance in CRC, the exact mechanism through which miR-22 influences CRC progression is far from understood. [score:1]
miR-22 can affect various CRC phenotypes, including proliferation, migration, chemoresistance, apoptosis and angiogenesis [37– 40]. [score:1]
Fig. 8 Working mo del of the Jun/miR-22/HuR axis in CRC Additional file 1: Table S1. [score:1]
Yang et al. reported that in ischaemia-reperfusion (I/R) -induced myocardial injury, miR-22 could repress the level of c-Jun-AP-1 and p-c-Jun-AP-1 by reducing p38 MAPK [59]. [score:1]
This finding, combined with our results, suggests that Jun, miR-22 and HuR participate in a double -negative feedback loop in CRC cells. [score:1]
Among them, miR-22 and miR-129 showed the highest enrichments. [score:1]
Briefly, for miRNA binding site tests, pMIR-report luciferase vectors containing binding sites for miR-22 or miR-129 on HuR’s 3’-UTR were constructed. [score:1]
Colorectal cancer HuR miR-22 Jun Proliferation Migration Colorectal cancer (CRC) is one of the most malignant cancer types around the world due to its high morbidity and mortality [1, 2]. [score:1]
f- i qRT-PCR analysis of miR-22 and miR-129 levels and the correlation between fold changes of miRNA and HuR levels in CRC tissue pairs. [score:1]
Kaplan-Meier curves showed that higher miR-22 or miR-129 levels predicted longer survival in CRC patients, which was contrary to that of HuR (Additional file  6: Figure S4a and b). [score:1]
e Luciferase activities of different miR-22 promoter reporter constructs, co -transfected with si-Jun or a negative control. [score:1]
e and f Schematic descriptions of the hypothetical duplexes formed by miR-22 or miR-129 with the 3’-UTR of HuR. [score:1]
b- e qRT-PCR analysis of miR-22 and miR-129 levels and the correlation between miRNA and HuR levels in the aforementioned 8 cell lines. [score:1]
As expected, LV-miR-22-infected or HuR vector -transfected groups showed higher miR-22 or HuR levels, respectively, than the control groups (Fig. 5d and e). [score:1]
As shown in Fig. 3f– i, miR-22 and miR-129 were inversely associated with the level of HuR in CRC tissues. [score:1]
d qRT-PCR analysis of miR-22 levels in CRC xenografted tumours. [score:1]
a Schematic descriptions of the genomic location of miR-22 and Jun’s putative binding sites in the promoter region of miR-22 host gene C17orf91. [score:1]
The miR-22 binding site was mutated from GGCAGCT to CCGTCGA, and the binding site of miR-129 was mutated from CAAAAA to GTTTTT. [score:1]
Among these myriad CRC-related miRNAs, miR-22 is one of the most important. [score:1]
We utilised Kaplan-Meier curves to compare overall survival differences between “high” and “low” expression groups and calculated p values using the log-rank test in the survival package in R. To predict transcriptional factors that could affect miR-22, JASPAR (http://jaspar. [score:1]
a- c miR-22 slowed down CRC xenografted tumour growth. [score:1]
, Western blot and luciferase assay were utilized to demonstrate the direct binding of miR-22 on HuR’s 3’-UTR. [score:1]
Fig. 7The Jun/miR-22/HuR axis exists in SW480 and CRC tissues. [score:1]
Restoring HuR increased the proliferation rate repressed by LV-miR-22 (Fig. 5f and g). [score:1]
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Other miRNAs from this paper: hsa-mir-22
Our results suggested that miR-22 was downexpressed in HCC and inhibited HCC cell proliferation, migration and invasion through downregulating cancer -associated gene CD147 which may provide a new bio-target for HCC therapy. [score:10]
Recently, several targets of miR-22 were reported to mediate its tumorsuppressive effect, such as tumor-suppressive PTEN, Max genes, p21, Sp1, CD147 and oncogene c-myc expression, etc. [score:9]
miR-22 plays a tumor-suppressive role by downregulating oncogenic target genes in many kinds of cancer [10, 24, 30, 31]. [score:8]
In conclusion, miR-22 down-expressed in HCC and the overexpression of miR-22 inhibited cell migration and invasion of HCC cells in vitro, and decrease HCC tumor growth in vivo. [score:7]
The expression of CD147 was significantly down-regulated after over expression of miR-22 at the mRNA level (Fig.   4a) and the protein level (Fig.   4b) compared with negative control, respectively. [score:7]
To confirm that CD147 is a target gene for miR-22, real time RT-PCR and western blot analysis were used to detect the expression of CD147 after transfected with miR-22 overexpression vector in MHCC-97H and SMMC-7721. [score:7]
miR-22, originally identified in HeLa cells, has been found to be overexpressed in prostate cancer, but down-regulated in breast cancer, cholangiocarcinoma, multiple myeloma, and hepatocellular carcinoma [27]. [score:6]
The reported paradoxical functions of miR-22 imply that miR-22 might act as a tissue/cell-specific or context -dependent tumor suppressor microRNA and the function diversely depending on its target genes and related regulatory networks. [score:6]
d Analysis for correlation of miR-22 mRNA and CD147 protein expression in HCC tissues Furthermore, we also detected the CD147 expression in thirty-four pairs of HCC and normal tissues by immunohistochemistry. [score:5]
Our results indicate that miR-22 worked as a tumor suppressor microRNA and contributed to inhibit HCC cells migration and invasion in vitro. [score:5]
a Transfection of miR-22 overexpression vector to MHCC-97H and SMMC-7721 cells increases the expression of miR-22 detected by real-time quantitative RT-PCR. [score:5]
Overexpression of miR-22 in MHCC-97H and SMMC-7721 cells significantly inhibited cellular proliferation, migration and invasion capability in vitro. [score:5]
The expression of CD147 was inversely correlated with miR-22 expression in HCC tissues. [score:5]
Fig.  2Overexpression of miR-22 inhibited HCC cell proliferation and metastasis in vitro. [score:5]
miR-22 might act as a tumor suppressor and serve as a potential therapeutic target in HCC. [score:5]
Hence, our work indicates that miR-22 is an important suppressor in HCC invasion and metastasis, and CD147 seems to be a major downstream effector of miR-22 in its target network. [score:5]
Furthermore, the expression of miR-22 in metastatic HCC tissues was much lower than in no metastatic HCC tissues which indicated that the miR-22 expression was correlated with the HCC metastatic ability. [score:5]
Taken together, our results suggest that miR-22 worked as a tumor suppressor miRNA and contributed to inhibit HCC cells migration and invasion in vitro. [score:5]
Furthermore, the expression of miR-22 in metastatic HCC tissues was much lower than in no metastatic HCC tissues (Fig.   1a) which indicated that the miR-22 expression was negatively correlated with the HCC metastatic ability. [score:5]
miR-22 inhibited the expression of CD147 at the mRNA level a and the protein level b in MHCC-97H and SMMC-7721 cells. [score:5]
It has been reported that miR-22 inhibits cell migration and invasion through targeting CD147 in breast cancer [11]. [score:5]
d Analysis for correlation of miR-22 mRNA and CD147 protein expression in HCC tissues Furthermore, we also detected the CD147 expression in thirty-four pairs of HCC and normal tissues by immunohistochemistry. [score:5]
Our results showed that overexpression of miR-22 could significantly suppress HCC cell proliferation (P < 0.05, Fig.   2b). [score:5]
Moreover, overexpression of miR-22 could significantly inhibit the HCC cell proliferation, migration and invasion in vitro and decrease HCC tumor growth in vivo. [score:5]
First, we performed gain-of-function analysis and transfected miR-22 overexpression vector into MHCC-97H and SMMC-7721 cells to increase miR-22 expression. [score:5]
The expression of miR-22 is downexpressed in HCC tissues and cell lines. [score:5]
Furthermore, we identified CD147 as a target gene for miR-22 to regulate the invasion and metastasis of HCC cells in vitro. [score:4]
Down-regulation of CD147 mediated miR-22 function. [score:4]
Our results are also shown that CD147 is negatively regulated by miR-22 at the posttranscriptional level, via a specific target site within the 3′UTR. [score:4]
As expected, transfection of miR-22 overexpression vector resulted in substantial increase of miR-22 expression compared with pcDNA3.1 control transfected cells (Fig.   2a). [score:4]
As shown in Fig.   1a, miR-22 expression levels were downexpressed in HCC tissues compared with ANT tissues (P < 0.05). [score:4]
Finally, we found that miR-22 interacted with CD147 and decreased its expression, via a specific target site within the CD147 3′UTR by luciferase reporter assay. [score:4]
CD147 is a direct target of miR-22. [score:4]
This correlation indicates that miR-22 could negatively regulateCD147 expression in HCC tissues. [score:4]
miR-22 negatively regulates CD147 gene expression. [score:4]
We next asked whether miR-22 could inhibit HCC development in vivo. [score:4]
And miR-22 expression of each cell line was compared to the average expression level of miR-22 of three normal liver cell lines. [score:4]
Student’s t test was used to analyze the significant differences It has been reported that miR-22 could regulate CD147 expression in breast cancer [11]. [score:4]
b The relative luciferase activity in MHCC-97H and SMMC-7721 cells were determined after the CD147 3′UTR or mutant plasmids were co -transfected with miR-22 overexpression vector or negative control Hepatocellular carcinoma is one of the most frequently occurring cancers with poor prognosis. [score:3]
This newly identified miR-22/CD147 link provides a new, potential therapeutic target to treat HCC. [score:3]
The miR-22 overexpression vector was constructed according to previous [24] named as pcDNA3.1-miR-22. [score:3]
Fig.  5The CD147 3′UTR is a target of miR-22. [score:3]
miR-22 is a 22-nt non-coding RNA and originally identified in HeLa cells as a tumor-suppressing miRNA. [score:3]
We found that the expression of miR-22 in HCC tissues and cell lines were much lower than that in normal control, respectively. [score:3]
In the HCC tumor mo dels, miR-22 expression vector decreased the HCC tumors growth. [score:3]
miR-22 inhibits HCC cell proliferation, migration and invasion in vitro and decreases HCC tumor growth in vivo. [score:3]
a Analysis of the expression pattern of miR-22 in non-metastasis tumors and metastasis tumors of HCC correlated with adjacent non-tumor tissues using real-time RT-PCR. [score:3]
miR-22 expression in MHCC-97H, FHCC-98 and SMMC-7721 cells was relatively low. [score:3]
These results indicated that miR-22 served as a tumor metastasis suppressor in HCC cell through the CD147 pathway. [score:3]
Using HCC tumor mo dels, the control mice showed the apparent presence of primary tumor, whereas those injected with miR-22 expression vector decreased the volume and weight of tumors during the same observation period (Fig.   3). [score:3]
The lower expression of miR-22 in HCC cells with low metastatic potential suggested a causal role for miR-22 in the migration and invasion of HCC cell lines. [score:3]
miR-22 inhibits cell growth and induces cell-cycle arrest, apoptosis and senescence in breast cancer, colon cancer and lung cancer [29]. [score:3]
1 × 10 [6] cells were seeded in six-well plates, cultured overnight, and transfected with miR-22 overexpression vector or NC, respectively. [score:3]
In contrast, expression levels of miR-22 in HepG2 and MHCC-97L cells were relatively high. [score:3]
However, on the other side, miR-22 was recently suggested having an oncogenic role by targeting PTEN or TET family [8, 32]. [score:3]
a Representative figures of tumors in negative control and miR-22 overexpression groups. [score:3]
Taken together, our results suggest that and that CD147 is a potential target gene of miR-22. [score:3]
Correlation analysis indicated that there was a significant inverse correlation between the miR-22 mRNA and CD147 protein expression with a correlation coefficient (r) = −0.6684 and R [2] = 0.4467 (Fig.   4d). [score:3]
To verify whether miR-22 directly targeted CD147 in HCC cell lines, luciferase reporter assays were conducted. [score:3]
The expression of miR-22 was inversely correlated with HCC metastatic ability. [score:3]
A total of 1 × 10 [7] MHCC-97H cells stably expressing miR-22 were injected subcutaneously into nude mice. [score:3]
b The relative luciferase activity in MHCC-97H and SMMC-7721 cells were determined after the CD147 3′UTR or mutant plasmids were co -transfected with miR-22 overexpression vector or negative control To identify the expression of miR-22 in the HCC, thirty-four paired of HCC and normal tissues were measured by real time RT-PCR. [score:3]
Student’s t test was used to analyze the significant differences, * P < 0.05, ** P < 0.01 The miR-22 expression in HCC and normal liver cell lines were also detected. [score:3]
Subsequently, miR-22 was identified to be ubiquitously expressed in a variety of tissues [7]. [score:3]
Recently, miR-22 is identified as a tumor-suppressing microRNA in many human cancers. [score:3]
miR-22 inhibits HCC cell migration and invasion through the CD147 pathway. [score:3]
Student’s t test was used to analyze the significant differences, * P < 0.05, ** P < 0.01 The miR-22 expression in HCC and normal liver cell lines were also detected. [score:3]
In the present study, we found an inverse correlation between miR-22 and CD147 expression in the HCC tissues. [score:3]
c Overexpression of miR-22 presented a slower closing of scratch wound, compared with pcDNA3.1 control, at 48 h after transfection in MHCC-97H and SMMC-7721 cells. [score:2]
CD147 contains the binding site for miR-22 and is negatively regulated by miR-22. [score:2]
In this study, we demonstrated that miR-22 expression was decreased in HCC tissues and cell lines compared detected by real– time RT– PCR. [score:2]
To the best of our knowledge, this is the first study to examine the regulation mechanism of miR-22 and CD147 in HCC migration and invasion. [score:2]
The relationship of miR-22 and its target gene CD147 was also investigated. [score:1]
Judging from data between the controls and miR-22 -treated groups at the points of the experiment, miR-22 treatment resulted in a mean of decreasing in tumor growth. [score:1]
In the current study, we validate the differential expression of miR-22 in HCC and investigated the function of miR-22 in migration and invasion of HCC cells. [score:1]
As shown in Fig.   1b, miR-22 levels of all cell lines were lower than that of normal liver cell lines. [score:1]
So we want to explore whether there exists this relationship of miR-22 and CD147 in the HCC progression. [score:1]
The effect of miR-22 on HCC in vivo was validated by murine xenograft mo del. [score:1]
Perhaps, miR-22 may play more complex roles that exceed our perception in cancer, which needs us to explore it more deeply. [score:1]
We constructed pmirGLO-CD147-3′-UTR and pmirGLO-CD147-3′-UTR-mut with a substitution of four nucleotides within the miR-22 binding site (Fig.   5a). [score:1]
To identify the expression of miR-22 in the HCC, thirty-four paired of HCC and normal tissues were measured by real time RT-PCR. [score:1]
Synthetic miR-22 mimic treatments for cancer will become a significant scientific and therapeutic challenge. [score:1]
Moreover, the cell migration and invasion assay showed that overexpression of miR-22 resulted in reduced migration rate and invasion rate of MHCC-97H and SMMC-7721 cells compared with the control (Fig.   2d). [score:1]
We measured miR-22 expression level in 34 paired of HCC and matched normal tissues, HCC cell lines by real-time quantitative RT-PCR. [score:1]
b The relative levels of miR-22 in the seven HCC and three normal liver cell lines. [score:1]
Next, the wound-healing assay showed that HCC cells with miR-22 overexpression presented a slower closing of scratch wound, compared with the negative controls (P < 0.05, Fig.   2c). [score:1]
a Diagram of the luciferase reporter plasmids: plasmid with the full length CD147 3′UTR insert and plasmid with a mutant CD147 3′UTR which carried a substitution of four nucleotides within the miR-22 binding site. [score:1]
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In contrast, miR-22 has been reported to be upregulated in PCa, where it downregulates expression of the tumor suppressor gene pTEN [59]. [score:11]
In contrast, stable or tamoxifen -induced MYC overexpression in LNCaP cells upregulated the expression of PHF8 and KDM3A protein and downregulated that of miR-22 (Figure 3C and 3D). [score:11]
Figure 8 DuringNED (left), androgen deprivation reduces AR activity and MYC expression, miR-22 is derepressed from the downregulated MYC and consequently, PHF8 and KDM3A are downregulated by the elevated miR-22. [score:9]
D. Expression of miR-22 in LNCaP cells overexpressing mock-ER or MYC-ER-HA as in C. E. Expression of the indicated proteins, as assessed by western blotting, in LNCaP cells over -expressing a doxycycline-inducible MYC-HA construct and treated with medium containing vehicle (Reg), 20 ng/ml IL-6 (IL-6) or CS-FBS (CS-FBS) for 6 days. [score:9]
Notably, miR-22 is also targeted and upregulated by AR [42], suggesting complexed regulatory mechanisms of miR-22 expression. [score:9]
DuringNED (left), androgen deprivation reduces AR activity and MYC expression, miR-22 is derepressed from the downregulated MYC and consequently, PHF8 and KDM3A are downregulated by the elevated miR-22. [score:9]
B. Expression of miR-22, as assessed by RT-qPCR, in cells treated as in A. C. Expression of the indicated proteins, as assessed by western blotting, in LNCaP cells over -expressing a constitutively active MYC construct and a tamoxifen-inducible mock construct (mock-ER) or MYC-ER-HA. [score:7]
Taken together, our data revealed that IL-6 upregulates miR-22, which mediates the downregulation of PHF8 in this context. [score:7]
Since, miR-22 was reported to target and regulate KDM3A in Ewing sarcoma [43], these findings suggest that miR-22 may regulate both PHF8 and KDM3A in LNCaP cells, at steady state as well as in the presence of CS-FBS or IL-6. Figure 2 A. Expression of miR-22, as assessed by RT-qPCR, in LNCaP cells cultured under normal conditions (Nor) or following treatment with 1% O [2] (Hyp), 20 ng/ml IL-6 (IL-6), or CS-FBS for 6 days, and in LNCaP-Abl and LNCaP-IL-6 cells. [score:7]
To determine if miR-22 directly targets the PHF8 3′ UTR and regulates its expression, we retrieved data from Ago2 CLIP-seq studies using starBase v2.0 [44, 45]. [score:7]
The upregulation of miR-22 can be caused by the elevated AR activity and the derepression from the downregulated MYC. [score:7]
E. Expression of miR-22, as assessed by RT-qPCR, in cells treated with IL-6 as in D. F. Expression of the indicated proteins, as assessed by western blotting, in LNCaP cells transfected with 50 nM control (Ctrl) or miR-22 inhibitor at 72 hours following treatment with vehicle or IL-6 (+IL-6). [score:7]
Since, miR-22 was reported to target and regulate KDM3A in Ewing sarcoma [43], these findings suggest that miR-22 may regulate both PHF8 and KDM3A in LNCaP cells, at steady state as well as in the presence of CS-FBS or IL-6. Figure 2 A. Expression of miR-22, as assessed by RT-qPCR, in LNCaP cells cultured under normal conditions (Nor) or following treatment with 1% O [2] (Hyp), 20 ng/ml IL-6 (IL-6), or CS-FBS for 6 days, and in LNCaP-Abl and LNCaP-IL-6 cells. [score:7]
The induction of MYC rescued the PHF8 downregulation that normally occurs in the context of treatment with CS-FBS (Figure 3E, compare lane 7 with 8 and 9), and is accompanied by marginal downregulation of miR-22 (Figure 3F). [score:7]
siRNA -mediated MYC knockdown in LNCaP, LNCaP-Abl and LNCaP-IL-6 cells led to reduced expression of the PHF8 and KDM3A proteins, and to increased expression of miR-22 (Figure 3A and 3B). [score:6]
In sum, we have discovered a novel regulatory axis that involves AR, MYC, miR-22, PHF8 and KDM3A and that functions during NED and in CRPC cells, as illustrated in Figure 8. The high expression and proliferative function of PHF8 in CRPC cells support its candidacy as a therapeutic target for patients with advanced PCa. [score:6]
miR-22 has been reported to be downregulated in PCa [42, 57], and the use of miR-22 mimics inhibits the migration of both LNCaP and PC3 cells [42]. [score:6]
Moreover, miR-22 also targets MYCBP1 to downregulate MYC function [58]. [score:6]
Transient transfection of miR-22 mimics also downregulated the expression of PHF8 and KDM3A in LNCaP, LNCaP-Abl and LNCaP-IL-6 cells (Figure 2B). [score:6]
In LNCaP cell lines stably expressing either pLenti-GFP-empty or pLenti-GFP- PHF8 3′ UTR, transient transfection of miR-22 mimics, but not control mimics, significantly downregulated GFP- PHF8 3′ UTR. [score:6]
In this regard, it is notable that miR-22 targets and regulates IPO7 [57] and LAMC1 [42], both of which are overexpressed and have oncogenic functions in PCa. [score:6]
A close examination of the expression of PHF8 and miR-22 revealed that the miR-22 elevation peaked at 72 hours, preceding the downregulation of PHF8 at the protein, but not mRNA, level (Figure 2D, 2E and Supplementary Figure 3). [score:6]
Indeed, transient transfection of the cells with miR-22 inhibitors 72 hours after initiation of IL-6 treatment partially restored the levels of PHF8 protein (Figure 2F), indicating that miR-22 is involved in IL-6 induced downregulation of PHF8. [score:6]
In our NED-CRPC cell system, the expression of miR-22 was upregulated by treatment with CS-FBS, consistent with the previous study [41]. [score:6]
In LNCaP cells, the unaffected miR-22 expression suggests that AR and MYC play regulatory roles in activating and repressing miR-22 expression, respectively. [score:6]
In the cases of PCa in which MYC is amplified, the downregulation of miR-22 may cause an increase in the expression of PHF8 and KDM3A. [score:6]
The high level of induction of miR-22 expression by IL-6, which reflects the dominant transactivation of miR-22 expression by AR, may play important additive roles in the induction of NED. [score:5]
The basal expression level of miR-22 partially contributes to the restored expression of PHF8 and KDM3A in CRPC cells. [score:5]
As levels of the PHF8 mRNA did not change during IL-6 treatment, miR-22 likely inhibits the translation of PHF8. [score:5]
C. Expression of the indicated proteins, as assessed by western blotting, in LNCaP cells stably overexpressing the GFP (mock) only or GFP-miR-22 construct. [score:5]
Since miR-22 is more profoundly upregulated by IL-6 than by the treatment with CS-FBS, we asked if it is involved in the regulation of PHF8 in this context. [score:5]
Moreover, stable overexpression of pri-miR-22 in LNCaP cells led to a reduction of both demethylases at the protein level (Figure 2C and Supplementary Figure 2D), supporting our hypothesis that miR-22 regulates PHF8 and KDM3A in PCa cells. [score:4]
Our analysis shows that treatment with IL-6 or CS-FBS leads to upregulation of miR-22, but that this activation is lost when cells take on an IL-6-producing, androgen-independent phenotype. [score:4]
Given the fact that miR-22 is subject to activation by AR [42] and to repression by MYC (Figure 3B), the upregulation of miR-22 in LNCaP-Abl and LNCaP-IL-6 cells suggests that the repression by MYC is dominant. [score:4]
Given that both the activation of MYC and loss of the PTEN tumor suppressor are frequently observed in PCa, and when these abnormalities are combined in mouse mo dels they drive genome instability and metastasis of PCa [60], it will be important to carefully evaluate the functions of miR-22 in PCa in the context of its upstream regulatory signals and downstream target genes. [score:4]
Such a mechanism may also contribute to the regulation of PHF8 and/or KDM3A in response to CS-FBS treatment given the elevated expression of miR-22 during NED induction by both IL-6 and CS-FBS. [score:4]
Among these microRNAs, only miR-22 was reported to be upregulated when LNCaP cells were treated with either CS-FBS or the AR antagonist bicalutamide [41]. [score:4]
However, miR-22 was not significantly upregulated in either LNCaP-Abl or LNCaP-IL-6 cells. [score:4]
Given that IL-6 enhances AR activity [36] and AR contributes to activation of miR-22 [42], it is likely that IL-6 -mediated miR-22 induction is more profoundly influenced by AR activation than by de-repression of downregulated MYC. [score:4]
These findings indicate that the expression of miR-22 is dynamically regulated. [score:4]
Indeed, miR-22 binding sites within the PHF8 3′ UTR were pulled down by Ago2, implicating miR-22 in directly targeting PHF8 (Supplementary Figure 2A). [score:4]
F. Expression of miR-22 in LNCaP cells treated as in E as assessed by RT-qPCR. [score:3]
Additionally, at steady state miR-22 expression is not as high in LNCaP-Abl and LNCaP-IL-6 cells as in LNCaP cells (Figure 2A), despite the fact that AR levels are high in these CRPC cell lines (Figure 1C). [score:3]
These complex regulatory mechanisms are illustrated in Figure 8. Taken together, these data demonstrate that PHF8 is downstream of AR, and that it is regulated by the MYC/miR-22 axis in CRPC cells. [score:3]
B. Expression of the indicated proteins, as assessed by western blotting, in LNCaP, LNCaP-Abl, and LNCaP-IL-6 cell lines following transfection with 20 nM control (ctrl) or miR-22 mimics for 48 hours. [score:3]
MYC sustains the expression of PHF8 and KDM3A by repressing miR-22. [score:3]
Moreover, PHF8 3′UTR may contain consensus target seed sequences for miRs other than miR-22 (miR-31, miR-182, miR-9 and let-7). [score:3]
These data implicate that transient miR-22 overexpression contributes to NED induction, but, does not induce full NED. [score:3]
A. Expression of miR-22, as assessed by RT-qPCR, in LNCaP cells cultured under normal conditions (Nor) or following treatment with 1% O [2] (Hyp), 20 ng/ml IL-6 (IL-6), or CS-FBS for 6 days, and in LNCaP-Abl and LNCaP-IL-6 cells. [score:3]
The expression of miR-22 was normalized to the vehicle treatment (no doxycycline). [score:3]
miR-22 mimics (GenePharma) or inhibitors (Integrated DNA Technologies) were used at a final concentration of 20 nM or 50 nM, respectively. [score:3]
miR-22 mediates the regulation of PHF8 and KDM3A by IL-6. miR-22 mediates the regulation of PHF8 induced by IL-6.. [score:3]
Expression of miR-22, in contrast, was de-repressed only in LNCaP-Abl and LNCaP-IL-6 cells (compare Figure 5A to 5B and 5C). [score:3]
Although we propose that an AR/MYC/miR-22/PHF8 regulatory axis exists, we acknowledge that this axis is likely context dependent. [score:2]
Notably, the effects of MYC knockdown on the reduction of PHF8 and KDM3A protein levels via miR-22 were greater in LNCaP and LNCaP-IL-6 cells than in LNCaP-Abl cells, implying that MYC plays distinct roles in these contexts. [score:2]
Schematic illustration of the mechanisms underlying the regulation of PHF8 and KDM3A by AR, MYC and miR-22. [score:2]
From a mechanistic standpoint, our study revealed that MYC regulates PHF8 and KDM3A through miR-22 in both androgen -dependent and -independent LNCaP cells, as well as during the induction of NED by treatment with IL-6 and CS-FBS. [score:2]
Interestingly, in the context of IL-6 treatment, MYC induction failed to repress miR-22 (Figure 3F) and to restore PHF8 protein levels (Figure 3E, compare lane 4 with 5 and 6). [score:1]
Transient transfection of miR-22 mimics in LNCaP cells slightly increased the length of neurites (Supplementary Figure 4A and 4B), increased the intermediate CgA protein and the mRNA level of CHGB (Supplementary Figure 4C). [score:1]
Additionally, pMSCV-PIG-pri- miR-22 LNCaP cells were FACS sorted to enrich for GFP -positive clones. [score:1]
c-MYC (hereafter referred to as MYC) -mediated repression of miR-22 has been reported in several cell types [46, 47], yet it is unclear whether this occurs in PCa cells. [score:1]
We next asked if miR-22 plays a role in NED. [score:1]
Thus, activation by AR appears to supersede repression of miR-22 by MYC. [score:1]
Our findings that miR-22 mimics slightly increase the length of neurite, intermediate CgA and the mRNA level of CHGB suggest that miR-22 plays an additive role, with other factors dominant in NED induction. [score:1]
This evidence supports the tumor repressive function of miR-22. [score:1]
In CRPC cells (right), miR-22 is repressed by MYC, despite of elevated AR activity. [score:1]
Pri- miR-22 (locus NR_028502) was cloned into the BglII and XhoI sites of pMSCV-PIG. [score:1]
Thus, an understanding of the relationship between AR and the MYC/miR-22/PHF8 axis is critical to evaluating the potential therapeutic significance of inhibiting PHF8 in combination with the application of AR antagonists. [score:1]
AR is upstream of the MYC/miR-22/PHF8 axis in CRPC cells. [score:1]
Mechanistically, we identified the c-MYC/ miR-22/PHF8 axis and its connection with AR. [score:1]
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We found that miR-22 overexpression in cDCs upregulated MHC II expression, relative to MHC II amounts observed with mut miR-22 overexpression (Fig. 3, upper panels). [score:10]
For example, miR-22, miR-142-3p and miR-142-5p were upregulated in CD11c [+] CD11b [+] B220 [−] cDCs and downregulated in pDCs relative to progenitor expression levels, while miR-20a, miR-17-5p and miR-130a showed the reverse pattern. [score:9]
This distinct expression pattern is consistent with miR-22 function in DC lineage differentiation, as our overexpression and knockdown of miR-22 supports the idea that miR22 promotes CD11c [+] CD11b [+] B220 [−] cDC production and inhibits pDC development. [score:9]
These results collectively suggest that miR-22 expression is regulated during DC development, with upregulation in CD11c [+] CD11b [+] B220 [−] cDCs and suppression in pDCs compared to DC progenitors. [score:9]
We used GFP-encoding miR-22 overexpression or knockdown vectors to manipulate miR-22 expression, and analyzed MHC class II (MHC II), CD80 and CD86 expression on GFP [+] CD11c [+] CD11b [+] B220 [−] cDCs. [score:8]
In addition to our results that identify miR-22 as a negative regulator of the DC transcription factor IRF8 by controlling Irf8 mRNA abundance, recent studies by others have shown that miR21, miR34a, miR-221 and miR-222 are differentially expressed in pDCs and cDCs, and play a role in DC differentiation via inhibitory functions on Jag1, Wnt1, and possibly the pDC master regulator Tcf4 (E2–2), respectively [62]– [66]. [score:7]
To assess whether Irf8 and Batf3 are targets of miR-22, we quantified their mRNA amounts in lin [−] Flt3 [+] DC progenitors following enforced overexpression of wt or mut miR-22, or in response to miRZip22 -mediated miR-22 knockdown. [score:6]
miR-22 overexpression or knockdown did not appear to affect Batf3 mRNA, with the exception of increased Batf3 mRNA amounts in GM-CSF cultures with miR-22-overexpression (Fig. 4C). [score:6]
To determine whether miR-22 regulates DC development in vivo, Flt3L- or GM-CSF-cultured CD45.1 [+] DC progenitors were infected with miR-22-overexpression or knockdown viruses, or the appropriate controls, then transferred into CD45.2 [+] recipient mice. [score:6]
Two days later, cells were infected with retroviruses expressing wt or mut miR-22 (overexpression), or with miRZip22 or miRZip000 lentiviruses (knockdown). [score:6]
miR-22 was thought to be a ubiquitously expressed miRNA [48], yet we show here that miR-22 is highly enriched in murine CD11c [+] CD11b [+] B220 [−] cDCs in comparison to pDCs, suggesting important regulation of miR-22 expression occurs in the hematopoietic system. [score:6]
By contrast, we found that Irf8 was expressed at lower amounts in lin [−] Flt3 [+] DC progenitors cultured with GM-CSF compared to Flt3L, and miR-22 overexpression did not appear to affect Irf8 expression in GM-CSF conditions (Fig. 4B). [score:6]
We also observed a modest increase in CD80 and CD86 expression upon miR-22 overexpression (Fig. 3, upper panels). [score:5]
While Batf3 and Stat5 were identified in our software analyses as putative miR-22 targets, we were unable to obtain evidence for their direct regulation by miR-22. [score:5]
Thus, our results suggest that miR-22 directly or indirectly enhances cell surface expression of MHC II and costimulatory molecules in CD11c [+] CD11b [+] B220 [−] cDCs. [score:5]
The enhanced expression of wt and mut miR-22 observed in DC progenitors cultured with GM-CSF versus Flt3L is likely due to higher endogenous miR22 levels in GM-CSF conditions or suppressive effects of Flt3L (Fig. 1C), as indicated by the mock-infected controls. [score:5]
These, and other miRNAs that are specifically regulated in humans, may be involved in controlling human IRF8 expression in analogous but independent regulatory pathways from the miR-22 -mediated mechanism described herein. [score:5]
To identify potential targets of miR-22, we performed an algorithm -based prediction using two wi dely utilized software programs (Target Scan and MiRanda). [score:5]
We found that overexpression of wt miR-22 enhanced the production of CD11c [+] CD11b [+] B220 [−] cDCs and inhibited generation of pDCs in response to Flt3L, as evidenced by corresponding changes in the frequency (Fig. 2C upper panels) and absolute number (Fig. 2F) of each DC subset. [score:5]
In addition, we found that the miRZip lentiviral vector -based anti-miR-22, which antagonizes miR-22 function by blocking binding to target mRNAs, was expressed in >90% transfected 293 T cells (Fig. 2B), indicating efficient generation of anti-miR-22 lentiviruses. [score:5]
Moreover, we demonstrated that miR-22 -binding sites in the Irf8 3′UTR are required for miR-22 -mediated repression of reporter activity, as the truncated Irf8 3′UTR reporter constructs that lack one or both miR-22 -binding sites were either partially or completely refractory to miR-22 -mediated regulation in both overexpression and knockdown settings (Fig. 5B, 5C). [score:5]
To examine the role of miR-22 in DC development and function, we employed GFP-encoding retro- and lentiviral constructs to enforce its overexpression or knockdown. [score:5]
Cells were infected with retroviral vectors expressing wt or mut miR-22 (B) or lentiviral vectors expressing control (miRZip000) or anti-miR-22 (miRZip22) as indicated (C). [score:5]
As one miRNA may have hundreds of target genes, the regulatory function of miR-22 in these signaling cascades may contribute to its effects on DC development and function. [score:5]
Furthermore, we found that miR-22 directly regulates Irf8 mRNA amounts in DCs, potentially via targeting Irf8 mRNA for destruction. [score:5]
By contrast, when miR-22 was blocked by miRZip22, pDC development was enhanced and CD11c [+] CD11b [+] B220 [−] cDC generation was suppressed in both Flt3L and GM-CSF cultures (Fig 2C–D lower panels; 2F). [score:4]
By contrast, here we show that miR-22 targets murine Irf8 mRNA directly through a complementary seed region in the Irf8 3′UTR. [score:4]
E. 10 [5] lin [−] Flt3 [+] DC progenitors from CD45.1 [+] congenic mice were cultured with Flt3L (upper panel) or GM-CSF (lower panel) for 2 d, followed by viral infection to overexpress or knockdown miR-22 as described in C–D. [score:4]
By profiling miRNA expression in mouse pDCs and cDCs, we found that miR-22 is highly enriched in CD11c [+] CD11b [+] B220 [−] cDCs and suppressed in pDCs compared to its abundance in DC progenitors. [score:4]
miR-22 facilitates cDC generation while suppressing pDC development. [score:4]
D2SC/1 cells were transfected using Lipofectamine 2000 with pGL3 constructs described in A, phRL-TK, and miR-22 overexpression (B) or knockdown (C) plasmids. [score:4]
The GM-CSF-STAT5- and miR-22 -mediated regulatory pathways may work cooperatively at transcriptional and post-transcriptional levels, respectively, to precisely control the amount of Irf8 mRNA expression during DC subset differentiation. [score:4]
Two days later, cells were incubated with retroviruses expressing wt or mut miR-22, or with miRZip22 or miRZip000 lentiviruses for 8 hours. [score:3]
We found that miR-22 is highly enriched in all splenic cDC subsets, including CD4 [+], CD8α [+] and CD4 [−] CD8α [−] cDCs, while being expressed at relatively lower amounts in pDCs from bone marrow or spleen (Fig. 1B). [score:3]
miR-22 targets the 3′UTR of Irf8. [score:3]
To generate retroviral constructs that co-express miR-22 and GFP, sequences encoding the wild type (wt) or mutant (mut) miR-22 were released by XhoI and EcoRI digestion from pSuper-retroviral plasmids (kindly provided by Dr. [score:3]
By contrast, we found that miR-22 knockdown suppressed surface presentation of MHC II, CD80 and CD86 compared to cells infected with the miRZip000 control vector (Fig. 3, lower panels). [score:3]
By contrast, human IRF8 3′UTR does not appear to contain a miR-22 seed region and miR-22 is not differentially expressed in human pDCs and cDCs (data not shown). [score:3]
In addition, we found that miR-22 modestly enhances MHC class II and costimulatory molecule expression in CD11c [+] CD11b [+] B220 [−] cDCs, suggesting it also affects genes that are involved cDC antigen presentation, a major function for the cDC subsets. [score:3]
0052341.g002 Figure 2 A. lin [−] Flt3 [+] DC progenitors were cultured with Flt3L or GM-CSF for 2 days, and infected with retroviruses expressing wt or mut miR-22 or with empty vector (mock), as indicated. [score:3]
To address whether Irf8 mRNA is a direct target of miR-22, we performed luciferase reporter assays in a cDC cell line, D2SC/1 [34]. [score:3]
Consistent with the ex vivo results, overexpression of miR-22 in Flt3L-stimulated DC progenitors significantly enhanced CD11c [+] CD11b [+] B220 [−] cDC production while repressing pDCs (Fig. 2E upper panel). [score:3]
0052341.g003 Figure 3Total bone marrow cells were cultured with Flt3L or GM-CSF for 3 days, followed by infection with retroviruses expressing wild type (wt) or mutant (mut) miR-22. [score:3]
These results suggest that the developmental effects of miR-22, potentially via Irf8 regulation, may occur at pre-cDC population prior to cDC subset diversification. [score:3]
A. lin [−] Flt3 [+] DC progenitors were cultured with Flt3L or GM-CSF for 2 days, and infected with retroviruses expressing wt or mut miR-22 or with empty vector (mock), as indicated. [score:3]
To investigate whether miR-22 controls pDC and/or cDC differentiation, we cultured lin [−] Flt3 [+] DC progenitors in Flt3L or GM-CSF for 2 days, infected cells with miR-22 overexpression or knockdown viruses, and analyzed the development of CD11c [+] CD11b [−]B220 [+] pDCs and CD11c [+] CD11b [+] B220 [−] cDCs within the GFP [+] population. [score:3]
We observed a dramatic (∼10-fold) reduction of Irf8 mRNA amounts upon miR-22 overexpression in lin [−] Flt3 [+] DC progenitors cultured with Flt3L (Fig. 4B). [score:3]
A. Summary of potential miR-22 target sites in the 3′-UTR of Irf8 and Batf3 mRNAs. [score:3]
C. lin [−] Flt3 [+] DC progenitors were cultured in the presence of Flt3L or GM-CSF for 72 h; cells were analyzed for miR-22 expression by qPCR. [score:3]
We found that wt miR-22 inhibited reporter activity of the construct containing the full length Irf8 3′UTR, relative to effects of the mut miR-22 on reporter activity (Fig. 5B). [score:3]
To confirm differential miR-22 expression in DCs and their progenitors, we performed qPCR analysis on RNA samples from cell populations isolated from bone marrow or spleen. [score:3]
B. miR-22 expression in FACS-purified lin [−] Flt3 [+] DC progenitors (DP), pDCs or individual cDC subsets, isolated from bone marrow or spleen as indicated, was analyzed by qPCR. [score:3]
Consistent with this, we observed that miRZip22 -mediated miR-22 knockdown enhanced Irf8 mRNA levels in GM-CSF-cultured progenitors in comparison to miRZip000 control, while miR-22 knockdown had only modest effects upon the already high amounts of Irf8 mRNA in Flt3L cultures (Fig. 4C). [score:3]
We confirmed that wt or seed nucleotide mut miR-22 was overexpressed by pSUPER retroviral vectors in Flt3L- or GM-CSF-cultured lin [−] Flt3 [+] DC progenitors, relative to mock-infected controls, using qPCR analysis (Fig. 2A). [score:3]
Two days after infection, cells were collected and analyzed for miR-22 expression by qPCR. [score:3]
To examine whether miR-22 is regulated during DC development, we cultured lin [−] Flt3 [+] DC progenitors ex vivo with Flt3L or GM-CSF, conditions that promote, respectively, the differentiation of pDCs and cDCs in an approximate 1:1 ratio, or selective cDC differentiation including CD11c [+] CD11b [+] B220 [−] cDCs (reviewed in [25]). [score:3]
To generate miR-22 overexpressing retroviruses, 293T cells were transfected with pSuper-GFP plasmids encoding wt or mut miR-22, in addition to the viral packaging plasmid pCL-Eco. [score:3]
miR-22 is differentially expressed in pDCs and cDCs. [score:3]
D2SC/1 cells [34] were then transfected with the pGL3 constructs containing full length or truncated Irf8 3′UTRs, phRL-TK (encoding Renilla luciferase), and plasmids that overexpress or block miR-22, using Lipofectamine 2000 (Invitrogen). [score:3]
Total bone marrow cells were cultured with Flt3L or GM-CSF for 3 days, followed by infection with retroviruses expressing wild type (wt) or mutant (mut) miR-22. [score:3]
miR-22 promotes MHC and costimulatory molecule expression on cDCs. [score:3]
Since miR-22 was predominantly expressed in CD11c [+] CD11b [+] B220 [−] cDCs compared to pDCs (Fig. 1), we examined its function in cDCs derived from GM-CSF cultures. [score:2]
miR-22 has been previously implicated in regulating histone modifications [49], [50], as well as tumorigenesis by controlling tumor cell proliferation, migration/invasion and apoptosis [51]– [54]. [score:2]
B. 293T cells were transfected with miR-22-knockdown plasmid miRZip22 or miRZip000 control vector, together with pPACK packaging plasmids. [score:2]
These results suggest that miR-22 negatively regulates transcription of the firefly luciferase reporter gene in the presence of the Irf8 3′UTR. [score:2]
To our knowledge, this is the first study demonstrating the role of miR-22 in DC development, suggesting miR-22 involvement in normal hematopoiesis and cell differentiation. [score:2]
miR-22 regulates Irf8 mRNA abundance. [score:2]
Collectively, these data suggest that miR-22 influences DC subset development. [score:2]
miR-22 affects Irf8 mRNA through direct binding to its 3′UTR. [score:2]
Moreover, miR-22 knockdown in progenitors exposed to GM-CSF had the opposite effects (Fig. 2E lower panel). [score:2]
miR-22 showed the most remarkable difference between the two DC subsets (Fig. 1A), and thus we selected it for further analysis. [score:1]
We found that the 3′ UTR of Irf8 mRNA (∼1500 bp) contains 2 putative miR-22 binding sites, while the 3′UTR of Batf3 (∼400 bp) contains 1 potential binding site (Fig. 4A). [score:1]
The firefly luciferase activity of all three constructs is controlled by the SV40 promoter, and the addition of Irf8 3′UTR with or without the miR-22 seed region(s) allows us to monitor the changes in reporter activity fine-tuned by miR-22 binding. [score:1]
To prepare anti-miR-22 lentiviruses, 293T cells were transfected with miRZip000 vector or miRZip22 plasmids, along with the viral packaging plasmids pPACKH1-GAG, pPACKH1-REV and pVSV-G. Virus-containing supernatants were collected at 48 and 72 h and used to infect cultured DC progenitor cells via a spin infection method (2300 rpm, 60 min). [score:1]
Consistently, knockdown of miR-22 function by miRZip22 induced an approximate 2-fold increase in the activity of the full length Irf8 3′UTR reporter compared to effects of the miRZip000 control on reporter function (Fig. 5C). [score:1]
miR-22 reduces Irf8 mRNA amounts, suggesting posttranscriptional control of Irf8 that may play a role in mediating DC lineage decisions. [score:1]
Interestingly, we did not observe a significant difference in miR-22 amounts in splenic CD4 [+], CD8α [+] or CD4 [−] CD8α [−] cDC subsets, although these populations have differential requirements for IRF8 [35], [38]. [score:1]
miR-22 affects DC subset differentiation and maturation. [score:1]
These results collectively indicate that miR-22 interacts with miR-22 seed regions in the Irf8 3′UTR and mediates Irf8 mRNA repression. [score:1]
We show that miR-22 binds to the 3′UTR of Irf8 mRNA, which encodes IRF8, a transcription factor that is essential for pDC, CD8α [+] cDC and CD103 [+] cDCs, but not for CD11c [+] CD11b [+] B220 [−] cDCs. [score:1]
The GFP [+] lentiviral vector -based anti-miR-22 or scrambled hairpin control, miRZip22 and MiRZip000, respectively, were kindly provided by Dr. [score:1]
These data indicate that miR-22 specifically reduces Irf8 mRNA abundance, potentially via enhanced mRNA degradation. [score:1]
We found that miR-22 was highly induced in GM-CSF cultures, while slightly repressed in Flt3L cultures (Fig. 1C). [score:1]
We report here that miR-22 enhances the generation of CD11c [+] CD11b [+] B220 [−] cDCs from DC progenitors in vivo and in vitro and stimulates the mature phenotype of this subset, consistent with abundant miR-22 amounts observed in CD11c [+] CD11b [+] B220 [−] cDCs relative to pDCs or DC progenitors. [score:1]
Transcription of the firefly luciferase gene is constitutively controlled by the SV40 promoter, and is affected by the Irf8 3′UTR through the binding of miR-22. [score:1]
Truncated Irf8 3′UTR sequences that lack of one or both predicted miR-22 seed regions were cloned via a similar approach, as indicated in the figure legends. [score:1]
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Other miRNAs from this paper: mmu-mir-126a, mmu-mir-200b, mmu-mir-200a, mmu-mir-200c, mmu-mir-126b
Early on, Chen et al. [44] reported that also in breast cancer the important portal protein of glucose uptake, Glucose transporter 1 (GLUT1) was proved to be a direct target of miR-22, and dysregulated miR-22 expression functioned at the suppression of cancer cell proliferation and invasion. [score:9]
The downregulated effect of ACLY mediated by miR-22 may decrease the common intermediates expressions in the mevalonate pathway, and therefore lead to the suppression of tumor cell invasion and metastasis. [score:8]
G. Analysis of ACLY protein expression in the four cancer cell lines treated with miR-22 mimic or miR-22 inhibitor as well as cotransfected by ACLY -overexpressed vector or siRNA. [score:7]
miR-22 reduces in vitro cancer cell growth and invasion but promotes apoptosis by targeting ACLYTo evaluate the potential role of miR-22 in tumor biological processes by inhibiting ACLY, the four tumor cells were treated with the miR-22 mimic, miR-22 inhibitor, ACLY siRNA or the ACLY -overexpressed vector, and MTT assays were performed to detect cell proliferation. [score:6]
Song et al. [35] have emphasized that miR-22 can enhance epithelial-mesenchymal transition and metastasis in mouse xenografts by silencing antimetastatic miR-200 through direct targeting of the TET family of methylcytosine dioxygenases, thus resulting in the inhibition of the miR-200 promoter demethylation. [score:6]
The lipid metabolic reprogramming triggered by the miR-22 restoration and ACLY repression is associated with the inhibition of tumor development effects, resulting in the suppression of tumor growth and metastasis in the four types of cultured cancer cells as well as the animal mo dels. [score:6]
Using the A549 cell as an in vitro experimental mo del, our results showed a concurrent downregulation both in the mRNA and protein levels of these two enzymes, which was in lines with the decreasing expression of ACLY treated by miR-22 (Figures 6A-6E). [score:6]
In this study, we have identified a novel link between miR-22, lipid anabolism and tumor suppression via downregulating the key metabolic enzyme ACLY. [score:6]
Site-directed mutation of the miR-22 targeting site of the 3′ UTR fragment was performed by using a QuikChange Lightning Site-Directed Mutagenesis Kit (Stratagene, La Jolla, CA, USA). [score:6]
Our data have shown that the inhibition of ACLY by miR-22 led to the decreasing expression of the downstream enzymes such as FASN and HMGCR, and thus ended up with the reducing output of triglycerides (the reservoir of fatty acids) and cholesterol. [score:5]
In our work, we documented the direct downregulation relationship between miR-22 and ACLY in cancers such as osteosarcoma, prostate, cervical and lung cancers. [score:5]
Figure 6miR-22 reduces ACLY -mediated de novo lipid synthesis A. The protein expressions of FASN and HMGCR in the A549 cells transfected with the miR-22 mimic or inhibitor. [score:5]
The miR-22 treated tumors presented a distinct loss of ACLY protein expression in comparison with the NC group, with ensuing the decreasing expression of two classical proliferative markers, PCNA and Ki-67 (Figure 4M). [score:5]
A. The protein expressions of FASN and HMGCR in the A549 cells transfected with the miR-22 mimic or inhibitor. [score:5]
The siRNA targeting ACLY, miRNA mimic, inhibitor and agomiR of miRNA-22, along with the negative controls (NC and anti-NC) were synthesized by GenePharma. [score:5]
Accordingly, specific miRNAs like miR-22 may act mainly as a tumor suppressor whereas sometimes as an oncogene [36], depending on the different cellular environment, the diverse tumor systems and the particular functions of their target genes. [score:5]
On the contrary, the miR-22 inhibitor enhanced the expression of ACLY, which restricted the interference of ACLY siRNA. [score:5]
Twenty-four hours later, the cells were transfected with the miR-22 mimic, miR-22 inhibitor, NC, anti-NC and si-ACLY or ACLY -overexpressed vector separately cultured for another 24 h, 48 h or 72 h. Then, 10 μL of MTT (5 mg/mL) was added to each well. [score:5]
miR-22 downregulates ACLY -mediated de novo lipid synthesisFatty acid synthase (FASN) and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) are the two crucial enzymes, respectively catalyzing the downstream lipid anabolism pathways for generating saturated fatty acids and cholesterol. [score:4]
In this study, we investigated the four representative tumors, including osteosarcoma, prostate, cervical and lung cancers, and uncovered that ACLY is directly downregulated by miR-22, which has implications for the potential therapeutic disruption of tumor development and progression. [score:4]
All these results pointed out that ACLY is directly targeted by miR-22. [score:4]
miR-22 directly targets ACLY. [score:4]
miR-22 downregulates ACLY -mediated de novo lipid synthesis. [score:4]
ACLY is a direct target of miR-22. [score:4]
Our results showed that in the Saos-2 cell lines, the ACLY protein levels dropped by around 50% after the miR-22 mimic transfection compared to the NC -treated cells, while the introduction of an overexpression plasmid could largely counteract the inhibitory effects that miR-22 exerted on ACLY. [score:4]
To evaluate the potential role of miR-22 in tumor biological processes by inhibiting ACLY, the four tumor cells were treated with the miR-22 mimic, miR-22 inhibitor, ACLY siRNA or the ACLY -overexpressed vector, and MTT assays were performed to detect cell proliferation. [score:4]
To validate the downregulation effects of miR-22 in the tumor cell lines, western blots analyses against ACLY were used. [score:4]
Verifications of the downregulation relationship between the ACLY protein and miR-22 in the clinical samples of osteosarcoma, prostate, cervical and lung cancers. [score:4]
Similar inhibitory effects of miR-22-ACLY regulation were found among the Saos-2, PC-3 and Hela cell lines (Figure S5). [score:4]
miR-22 attenuates cancer cell proliferation and invasion, but promotes cell apoptosis by targeting ACLY. [score:3]
E. Site-directed mutations of the miR-22 seeding region of ACLY 3′UTR (shown in grey). [score:3]
In this study, we chose four different types of cancer that are tightly associated with human life and health, and demonstrated that ACLY acted as a common target of miR-22 despite of the tumor types. [score:3]
Spearman's rank correlation was used to determine the relationship between the miR-22 and ACLY expressions. [score:3]
And these targets were associated with poorer clinical outcomes that can be rescued by miR-22 modulation. [score:3]
ACLY and miR-22 expression in primary tumors. [score:3]
Further work will be needed to explore and develop the clinical translational value of miR-22-ACLY axis. [score:3]
In the mice mo dels of the four tumors, consistent with the decline of ACLY, evident lower levels of FASN and HMGCR expression were revealed by IHC staining after the anti-tumor treatment of miR-22 (Figures 6H and S5). [score:3]
The impairment of ACLY expression by miR-22 with ensuing inefficient de novo lipid synthesis may help to hinder the cell proliferation and invasion of these tumors. [score:3]
Taken together, we proposed a working mo del of a miR-22-ACLY axis that contributed to the suppression of de novo lipogenesis as well as the dysfunction of tumor growth and invasion (Figure 6I). [score:3]
miR-22 suppresses in vivo tumor colonization and metastasis. [score:3]
miR-22 reduces in vitro cancer cell growth and invasion but promotes apoptosis by targeting ACLY. [score:3]
B. Typical images of the cell invading behavior 24 hours after the transfection of the miR-22 mimic or inhibitor in the four tumor cells, respectively (100X, scale bar 200 μm). [score:3]
H. Representative IHC staining pictures of FASN and HMGCR expressions between the miR-22 and NC treatment groups of the four tumorigenic animal mo dels (100X, scale bar 200 μm). [score:3]
C. Analyses of the correlation relationship between ACLY and miR-22 expressions in the four tumors, and the size of the dot in the graphs was referred to the number of the cases. [score:3]
miR-22 suppresses tumor growth and metastasis in animal mo dels of osteosarcoma and prostate cancer. [score:3]
B. Representative images of miR-22 expression in osteosarcoma, prostate cancer, cervical cancer, lung cancer samples and the normal adjacent tissues displayed by RISH (400X, scale bar 50 μm). [score:3]
In a related systemic study, Koufaris et al. [43] have revealed that in breast cancer there existed three target genes of miR-22 including ACLY, which participate in different metabolic pathways such as de novo lipogenesis, fatty acid elongation and mitochondrial one-carbon metabolism. [score:3]
Some of the previous studies also reported a tumor-suppressive role of miR-22 in various neoplasms, including hepatocellular carcinoma [30], colon [24], ovarian [31] and breast cancers [32– 34]. [score:3]
By aiming at a variety of targets in different tissues, miR-22 has been proved to reduce cancer cell proliferation, promote apoptosis as well as decrease cell migration and invasion. [score:3]
miR-22 suppresses tumor growth and metastasis in animal mo dels of cervical and lung cancers. [score:3]
I. Hypothesis of the miR-22-ACLY axis suppressing tumor growth and metastasis through de novo lipogenesis repression. [score:3]
The correlation analysis showed that the level of miR-22 was inversely associated with the ACLY protein expression among the four clinical samples respectively (Figure 3C). [score:3]
To detect miR-22 expression, based on the previous study [24], the normal and malignant colon tissues were determined respectively as the positive and negative control (Figure S3). [score:3]
Data from the animal studies also indicated the beneficial effects of miR-22-ACLY regulation on the clinical prognosis. [score:2]
Compared to the NC miRNA, the luciferase activity of the wild-type reporter diminished by approximately 50% with the introduction of miR-22, and the mutant reporter was able to reverse this suppressive effect (P=0.000, separately; Figure 1F). [score:2]
A. Cell proliferation analyses of the Saos-2, PC-3, Hela and A549 cells treated with the miR-22 mimic or inhibitor by the MTT assay (** P<0.01). [score:2]
Figure 2 A. Cell proliferation analyses of the Saos-2, PC-3, Hela and A549 cells treated with the miR-22 mimic or inhibitor by the MTT assay (** P<0.01). [score:2]
To sum up, miR-22 is considered to be a feasible approach in the suppression of various tumors, and ACLY is one of the most important component parts of its metabolic posttranscriptional control. [score:2]
In the Saos-2 cells, for example, we found that the introduction of miR-22 led to an obvious defect in cell viability compared to the NC group, while the cell proliferating capacity could be partially compensated by the additional overexpression of ACLY. [score:2]
Measured by the specific enzymatic assay kits, we found that in the A549 cells, the treatment of miR-22 mimic produced an inhibitory effect both in the cellular triglycerides and cholesterol levels, whereas the introduction of miR-22 inhibitor showed the opposite effect (Figures 6F and 6G). [score:2]
F. Relative luciferase activities of reporter plasmids of the four cancer cell lines cotransfected with psiCHECK-2-3′UTR-WT (ACLY-3′UTR-WT) or psiCHECK-2-3′UTR-Mut (ACLY-3′UTR-Mut), as well as NC miRNA or miR-22 mimic (** P<0.01). [score:1]
To detect miR-22, the specific miRCURY LNA™ probe labeled with digoxigenin at both 5′ and 3′ end was ordered from Exiqon Life Sciences. [score:1]
E and K. The survival time curvesbetween the NC and miR-22 treatment groups. [score:1]
As illustrated in Figures 2C and S2, the treatments with the miR-22 accelerated the tumor cells towards apoptosis in comparison with the NC group. [score:1]
No mice treated by the NC miRNA survived at the end of the experiment, whereas no distant metastasis was found in the miR-22 group (Figures 4E, 4F and Supplementary Figure S4). [score:1]
These findings indicated a potent functional connection between ACLY and miR-22, whose binding site was conserved across many other mammalian species (Figure 1C). [score:1]
miR-22 reduces ACLY -mediated de novo lipid synthesis. [score:1]
However, a recent study of the role of miR-22 in breast cancer proposed contradictory findings. [score:1]
C. A putative miR-22 binding site in the 3′UTR of ACLY mRNA across different species (shown in red). [score:1]
Cancer cells transfected with the above miR-22 analogs for 24h were harvested with 0.25% trypsin (Gibco), resuspended in serum -depleted media at a density of 1×10 [5] cells and plated onto the 8 μm invasion compartment (Corning, Corning, NY, USA) coated with basement membrane Matrigel (BD, San Jose, CA, USA). [score:1]
By contrast, the mice treated with miR-22 only exhibited slight impairments in the cortex of the tibia (Figure S4). [score:1]
For the further verification of the relationship between ACLY and miR-22 in osteosarcoma, prostate, cervical and lung cancers, immunohistochemistry (IHC) staining and a RISH method were performed on human tissue microarrays. [score:1]
When the mice died or got sacrificed, the tumors were excised, photographed B and H. and weighed D and J. (** P<0.01), and the mice organs (Lu, Lung; Li, Liver; Sp, Spleen; Ki, Kidney; In, Intestine) were taken out for bioluminescence imaging F and L. The survival time of the mice with treatments of NC or miR-22 were analyzed by a Kaplan-Meier curve E and K. Finally, the tumor tissues were examined by H&E or IHC staining (100X, scale bar 200 μm) M and N. In the subcutaneously implanted mo dels of PC-3 cells, the anti-tumor effects were seen with statistical differences 7 days after the drug injection (Figures 4G and 4I). [score:1]
As a result, fewer miR-22 staining was revealed in the four tumors than in the normal samples (Figures 3B and Supplementary Figure S3). [score:1]
On the other hand, in vitro transwell assays showed that the treatment of miR-22 resulted in evident invasion suppressions in the relevant tumor cells compared with the NC -transfected ones (Figures 2B and Supplementary Figure S2). [score:1]
When the mice died or got sacrificed, the tumors were excised, photographed B and H. and weighed D and J. (** P<0.01), and the mice organs (Lu, Lung; Li, Liver; Sp, Spleen; Ki, Kidney; In, Intestine) were taken out for bioluminescence imaging F and L. The survival time of the mice with treatments of NC or miR-22 were analyzed by a Kaplan-Meier curve E and K. Finally, the tumor tissues were examined by H&E or IHC staining (100X, scale bar 200 μm) M and N. In the subcutaneously implanted mo dels of PC-3 cells, the anti-tumor effects were seen with statistical differences 7 days after the drug injection (Figures 4G and 4I). [score:1]
Besides, with the application of Annexin V/PI double-staining and the flowcytometry, we examined the sensitization of cell apoptosis influenced by miR-22. [score:1]
Animals were imaged and treated with an intratumoral injection of miR-22 or NC miRNA every week until the date of death. [score:1]
In contrast, after the treatment of miR-22, the tumor tissues developed sparse and well-differentiated structures. [score:1]
As a result, miR-22, in particular, yielded a notable and consistent decline in the four tumor cells (Figure 1B). [score:1]
miR-22 suppresses in vivo tumor colonization and metastasisWe established the in vivo mo dels of tumorigenesis on nude mice, and investigated the treatment effects of miR-22. [score:1]
F and G. Analyses of the intracellular triglycerides and cholesterol levels after the treatment of miR-22 (** P<0.01). [score:1]
Accordingly, miR-22-ACLY axis may have the similar effect on cancer cell mobility and the overall malignant progression. [score:1]
In situ hybridizationTo detect miR-22, the specific miRCURY LNA™ probe labeled with digoxigenin at both 5′ and 3′ end was ordered from Exiqon Life Sciences. [score:1]
For the Saos-2 originated tumor, in comparison with the NC -treated group, the therapeutic effect of miR-22 began to show 14 days after the drug administration, which followed by a continuous decline in the peak signal of fluorescence (Figures 4A and 4C). [score:1]
When the mice died or got sacrificed, the tumors were excised, photographed B and H. and weighed D and J. (** P<0.01), and the mice organs (Lu, Lung; Li, Liver; Sp, Spleen; Ki, Kidney; In, Intestine) were taken out for bioluminescence imaging F and L. The survival time of the mice with treatments of NC or miR-22 were analyzed by a Kaplan-Meier curve E and K. Finally, the tumor tissues were examined by H&E or IHC staining (100X, scale bar 200 μm) M and N. A and G. Representative bioluminescence images of mice with the xenografts of cervical and lung cancers. [score:1]
The miR-22 group was intratumorally treated twice a week with the agomiR of miR-22 carried by the in vivo-jetPEI [®] Delivery Reagent (Polyplus Transfection, New York, NY, USA) according to the manufacturer's protocols, and correspondingly the NC group was injected with the negative control (NC) miRNA. [score:1]
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Therefore, downregulation of SIRT1, PGC-1α, and PPARα expression levels resulting from unchecked miR-22 cardiac expression may represent a synergistic pathogenic mechanism for elicitation of contractile dysfunction. [score:8]
To minimize the concern that changes in PGC-1α and PPARα expression levels are secondary to cardiac dysfunction and/or hypertrophy in transgenic mice, we then asked whether miR-22 could inhibit these targets in primary cultures of neonatal rat ventricular cardiomyocytes (NRVC). [score:7]
miR-22 regulates PGC-1α, PPARα and SIRT1 cardiac expression levelsA large number of important transcription factors or regulators implicated in cardiomyopathy have been identified as bona-fide targets of miR-22, including Purb [12], Hdac4 [13], Ppara [16], Sirt1 [17], and Pgc1a [18]. [score:7]
To determine if enforced expression of miR-22 suppresses PGC-1α, PPARα and SIRT1 expression levels in concert, initially we performed qPCR and immunoblots on miR-22 transgenic and WT mice. [score:7]
miR-22 inhibits a large number or genes associated with cell growth, cell death, and energy substrate metabolismAs an initial step to delineate miR-22 mRNA targets and downstream networks, we performed genome wide gene expression analysis via microarray on ventricles of 12-week old TG-H and WT controls. [score:7]
Using a combination of gain-of-function (GOF) experiments in mice and cultured cardiomyocytes, we demonstrate that miR-22 directly inhibits PGC-1α, PPARα, and SIRT1 expression levels leading to HF. [score:6]
Cardiomyocyte-specific overexpression of miR-22 impairs calcium handlingThe observed alterations in contractile and calcium handling gene expression seen in miR-22 transgenic mice are predicted to directly affect the magnitude of the Ca [2+] transient and Ca [2+] loading in the sarcoplasmic reticulum (SR). [score:6]
Its worthy of note that miR-22 has been reported to be both up- and down-regulated in human heart disease [26– 28]. [score:6]
As an initial step to delineate miR-22 mRNA targets and downstream networks, we performed genome wide gene expression analysis via microarray on ventricles of 12-week old TG-H and WT controls. [score:5]
In the future it will be important to determine if miR-22 is inversely correlated with expression levels of SIRT1, PGC-1α, and PPARα in human diseased hearts. [score:5]
Ingenuity analysis revealed many dozens of miR-22 target candidates associated with “cellular growth and proliferation”, “lipid metabolism”, and “cardiovascular disease” respectively (Table S3). [score:5]
miR-22 -mediated cardiomyopathy is associated with impaired ERR/PPAR target gene signatureWe reasoned that hypertrophy and cardiac dysfunction in miR-22 transgenic mice could be due, at least in part, to decreased expression of SIRT1, PGC1α, and PPARα. [score:5]
Collectively, these results indicate that enhanced miR-22 expression has a negative effect on calcium handling, which could be the result of impaired SR Ca [2+] resequestration, suggesting at least in part, a mechanism where overexpression of miR-22 elicits dysfunction in miR-22 transgenic mice. [score:5]
Application of the TargetScan algorithm did not find mouse/human conserved miR-22 target sites in other PGC1α, PPARα, and ERRα transcription factor family members. [score:5]
Collectively, this data suggest a pathogenic role of miR-22 in mediating hypertrophy and cardiac dysfunction by suppressing ERR/PPAR -dependent gene expression via silencing of SIRT1, PGC1α, and PPARα. [score:5]
Our interpretation of how enforced miR-22 expression promotes cardiomyopathy is that miR-22 proximally compromises contractile function, which then leads to the progressive chamber dilatation and apoptosis as seen in the higher expressing transgenic line. [score:5]
The observed alterations in contractile and calcium handling gene expression seen in miR-22 transgenic mice are predicted to directly affect the magnitude of the Ca [2+] transient and Ca [2+] loading in the sarcoplasmic reticulum (SR). [score:4]
This interpretation is supported by the molecular signature of enhanced miR-22 in which ERR and PPAR genes involved in involved in each step of excitation contraction coupling, contractile work, fatty acid/glucose substrate utilization, Krebs cycle activity, ATP synthesis by OXPHOS and hypertrophy gene transcription are downregulated in the heart. [score:4]
Sylamer showed prominent miR -mediated mRNA destabilization since the motifs complementary to the common “seed” region of miR-22 were specifically enriched within the 3’ UTRs of downregulated genes (Figure S3A). [score:4]
A large number of important transcription factors or regulators implicated in cardiomyopathy have been identified as bona-fide targets of miR-22, including Purb [12], Hdac4 [13], Ppara [16], Sirt1 [17], and Pgc1a [18]. [score:4]
miR-22 regulates PGC-1α, PPARα and SIRT1 cardiac expression levels. [score:4]
Cardiomyocyte-specific overexpression of miR-22 promotes hypertrophic growth and cardiomyopathyWe previously described cardiac myocyte-specific miR-22 overexpressing transgenic mice that showed signs of cellular and organ level hypertrophic growth compared to their WT littermates beginning at 5-weeks of age [12]. [score:4]
Gain-of-function data presented here clearly shows that miR-22 is sufficient to induce cardiac hypertrophy and dysfunction and it sheds new light linking overexpression of miR-22 to ERR/PPAR -dependent transcription. [score:3]
Enforced miR-22 expression impairs ERR/PPAR -dependent transcription in the heart. [score:3]
0075882.g001 Figure 1Enforced expression of miR-22 in the heart is sufficient to induce cardiomyopathy. [score:3]
Table S3 Potential Targets of miR-22 in the heart. [score:3]
Our molecular analysis in the miR-22 LOF mo del suggested that miR-22 works, in large part, within myocytes to sustain maximal expression levels of virtually all muscle-restricted serum response factor -dependent genes. [score:3]
Higher miR-22 expressing mice exhibited four chamber dilatation, myocardial apoptosis, diastolic ventricular dysfunction and atrial fibrillation. [score:3]
We combined this list with the potential targets we identified earlier in miR-22 [-/-] hearts [12]. [score:3]
Initially, since ERRα is major transcriptional partner of PGC-1α, and PGC-1α is required for ERRα expression/activity itself [7], we wished to determine whether mRNA levels encoding ERRα (Essra) were decreased in 5-week old miR-22 transgenic mice. [score:3]
In this study, we set out to decipher the molecular and pathological consequences of enforced miR-22 expression on the heart. [score:3]
Next we scrutinized the expression of genes under transcriptional control by PGC-1α/PPARα complex in hearts of miR-22 transgenic mice. [score:3]
Extending previous observations, we show that cardiac-specific enforced expression of miR-22 in mice elicits contractile dysfunction and HF. [score:3]
0075882.g003 Figure 3Enforced miR-22 expression impairs ERR/PPAR -dependent transcription in the heart. [score:3]
Figure S3 Transcriptome microarray detection of miR-22 targeting effects. [score:3]
Taken as a whole, these data indicate that enforced miR-22 expression in heart is deleterious. [score:3]
Cardiomyocyte-specific overexpression of miR-22 promotes hypertrophic growth and cardiomyopathy. [score:3]
Figure S4 Cellular and molecular effects of increased miR-22 expression in primary cultures of neonatal rat ventricular cardiac myocytes (NRVC). [score:3]
Collectively, these data establish SIRT1, PGC-1α, and PPARα as bona-fide miR-22 targets in the heart. [score:3]
Although both miR-22 transgenic mice lines show dosage sensitive negative effects on ERR/PPAR -dependent gene expression, secondary complications associated with cardiomyopathy could not be completely discounted. [score:3]
Consequently, at one level, enforced miR-22 expression levels may cause a decline in the transcription of these genes culminating in impaired calcium handling and pump dysfunction. [score:3]
PPAR/ERR responsive genes involved in glucose transport and oxidation [9, 10, 22] were also aberrantly expressed in miR-22 transgenic hearts (Figure 3B, 3H and Table S2). [score:3]
To gain more insight into the pathologic effects associated with enforced miR-22 cardiac expression, echocardiographic and Doppler flow measurements and electrocardiograms were obtained from the higher miR-22 expressing TG-H line. [score:3]
We also showed that miR-22 overexpression in cultured neonatal cardiomyocytes promotes classic features of hypertrophy. [score:3]
We reasoned that hypertrophy and cardiac dysfunction in miR-22 transgenic mice could be due, at least in part, to decreased expression of SIRT1, PGC1α, and PPARα. [score:3]
miR-22 -mediated cardiomyopathy is associated with impaired ERR/PPAR target gene signature. [score:3]
Moderate expression levels of miR-22 resulted in hypertrophic signaling and an apparent hypocontractile cardiac phenotype. [score:3]
miR-22 inhibits a large number or genes associated with cell growth, cell death, and energy substrate metabolism. [score:3]
Enforced expression of miR-22 in the heart is sufficient to induce cardiomyopathy. [score:3]
Repression: protein levels in miR-22 over -expressing cells relative to control miRNA. [score:3]
We therefore determined whether miR-22 overexpression hampers ERR/PPAR-responsive genes in NRVC. [score:3]
Next, we used mRNA microarray combined with real time PCR as a more global approach to determine whether the PGC1α/ERR, PGC1α/PPAR transcription cascades were inhibited by miR-22 in transgenic mice. [score:3]
Cardiomyocyte-specific overexpression of miR-22 impairs calcium handling. [score:3]
The level of miR-22 expression in the TG-M and TG-H mice were 4- and 9-fold higher respectively in comparison to non-transgenic littermate (WT) mice [12]. [score:3]
Furthermore, exogenous application of miR-22 in primary cultures of NRVC confirmed directed repression of PGC-1α, PPARα and SIRT1 (Figure S4B). [score:2]
Mutation of the putative miR-22 sites abrogated repression by miR-22, thus confirming functionality of sites (Figure 2D). [score:2]
Reporter assays with miR-22 expressing cells independently confirmed that miR-22 represses these genes (Figure 2D). [score:2]
To explore direct miR-22 -mediated miRNA-mRNA interactions, we applied the Sylamer tool on the microarray [12]. [score:2]
We previously described cardiac myocyte-specific miR-22 overexpressing transgenic mice that showed signs of cellular and organ level hypertrophic growth compared to their WT littermates beginning at 5-weeks of age [12]. [score:2]
Table S2 Genes Dysregulated in miR-22 transgenic hearts. [score:2]
A comprehensive annotation and search of miR-22 motifs revealed 276 repressed genes with miR-22 seed matches in their 3’ UTR (Figure S3B and Table S2). [score:1]
The mice harboring the null miR-22 mutant allele was described earlier [12]. [score:1]
A plausible mechanism accounting for miR-22 -mediated GOF cardiomyopathy came from our observation that vital cardiac genes SIRT1, PGC-1α, and PPARα are co-repressed by miR-22 in the heart. [score:1]
Figure S2 Apoptosis analysis in miR-22 transgenic mice. [score:1]
The generation of the two miR-22 transgenic cardiomyocyte-specific mice lines (herein referred to as TG-M and TG-H) [12], in which miR-22 was placed under the control of the Myh6 promoter, were previously described. [score:1]
It should be recognized that the mechanism(s) of miR-22 LOF and GOF mediated cardiomyopathy are especially complex because miR-22 operates upstream of many critical transcription factors with a high level of connectivity and therefore the phenotype(s) cannot be easily be assigned to a single gene. [score:1]
Independent in vivo studies in mice suggest that the heart enriched, microRNA-22 (miR-22) is involved in the pathogenesis of HF [12, 13]. [score:1]
We have previously shown that absence of miR-22 also renders the heart sensitive to dilatation and decompensation with stress provocation [12]. [score:1]
In agreement with a previous report, transfection of a miR-22 mimic lead to potent hypertrophy of NRVC characterized by increased protein synthesis, cell size, and increased Nppa expression (Figures S4A, and ] 14]). [score:1]
A limitation of our studies is that they did not address whether deranged ERR and PPAR transcription in miR-22 transgenic hearts are associated with ATP-depletion, mitochondrial dysfunction, and/or abnormal substrate utilization. [score:1]
We then asked whether in vivo absence of miR-22 [12] in the heart would lead to coordinate accumulation of Pgc1a, Ppara, Sirt1 transcript levels. [score:1]
Indeed miR-22 TG-M myocytes also exhibited defective calcium transients, as evidenced by reduced calcium transient amplitudes and diminished SR calcium load. [score:1]
As shown in Figure 2C, Pgc1a, Ppara and Sirt1 each contain highly conserved complementary sequences to miR-22. [score:1]
This would suggest that miR-22 functions within a tight threshold in the heart. [score:1]
Gene set enrichment analysis (GSEA) tool was applied on the transcriptome microarray to identify significantly repressed or induced Gene Ontology, Biological Process, Molecular Function, or Cellular Compartment categories in miR-22 transgenic hearts. [score:1]
In agreement with our previous observations, in general muscle-restricted genes encoding proteins in the vicinity of the cardiac Z disc/Titin cytoskeleton appeared either unaffected or induced in miR-22 transgenic hearts (Figures S3G and [12]). [score:1]
Transfections made use of Oligofectamine (Invitrogen) with 100 ng of indicated psiCheck-2 plasmid containing wild-type or miR-22 ‘seed’ mutant derivatives, along with the miRNA control or miR-22 duplex (Dharmacon) at a final concentration of 6 nM. [score:1]
As shown in Figure S4C-F, transfection of miR-22 into NRVC resulted in lower mRNA abundance of a range of genes influenced by PGC-1α/ERR and/or PGC-1α/PPAR in comparison with cells a control miR -mimic. [score:1]
These results were confirmed, indeed miR-22 transgenic myocytes exhibited defective calcium transients, as evidenced by reduced calcium transient amplitudes and diminished SR calcium load. [score:1]
This molecular signature of enhanced miR-22 is reminiscent of PGC-1α or ERRα gene disruption [9, 10, 19]. [score:1]
Also, our in-depth molecular analysis revealed a sizable correlation between the miR-22 transgenic gene signature and published HF related data sets. [score:1]
One interesting aspect of the miR-22 GOF effect in the heart was the reduced basal contractility seen in TG-M mice in the absence of chamber dilatation and myocardial scarring. [score:1]
0075882.g004 Figure 4Diminished sarcoplasmic reticulum (SR) Ca [2+] load and Ca [2+] transient in miR-22 transgenic mice. [score:1]
miR-22 seed heptamers are shown in shades of blue while all other mouse miRNA seeds are shown in grey. [score:1]
A subset of genes containing highly conserved miR-22 motifs in the 3’ UTR and linked to cardiomyopathy, including calmodulin binding transcription activator 2 (Camta2), Caveolin-3 (Cav3), Homer-1, and Pgc1a were confirmed as repressed in miR-22 transgenic hearts by quantitative PCR and/or immunoblot (Figure S3C-F and see below). [score:1]
We next determined whether cardiac/muscle specific transcription was broadly decreased in miR-22 transgenic hearts. [score:1]
miR-22 co-represses PGC-1α, PPARα, and SIRT1 in the heart. [score:1]
We previously showed that miR-22 -deficient mice exhibit increased fibrosis and increased tendency towards ventricular dilatation and cardiac dysfunction in response to pressure overload [12]. [score:1]
To explore if Pgc1a, Ppara and Sirt1 operate downstream of miR-22 in heart, we examined 3’ UTRs of these three genes for miR-22 binding motifs. [score:1]
Diminished sarcoplasmic reticulum (SR) Ca [2+] load and Ca [2+] transient in miR-22 transgenic mice. [score:1]
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7
[+] score: 154
To support functional targeting of P2rx7 mRNA by miR-22, we transfected neuronal cells (N2a) with either LNA -modified antagomirs to inhibit miR-22 (Ant22) or a mimic sequence (Mi22) to upregulate miR-22, and then recorded P2X7R agonist-evoked currents (Fig. 2K). [score:8]
Inhibition of miR-22 increases P2X7R protein and function in vivoTo obtain in vivo evidence that P2X7R is a target of miR-22 we tested the effects of inhibiting miR-22 in mice using antagomirs. [score:7]
Mimics targeting miR-34a have recently entered clinical trials for the treatment of cancer 44 and we therefore attempted to directly upregulate miR-22 in the hippocampus by intracerebroventricular microinjection of Mi22. [score:7]
To obtain in vivo evidence that P2X7R is a target of miR-22 we tested the effects of inhibiting miR-22 in mice using antagomirs. [score:5]
miR-22 mimic treatment reduces P2X7R expression and seizures in vivoLast, we sought to complement the antagomir findings and explore therapeutic potential by investigating whether over -expression of miR-22 would suppress P2X7R protein levels in the contralateral hippocampus and reduce spontaneous seizures. [score:5]
De-repression of the miRNA target by antagomirs triggered inflammatory responses that were not ordinarily seen in this brain region, and increased spontaneous seizures in mice, whereas delivery of miR-22 suppressed seizures. [score:5]
RNA therapeutics including miRNA mimics have recently entered clinical testing in humans 44 and we found that delivery of a sub-picomolar central injection of Mi22 was sufficient to upregulate miR-22 to a level comparable to that in the contralateral hippocampus and this had an anti-seizure effect. [score:4]
The major finding in the present study was that expression of the P2X7R is regulated post-transcriptionally by miR-22 within the contralateral hippocampus after status epilepticus and this restrains the emergent epilepsy phenotype. [score:4]
In animal studies where altered miR-22 expression was reported, the direction of change after status epilepticus was inconsistent 52 53. [score:4]
This pattern of cellular expression was confirmed in purified cultures of mouse hippocampal neurons, microglia and astrocytes, with highest basal levels of miR-22 found in cultured astrocytes (Fig. 2M). [score:3]
Last, we sought to complement the antagomir findings and explore therapeutic potential by investigating whether over -expression of miR-22 would suppress P2X7R protein levels in the contralateral hippocampus and reduce spontaneous seizures. [score:3]
Predicted targets of mmu-miR-22 were identified using miRanda and microRNA. [score:3]
Inhibition of miR-22 increases P2X7R protein and function in vivo. [score:3]
The most highly expressed miRNA unique to the contralateral hippocampus was miR-22-3p (hereafter miR-22) (Fig. 2G). [score:3]
However, data here show that blocking P2X7R using genetic or pharmacologic approaches was sufficient to obviate the main pro-inflammatory and pro-excitatory phenotype in miR-22 -inhibited mice. [score:3]
We next explored which cells expressed miR-22 in mouse brain tissue sections. [score:3]
Early work reported tumor-suppressor effects of miR-22 54 but anti-inflammatory and neuroprotective functions recently emerged for miR-22 in CNS mo dels 55 56. [score:3]
We then searched the 2902 predicted targets of mmu-miR-22 against the 468 mouse proteins with the term “ion channel” and found 15 proteins, which were Ank3, Arrb1, Clcc1, Cav3, Cnga2, Itpr1, Mylk, P2rx7, Ryr3, Tmc3, Trpc5, Trpm5, Trpm6, Trpm7 and Unc80. [score:3]
We did not observe a reduction in P2rx7 transcript levels due to miR-22 targeting. [score:3]
This suggests that, despite multi -targeting potential of miRNAs, the main effects of miR-22 in the contralateral hippocampus are via P2X7R. [score:3]
Thus, while our data point to miR-22 protecting via suppression of P2X7R and thus an anti-inflammatory mechanism, inflammatory signaling is not invariably pro-epileptogenic. [score:3]
To overexpress miR-22 we used chemically -modified double-stranded RNAs (mirVana™ mimics; Life technologies). [score:3]
Consistent with a role in suppressing neuroinflammation, we found that blocking miR-22 resulted in an early and sustained elevation in proinflammatory signaling and molecular markers of excitability in the contralateral hippocampus. [score:3]
Taken together, these findings are consistent with miR-22 targeting of P2X7R after status epilepticus in the contralateral hippocampus. [score:3]
miR-22 inhibition increases astrogliosis and impairs cognitive performance in epileptic mice. [score:3]
Based on these neuroinflammatory responses, we hypothesized that miR-22 inhibited mice would develop exacerbated epilepsy. [score:3]
miR-22 mimic treatment reduces P2X7R expression and seizures in vivo. [score:3]
Notably, specificity protein 1 (Sp1) was recently identified to control expression of P2X7R in neurons 73 and the miR-22 promoter contains putative Sp1 binding sites (C. C. personal communication). [score:3]
Among several miRNAs that could potentially target P2X7R, only miR-22 was up -loaded into the RISC. [score:3]
In vivo silencing of miR-22 exacerbates epilepsyBased on these neuroinflammatory responses, we hypothesized that miR-22 inhibited mice would develop exacerbated epilepsy. [score:3]
miR-22 inhibition exacerbates epilepsy in mice. [score:3]
These findings suggest miR-22 normally restrains development of a contralateral epileptogenic focus in this mo del and loss of miR-22, as with loss of miR-128 28, is pro-epileptic. [score:2]
MicroRNA-22 targets the P2X7R in the contralateral hippocampus. [score:2]
Thus, silencing miR-22 exacerbates epilepsy and leads to contralateral hippocampal involvement in spontaneous seizures. [score:1]
We found that miR-22 and the P2rx7 transcript were selectively uploaded to the RISC in the normally spared contralateral hippocampus of mice after status epilepticus triggered by intra-amygdala kainic acid. [score:1]
Further studies will be required to determine which cellular effect of miR-22 silencing is the most important contributor to the epilepsy phenotype. [score:1]
To investigate whether miR-22 inhibition also affected function of the P2X7R, we performed patch-clamp recordings from EGFP -positive dentate granule cells in ex vivo slices obtained from Scr- and Ant22 -treated P2rx7 reporter mice 12 h after status epilepticus (Fig. 3H). [score:1]
Combining both approaches identified miR-22 as the most abundant RISC -loaded miRNA unique to the contralateral hippocampus after status epilepticus. [score:1]
Sequence for the probes: anti-miR-22: CTTCAACTGGCAGCTT/3Dig_N and anti-antagomir; 5DigN/AGCTGCCAGTTGAAG/3Dig_N. [score:1]
Silencing miR-22 also caused a rapid escalation of epileptic seizure rates in mice. [score:1]
Mimic effects on miR-22 and seizures were short-lived, however, contrasting the prolonged effects of antagomirs in this study and reported previously 27. [score:1]
The miR-22 antagomir sequence was CTTCAACTGGCAGCT and scrambled was ACGTCTATACGCCCA. [score:1]
We proceeded next to study the effect of silencing miR-22 on seizures. [score:1]
The mature sequence of miR-22 is fully conserved between mouse and human (Fig. 2H). [score:1]
In silico analysis identified a putative miR-22 seed binding site in the 3′UTR of the P2rx7 transcript, comprising an 8 nt match, starting at the second nt (adenosine) from the 5′ end of the miRNA (Supplementary Fig. 2A). [score:1]
In situ hybridization detected a strong miR-22 signal in granule layer cells as well as hilar and pyramidal neurons and smaller cells, likely glia, as well as in the neocortex and other brain regions (Fig. 2L and Supplementary Fig. S2B). [score:1]
High P2X7R levels, however, render microglia susceptible to ATP -induced apoptosis 70 so it is possible silencing miR-22 promoted microglial cell death. [score:1]
The probes to detect miR-22 or the antagomir were 2′-O,4′-C methylene bicyclonucleoside monomer-containing oligonucleotides (LNA -modified. [score:1]
miR-22 is uploaded to the RISC in the contralateral hippocampus. [score:1]
Understanding what controls miR-22 activation may help explain why secondary epileptic foci form in some cases. [score:1]
It will require additional studies to determine why the seizure “dose” that reaches the contralateral hippocampus induces the pathway and why induction of miR-22 is not effective in the ipsilateral hippocampus. [score:1]
The distribution of miR-22 was similar in tissue sections from mice after status epilepticus (Fig. 2L). [score:1]
In vivo silencing of miR-22 exacerbates epilepsy. [score:1]
Notably, the miR-22 in situ signal was readily observed in ipsilateral neurons including dentate granule cells, where there was no RISC loading of the P2rx7 transcript. [score:1]
In vivo silencing of miR-22 exacerbates astrogliosisWe next examined pathological changes in the hippocampus after epilepsy monitoring in Ant22 and Scr mice. [score:1]
This may be due to the Ago2 search and selection process 72 or the transcriptional control of miR-22, the mechanisms of which are unknown in the brain. [score:1]
An interesting observation in the present study was the dramatic astrogliosis found in the contralateral hippocampus of miR-22 silenced epileptic mice. [score:1]
miR-22 manipulation alters P2X7R function in vitro and in vivo. [score:1]
This suggests de-repression of P2X7R by silencing miR-22 generates an early pro-inflammatory environment in the post-status contralateral hippocampus. [score:1]
Black arrows, granule neurons; miR-22 was also present in glia-like cells (white arrows). [score:1]
Determining which of the multiple potentially pro-epileptogenic effects of silencing miR-22 is most critical for the epilepsy phenotype will require further studies. [score:1]
Panels on right shows a staining control and higher-power images of miR-22 staining after SE. [score:1]
We also found that miR-22 modulation affected Tnfα levels. [score:1]
However, seizure rates during later monitoring (days 5–9) were similar to Scr levels (data not shown), perhaps as a result of the transient ability of Mi22 to enhance hippocampal miR-22 levels (see Fig. 6F). [score:1]
Pro-inflammatory phenotype in miR-22-silenced mice is P2X7R -dependent. [score:1]
In vivo silencing of miR-22 exacerbates astrogliosis. [score:1]
Silencing miR-22 increases markers of inflammation in the contralateral hippocampus. [score:1]
Injection of picomolar amounts of Mi22 produced dose -dependent, short-lasting increases in hippocampal miR-22 levels (Fig. 6E,F). [score:1]
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[+] score: 152
The results showed that downregulation of SIRT1 inhibited apoptosis in mouse granulose cells, suggesting that miR-22 may regulate apoptosis at least partly via the regulation of SIRT1. [score:8]
Overexpression of miR-22 suppressed mouse ovarian GC apoptosis at least in part by blocking SIRT1 expression. [score:7]
MicroRNA-22 (miR-22) overexpression is neuroprotective via general anti-apoptotic effects and may also target specific Huntington's disease-related mechanisms. [score:7]
miR-22 inhibits mGC apoptosis by downregulating SIRT1 directly in vitro. [score:7]
These findings demonstrated that miR-22 targeted sites of 3′-UTR region of SIRT1 and that there is an inverse correlation between the miR-22 expression level and the protein expression level of SIRT1. [score:7]
We found that miR-22 down-regulate SIRT1 expression through post-transcriptional regulation via a miR-22 -binding site within the 3′-UTR of SIRT1. [score:7]
To our knowledge, we for the first time demonstrated that miR-22 regulated apoptosis through suppressing SIRT1 expression in GC apoptosis. [score:6]
miR-22 directly inhibits the expression of SIRT1 via binding to its 3′-UTR. [score:6]
Fig. 3. miR-22 directly inhibits expression of SIRT1 via its 3′-UTR. [score:6]
Decreased Bax expression and increased Bcl-2 expression were observed in the miR-22 mimics group (Fig.  2A). [score:5]
To confirm SIRT1 was directly targeted and regulated by miR-22 in HEK293 cells, luciferase reporter genes with SIRT1 3′-UTR and the mutant counterpart at the miR-22 binding regions were co -transfected with miR-22 mimics or mimics NC into HEK293 cells. [score:5]
To make clear the precise mechanism by which miR-22 attenuated granulose cell apoptosis, we detected the expression level of SIRT1 in mGCs transfected with miR-22 mimics or miR-22 inhibitor. [score:5]
In this study, we found that SIRT1 was a target gene of miR-22 and inhibition of SIRT1 attenuated mouse ovarian GC apoptosis. [score:5]
The expression level of Bax, a apoptosis marker, were significantly decreased in human ovarian GCs transfected with miR-22, suggesting that miR-22 may inhibit ovarian GC apoptosis (Sirotkin et al., 2010). [score:5]
With identification of SIRT1 as a target for miR-22 in ovarian GCs, this study provided an improved understanding of molecular mechanisms of miR-22 -mediated follicular development, which may potentially be applied in future clinical applications. [score:4]
Luciferase reporter assay showed that overexpression of miR-22 significantly inhibited the luciferase activity of SIRT1 with the wild-type 3′-UTR, but not with the mutant 3′-UTR (Fig.  3B). [score:4]
U6 small nuclear RNA was used as an internal control for miR-22 mRNA expression. [score:3]
Real-time PCR (RT-PCR) was used to detect the expression level of miR-22 in healthy follicles (HF), early atretic follicles (EAF), and progressively atretic follicles (PAF). [score:3]
Furthermore, an experiment in cultured human ovarian GCs showed that transfection with miR-22 precursors remarkably affected expression of proliferation marker, PCNA, and proapoptotic marker, Bax (Sirotkin et al., 2010). [score:3]
miR-22 expression level was decreased during follicular atresia in mice. [score:3]
As shown in Fig.  3C, the expression of SIRT1 significantly decreased in miR-22 mimics group. [score:3]
miR-22 inhibits GC apoptosis. [score:3]
, Foster City, CA, USA) to detect the expression level of miR-22. [score:3]
RT-PCR was conducted to detect the expression levels of mature miR-22 in healthy follicles (HF), early atretic follicles (EAF), and progressively atretic follicles (PAF). [score:3]
The expression level of miR-22 was increased in EAF and PAF. [score:3]
Therefore, SIRT1 was a target gene of miR-22 and SIRT1 may play an important role in the process of miR-22 affecting GC apoptosis. [score:3]
A previous study suggested that miR-22 was capable of inhibiting neuronal apoptosis, as shown by its capability to attenuate activation of effector caspases (Jovicic et al., 2013). [score:3]
Fig. 1. The expression of miR-22 in mouse ovarian granulosa cells. [score:3]
miR-22 was increased during follicular atresia and suppressed granulosa cell apoptosis. [score:3]
The expression level of miR-22 was decreased in ovarian cancer tissues compared with healthy human ovarian surface epithelium (Wyman et al., 2009). [score:2]
As shown in Fig.  2B, the apoptosis rate of mGCs transfected with miR-22 mimics remarkably decreased compared with control groups, suggesting that miR-22 suppressed mGCs apoptosis in vitro. [score:2]
We further evaluated the effect of miR-22 on SIRT1 expression and elucidated the functional role of SIRT1 in apoptosis regulation. [score:2]
The results of the luciferase reporter assay indicated that SIRT1 was a target gene of miR-22. [score:2]
Fig. 2. Apoptosis rate of mGCs when transfecting with miR-22 mimics or mimics NC. [score:1]
The putative miR-22 -binding sites in mouse SIRT1 3′-UTR and the mutant SIRT1 gene 3′-UTR with modified binding sequence were shown in Fig.  3A. [score:1]
In the present study, we investigated the expression of miR-22 in mouse ovarian GCs during follicular atresia. [score:1]
Regulation of the expression of SIRT1 by miR-22 was evaluated using a luciferase reporter assay system. [score:1]
The data showed that miR-22 was significantly decreased during mouse follicular atresia (Fig.  1). [score:1]
These results demonstrated that miR-22 may be involved in apoptosis in mouse ovarian follicles. [score:1]
Then the cells were transiently co -transfected with 0.3 µg wild type or mutant SIRT1 3′-UTR luciferase reporter plasmid and 50 nM miR-22 mimics or miR-control using Lipofectamine 2000 transfection reagent (Invitrogen, Carlsbad, CA, USA). [score:1]
The relative expression levels of miR-22 were measured in healthy follicles (HF), early atretic follicles (EAF), and progressively atretic follicles (PAF) using qRT-PCR. [score:1]
The luciferase reporter plasmids fused with the 3′-UTR of mouse SIRT1 containing the putative miR-22 binding site were obtained from GenePharma (Shanghai, China). [score:1]
Flow cytometry was performed to assess the apoptosis of mouse granulosa cells (mGCs) treated with miR-22 mimics or negative control (NC) mimics. [score:1]
SIRT1 miR-22 Granulosa cell Apoptosis Follicle atresia A large number of follicles are present in the mammalian ovary at birth, and each follicle contains an oocyte that is surrounded by several layers of granulosa cells (GCs). [score:1]
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[+] score: 116
Other miRNAs from this paper: mmu-mir-155, mmu-mir-200b, mmu-mir-34a, mmu-mir-17
Taken together, these data demonstrate that miR-22, -34a, and -155 are up-regulated in the final step of iDC to mDC maturation and that all three microRNAs can directly regulate Csf1r expression by targeting its mRNA via 3′UTR interactions. [score:10]
Then we inhibited microRNA-22, -34a, or -155 on day 4 of GM-DC culture and observed that M-CSFR down-regulation upon LPS -induced DC maturation at day 7 was significantly prevented (Figure 4B), demonstrating that miR-22, -34a, and -155 regulate M-CSFR expression in DC in the final stage of maturation. [score:9]
From these, M-CSFR was the most likely target for microRNA regulation in iDC to mDC transition as three out of four conserved predicted binding sites in the 3′UTR of Csf1r mRNA were targeted by differentially expressed microRNAs, i. e., miR-22, -34a, and -155 (Figure 2A). [score:8]
At this point, it is reasonable to hypothesize that up-regulation of miR-22, -34a, and -155 is causally involved with Csf1r down-regulation. [score:7]
Interestingly, in these experiments we observed that not only down-regulation of M-CSFR was reduced on cells treated miR-22, -34a, or -155 inhibitors, compared to the cells transfected with control inhibitor, but that also the frequency of cells with a mDC phenotype (CD11c [+]MHCII [hi]CD86 [hi]) was significantly lower (p < 0.0001) (Figure 4C). [score:7]
Additionally, we show here that miR-22 and miR-34a also directly target Csf1r and are up-regulated upon final DC maturation. [score:7]
Here, we have shown that an additional level of Csf1r expression regulation occurs, on top of transcriptional and post-translational control, through the action of microRNAs miR-22, -34a, and -155. [score:6]
LPS stimulation of iDC or other maturation-inducing stimuli up-regulate miR-22, -34a, and -155, which bind to Csf1r mRNA and prevent translation of M-CSFR protein. [score:6]
In summary, these results show that in vitro inhibition of miR-22, -34a, and -155 reduces LPS -induced M-CSFR down-regulation in GM-DC. [score:6]
M-CSFR is a target of miR-22, -34a, and -155, which are up-regulated during final DC maturation. [score:6]
Inhibition of miR-22, -34a, and -155 dysregulates M-CSFR expression and blocks DC maturation. [score:6]
To substantiate this, we investigated whether M-CSFR protein down-regulation in maturing DC in vitro could be prevented by inhibiting miR-22, -34a, and -155 using microRNA inhibitor oligonucleotides. [score:6]
To test whether miR-22, -34a, and -155 actually can regulate Csf1r expression through direct 3′UTR interactions, we cloned the complete 3′UTR of Csf1r into the psiCHECK-2 reporter vector downstream the coding sequence of Renilla luciferase. [score:5]
Co-transfection of miR-22 precursor inhibited Renilla luciferase expression even almost 75%. [score:5]
Csf1r, the gene encoding the growth factor receptor M-CSFR (c-Fms, M-CSFR, CD115), is identified as a predominant common target regulated by the induced miR-22, miR-34a, and miR-155. [score:4]
Figure 2 Csf1r is a verified target of miR-22, -34a, and -155. [score:3]
HEK293T cells, described by Stewart et al. (32), were plated in a 48-well plate at a density of 6 × 10 [4] cells per well and then co -transfected the next day with 10 ng psiCHECK-2 vector containing the full 3′UTR of Csf1r mRNA, together with miR-22, -34a, -155, and control over -expression oligonucleotides (Ambion) at 50 nM final concentration using Lullaby transfection reagent (Boca Scientific). [score:3]
Expression of (B) miR-22, -34a, and -155 and (C) Csf1r mRNA in different sorted DC populations that were used for microRNA profiling, assessed using qPCR. [score:3]
HEK293T cells were transiently transfected with the psiCHECK-2 reporter vector containing (D) the wild-type mouse Csf1r-3′UTR or (E) a mutant Csf1r-3′UTR harboring three nucleotide point mutations in each seed region of the corresponding miR-22, -34a, and miR-155 binding sites (Csf1r-3′UTR mut all), or in the miR-22 site only (Csf1r-3′UTR mut22). [score:2]
To verify whether the repressive effects were microRNA-specific, we repeated these experiments with Csf1r-3′UTR reporter constructs harboring point mutations in all three (miR-22, -34a, and -155) microRNA binding sites or in just one (miR-22) microRNA binding site. [score:2]
Mutation of the miR-22 binding site alone (but not the miR-34a and -155 binding sites) completely impaired miR-22 -mediated Csf1r-3′UTR repression, whereas the repressive effects of miR-34a and -155 remained unaffected, with similar levels of repression as in our initial experiments with the wild-type mouse Csf1r-3′UTR (Figure 2E). [score:2]
PicTar, EIMMo) confirmed the miR-22, -34a, and -155 binding sites in both human and mouse Csf1r-3′UTR (not shown). [score:1]
Mutant Csf1r-3′UTR constructs were generated by introducing three basepair mismatches into each seed region of the corresponding miR-22, -34a, and -155 binding sites (Csf1r-3′UTR mut all) or the miR-22 site alone (Csf1r-3′UTR 22mut) [outsourced to Genscript (Piscataway, USA)]. [score:1]
Cells were co -transfected with the hairpin precursors of miR-22, miR-34a, miR-155, or control oligonucleotide, all at a final concentration of 50 nM. [score:1]
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10
[+] score: 84
We engineered HUVEC to trigger PDE5 hyper -expression and we found that miR-22 was highly upregulated (P < 0.01), with downregulation after sildenafil treatment occurring in both transduced (P < 0.001) and non-transduced cells (P < 0.01), (Fig. 6D). [score:9]
In the present study, we confirmed the downregulation of miR-22 by sildenafil in diabetic kidney and upregulation of its target BMP7, associated with tissue protection. [score:9]
In light of the observed downregulation of miR-22 in adipose tissue after sildenafil treatment 31, we decided to verify whether miR-22 underwent a similar pattern of downregulation in kidney. [score:7]
Sildenafil upregulates BMP7 and downregulates miR-22 in diabetic kidney. [score:7]
In this study, we demonstrate that sildenafil increases BMP7 expression in diabetes and that such effect occurs alongside the downregulation of miR-22, a known regulator of BMP7. [score:7]
To this end, we examined miR-22 expression by qPCR, finding that it was downregulated by sildenafil ~3 fold (P < 0.001), (Fig. 6C). [score:6]
How to cite this article: Pofi, R. et al. Phosphodiesterase-5 inhibition preserves renal hemodynamics and function in mice with diabetic kidney disease by modulating miR-22 and BMP7. [score:5]
We recently demonstrated that sildenafil determined a downregulation of circulating miR-22 in diabetic patients and in adipose tissue of db/db mice 31. [score:4]
MiR-22 is known to directly target BMP7, and deletion of miR-22 significantly attenuated renal fibrosis 30. [score:4]
We then provided molecular insights into involvement of the miR-22 and its direct target BMP7 in modulating angiogenesis and vascular stability in the diabetic kidney. [score:4]
First, we cannot demonstrate how sildenafil modulates the elements regulating miR-22 gene expression. [score:4]
Importantly, we provide a confirmation of involvement of PDE5 signaling on miR-22 expression. [score:3]
This indicates both a strong association between PDE5 and miR-22 expression and the ability of sildenafil to induce a marked reduction in this damage marker. [score:3]
Cells were maintained for 24 hours in the presence of sildenafil (5 μM) or vehicle and analyzed for miR-22 expression. [score:3]
It was previously demonstrated that BMP7 is regulated by miR-22 30. [score:2]
We also extended our in vivo observations, investigating whether the PDE5 pathway was directly involved in miR-22 expression in endothelial cells (HUVEC). [score:2]
Our results demonstrate that metabolic, hemodynamic and epigenetic factors combine to preserve vessel structure and function in DN and uncover the novel role of PDE5i/miR-22 regulatory relationship, which helps to preserve BMP7 homeostasis in the kidney. [score:2]
MiR-22 is also involved in blood pressure regulation. [score:1]
In vivo administration of antagomir of miR-22 to spontaneously hypertensive rat reduced blood pressure and revealed a new avenue for treatment of hypertension 50. [score:1]
This supports the nephroprotective role of PDE5i through the miR-22/BMP7 axis. [score:1]
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[+] score: 39
Table 1 The role of miRNAs in autoimmune diseases miRNA Predicted/Identified targets Function Related diseases miR-22 IRF8Enhances CD11c [+]CD11b [+]B220 [−] cDC generation at the expense of pDCs miR-142 IRF8Plays a pivotal role in the maintenance of CD4 [+] DCs miR-142-3p IL-6 Specifically inhibits IL-6 expression by moDC MS miR-21 IL-12p35, Wnt1 Negatively regulates the production of IL-12 by moDC; negatively regulate the development of moDC SLE, IBD, UC, MS miR-10a IL-12/IL-23p40 Suppress the production of IL-12 and IL-23 by moDC SLE miR-148/152 Calcium/Calmodulin- dependent protein kinase IIa Suppress the production of IL-12 and IL-6 SLE miR-23b Notch1, NF-κB Inhibits the production of IL-12 while promotes IL-10 production UC miR-155 SOCS1, SHIP1, TAB2 Positively regulates the production of several pro-inflammatory cytokines including IL-6, IL-23, IL-12, and TNF-α RA, IBD miR-146a IRAK1, TRAF6 Negatively regulates TLR4-NF-κB pathway in monocytes RA, SLE, IBD miR-34a JAG1 Negatively regulates the development of moDC MS miR-223 C/EBPβNegatively regulates LCs -mediated antigen-specific CD8 [+] T cell proliferation, production of inflammatory cytokine TNFα, IL-1β, and IL-23 by intestinal DCs. [score:25]
Overexpression of miR-22 during DC development enhanced CD11c [+]CD11b [+]B220 [−] cDC generation at the expense of pDCs, while miR-22 knockdown demonstrated an opposite effect (Li et al., 2012). [score:5]
Overexpression and knockdown of miR-22 showed significant effects on the mRNA abundance of IRF8, a transcription factor essential for pDC and CD8α [+] cDC development. [score:5]
It has been found that miR-22 is highly expressed in mouse CD11c [+]CD11b [+]B220 [−] cDCs compared to pDCs, and is induced in DC progenitor cell cultures with GM-CSF, which stimulates CD11c [+]CD11b [+]B220 [−] cDCs differentiation. [score:2]
These studies demonstrated that miR-22 was important in regulating the differentiation of DC subsets (Li et al., 2012). [score:2]
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[+] score: 35
MicroRNA-22 (miR-22) overexpression is neuroprotective via general anti-apoptotic effects and may also target specific Huntington's disease-related mechanisms. [score:7]
miRNA Number of targets in miRNA-gene bigraph network P-value miR-20a 9 8.16E-09 miR-17 10 1.30E-07 miR-34a 9 2.78E-07 miR-155 14 2.16E-07 miR-18a 5 4.04E-06 miR-22 5 6.18E-06 miR-26a 6 9.29E-06 miR-101 5 3.30E-05 miR-106b 5 3.30E-05 miR-125b 8 8.37E-05 It is well known that AD is a complex disease and devastating neurodegenerative disorder without effective disease-modifying or preventive therapies. [score:7]
In addition, microRNAs, including miR-20a, miR-17, miR-34a, miR-155, miR-18a, miR-22, miR-26a, miR-101, miR-106b, and miR-125b might regulate the expression of genes (nodes) in the sub-network, thereby disrupting the fine-tuning of genetic networks in SAMP8 mice. [score:4]
The top 10 miRNAs with P ≤ 8.37 e [5] were listed in Table 3. They are miR-20a, miR-17, miR-34a, miR-155, miR-18a, miR-22, miR-26a, miR-101, miR-106b, and miR-125b, indicating that these ten miRNAs could regulate the expression of nodes (genes) in the sub-network of SAMP8 mice and might be one cause inducing SAMP8 mice to exhibit significant nodes (or genes) and to display a distinct genetic sub-network in the brain. [score:4]
Furthermore, the gene expression of CDKN2A and MCM3AP were changed, and miRNAs, including miR-34a, miR-155, miR-18a, miR-22, miR-26a, miR-101, miR-106b, and miR-125b are important in SAMP8 mice in the present study. [score:3]
miRNA Number of targets in miRNA-gene bigraph network P-value miR-20a 9 8.16E-09 miR-17 10 1.30E-07 miR-34a 9 2.78E-07 miR-155 14 2.16E-07 miR-18a 5 4.04E-06 miR-22 5 6.18E-06 miR-26a 6 9.29E-06 miR-101 5 3.30E-05 miR-106b 5 3.30E-05 miR-125b 8 8.37E-05 Differentially expressed mRNA in the hippocampus and cerebral cortex of SAMP8 and SAMR1 mice at 2, 6, and 12 months were investigated using cDNA microarray (Cheng et al., 2007b). [score:3]
Overexpression of miR-22 decreased neurodegeneration in an in vitro mo del (Jovicic et al., 2013). [score:3]
MiR-22 targets the pro-apoptotic activities of mitogen-activated protein kinase 14/p38 (MAPK14/p38) and tumor protein p53-inducible nuclear protein 1 (Tp53inp1). [score:2]
Based on the miRNA-gene bipartite graph network in the brain of SAMP8 mice, we identified the top 10 miRNAs with P ≥ 8.37E-05, including miR-20a, miR-17, miR-34a, miR-155, miR-18a, miR-22, miR-26a, miR-101, miR-106b, and miR-125b (Table 3). [score:1]
In these miRNAs, we first indicated that miR-34a, miR-155, miR-18a, miR-22, miR-26a, miR-101, miR-106b, and miR-125b were important in SAMP8 mice. [score:1]
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[+] score: 34
Expression profiling of the 6 shortlisted miRNAs revealed that most of the miRNAs were downregulated in oral tumors and miR-22-3p and miR-30b-5p were significantly downregulated in undifferentiated tumors. [score:9]
We further analyzed the expression of miRNAs with reference to cellular differentiation status and observed low-level expression of miRNAs in undifferentiated tumors, and only miR-22-5p and miR-30b-5p expression were statistically significant (P = 0.0485 and 0.0440, respectively). [score:7]
For experimental validation in oral tumors, we narrowed down that candidate miRNAs to six (miR-137, miR-148a-3p, miR-30a-5p, miR-30b-5p, miR-338-3p and miR-22-3p) by reviewing the functional evidence present in the literature, analyzing their expression in HNSCC datasets from TCGA and correlating with OIP5-AS1 expression (Supplementary Table  S2). [score:5]
Except for miR-22-3p and miR-30b-5p, other miRNAs are significantly downregulated in oral tumors. [score:4]
Six miRNAs miR-137, miR-148a-3p, miR-338-3p, miR-30a/b-5p and miR-22-3p known to be associated with several cancers were chosen to study the expression levels in oral tumors 20, 25, 26. [score:3]
miR-30a-5p, miR-30b-5p, miR-338-3p and miR-22-3p shared maximum common downstream targets. [score:3]
Further, in undifferentiated tumors, OIP5-AS1 alone or together with other lncRNAs might sponge miR-22-3p and miR-30b-5p to a greater extent resulting in the derepression of the downstream target genes. [score:3]
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[+] score: 31
Description miR-451[39] Upregulated in heart due to ischemia miR-22[40] Elevated serum levels in patients with stablechronic systolic heart failure miR-133[41] Downregulated in transverse aortic constrictionand isoproterenol -induced hypertrophy miR-709[42] Upregulated in rat heart four weeks after chronicdoxorubicin treatment miR-126[43] Association with outcome of ischemic andnonischemic cardiomyopathy in patients withchronic heart failure miR-30[44] Inversely related to CTGF in two rodent mo delsof heart disease, and human pathological leftventricular hypertrophy miR-29[45] Downregulated in the heart region adjacent toan infarct miR-143[46] Molecular key to switching of the vascular smoothmuscle cell phenotype that plays a critical role incardiovascular disease pathogenesis miR-24[47] Regulates cardiac fibrosis after myocardial infarction miR-23[48] Upregulated during cardiac hypertrophy miR-378[49] Cardiac hypertrophy control miR-125[50] Important regulator of hESC differentiation to cardiacmuscle(potential therapeutic application) miR-675[51] Elevated in plasma of heart failure patients let-7[52] Aberrant expression of let-7 members incardiovascular disease miR-16[53] Circulating prognostic biomarker in critical limbischemia miR-26[54] Downregulated in a rat cardiac hypertrophy mo del miR-669[55] Prevents skeletal muscle differentiation in postnatalcardiac progenitors To further confirm biological suitability of the identified miRNAs, we examined KEGG pathway enrichment using miRNA target genes (see ). [score:31]
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[+] score: 28
[29] ST2 stromal cells unknownInduced double-strand DNA breaks and reactive oxygen speciesaccumulation in transfected cells [30] miR-22-3p SIRT1 CDK6 SP1Induced growth suppression and acquisition of a senescentphenotype in human normal and cancer cells [31] human HDAC6Promoted osteogenic differentiation and inhibits adipogenic differentiationof human adipose tissue-derived mesenchymal stem cells [32] human miR-31-5p RhoBTB1Repression of miR-31 inhibited colon cancer cell proliferation andcolony formation in soft agarose [33] HT29 cells unknownIs associated with marked change in the expression of specificmiRNA during aging in skeletal muscle [34] mouse miR-378-5p NephronectinGalNT-7Inhibited osteoblast differentiation [35] MC3T3-E1 miR-382-5p unknownDownregulated in skeletal muscle of old mice [34] mouse In order to validate the sequencing data, we selected several miRNAs from Table 2 for additional qRT-PCR validation, which the minimum normalized read count of miRNAs was 5 in young, adult and old groups, including miR-210 [29], miR-22 [31], [32], miR-31 [36], [37], and miR-10b [16](Figure 3). [score:14]
[29] ST2 stromal cells unknownInduced double-strand DNA breaks and reactive oxygen speciesaccumulation in transfected cells [30] miR-22-3p SIRT1 CDK6 SP1Induced growth suppression and acquisition of a senescentphenotype in human normal and cancer cells [31] human HDAC6Promoted osteogenic differentiation and inhibits adipogenic differentiationof human adipose tissue-derived mesenchymal stem cells [32] human miR-31-5p RhoBTB1Repression of miR-31 inhibited colon cancer cell proliferation andcolony formation in soft agarose [33] HT29 cells unknownIs associated with marked change in the expression of specificmiRNA during aging in skeletal muscle [34] mouse miR-378-5p NephronectinGalNT-7Inhibited osteoblast differentiation [35] MC3T3-E1 miR-382-5p unknownDownregulated in skeletal muscle of old mice [34] mouseIn order to validate the sequencing data, we selected several miRNAs from Table 2 for additional qRT-PCR validation, which the minimum normalized read count of miRNAs was 5 in young, adult and old groups, including miR-210 [29], miR-22 [31], [32], miR-31 [36], [37], and miR-10b [16](Figure 3). [score:14]
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16
[+] score: 26
Other miRNAs from this paper: hsa-let-7a-1, hsa-let-7a-2, hsa-let-7a-3, hsa-let-7b, hsa-let-7c, hsa-let-7d, hsa-let-7e, hsa-let-7f-1, hsa-let-7f-2, hsa-mir-17, hsa-mir-18a, hsa-mir-20a, hsa-mir-21, hsa-mir-22, hsa-mir-26a-1, hsa-mir-99a, hsa-mir-103a-2, hsa-mir-103a-1, hsa-mir-106a, hsa-mir-107, mmu-let-7g, mmu-let-7i, mmu-mir-99a, mmu-mir-101a, mmu-mir-125a, mmu-mir-125b-2, mmu-mir-126a, mmu-mir-127, mmu-mir-145a, mmu-mir-146a, mmu-mir-129-1, mmu-mir-206, hsa-mir-129-1, hsa-mir-148a, mmu-mir-122, mmu-mir-143, hsa-mir-139, hsa-mir-221, hsa-mir-222, hsa-mir-223, mmu-let-7d, mmu-mir-106a, hsa-let-7g, hsa-let-7i, hsa-mir-122, hsa-mir-125b-1, hsa-mir-143, hsa-mir-145, hsa-mir-125a, hsa-mir-125b-2, hsa-mir-126, hsa-mir-127, hsa-mir-129-2, hsa-mir-146a, hsa-mir-206, mmu-mir-148a, mmu-let-7a-1, mmu-let-7a-2, mmu-let-7b, mmu-let-7c-1, mmu-let-7c-2, mmu-let-7e, mmu-let-7f-1, mmu-let-7f-2, mmu-mir-18a, mmu-mir-20a, mmu-mir-21a, mmu-mir-26a-1, mmu-mir-129-2, mmu-mir-103-1, mmu-mir-103-2, rno-let-7d, rno-mir-335, rno-mir-129-2, rno-mir-20a, mmu-mir-107, mmu-mir-17, mmu-mir-139, mmu-mir-223, mmu-mir-26a-2, mmu-mir-221, mmu-mir-222, mmu-mir-125b-1, hsa-mir-26a-2, hsa-mir-335, mmu-mir-335, rno-let-7a-1, rno-let-7a-2, rno-let-7b, rno-let-7c-1, rno-let-7c-2, rno-let-7e, rno-let-7f-1, rno-let-7f-2, rno-let-7i, rno-mir-17-1, rno-mir-18a, rno-mir-21, rno-mir-22, rno-mir-26a, rno-mir-99a, rno-mir-101a, rno-mir-103-2, rno-mir-103-1, rno-mir-107, rno-mir-122, rno-mir-125a, rno-mir-125b-1, rno-mir-125b-2, rno-mir-126a, rno-mir-127, rno-mir-129-1, rno-mir-139, rno-mir-143, rno-mir-145, rno-mir-146a, rno-mir-206, rno-mir-221, rno-mir-222, rno-mir-223, hsa-mir-196b, mmu-mir-196b, rno-mir-196b-1, hsa-mir-20b, hsa-mir-451a, mmu-mir-451a, rno-mir-451, hsa-mir-486-1, hsa-mir-499a, mmu-mir-486a, mmu-mir-20b, rno-mir-20b, rno-mir-499, mmu-mir-499, mmu-mir-708, hsa-mir-708, rno-mir-17-2, rno-mir-708, hsa-mir-103b-1, hsa-mir-103b-2, mmu-mir-486b, rno-mir-126b, hsa-mir-451b, hsa-mir-499b, mmu-mir-145b, mmu-mir-21b, mmu-let-7j, mmu-mir-130c, mmu-mir-21c, mmu-mir-451b, mmu-let-7k, hsa-mir-486-2, mmu-mir-129b, mmu-mir-126b, rno-let-7g, rno-mir-148a, rno-mir-196b-2, rno-mir-486
After 6 and 12 wks of E [2] exposure, 15 miRNAs were down-regulated, e. g., miR-22, miR-99a, miR-106a, miR-127, miR-499, and 19 miRNAs were-up-regulated, e. g., miR-17-5p, miR-20a, miR-21, miR-129-3p, miR-106a, miR-22, and miR-127. [score:7]
miR-22 regulates ERα protein expression in a pancreatic cancer cell line [213]. [score:4]
Conversely, knockdown of miR-221 and miR-22 in ERα -negative MDA-MB-468 partially restored ERα protein expression and increased tamoxifen -induced apoptosis [212]. [score:4]
One of the predicted 3’UTR gene targets of miR-22 was ESR1 (ERα) [213]. [score:3]
In a study to identify curcumin gene targets, curcumin increased miR-22 by 65% in BxPC-3 human pancreatic carcinoma cells [213]. [score:3]
Follow-up studies showed that curcumin reduced ERα protein expression in BxPC-3 cells and that transfection of an antisense RNA oligonucleotide of miRNA-22 into BxPC-3 cells increased ERα protein by ~ 1.9-fold. [score:3]
Thus, miR-22 regulates ERα protein levels and the authors suggest a role for ERα as anti-tumorigenic in pancreatic cancer. [score:2]
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[+] score: 25
Of these differentially expressed miRNAs, miR-27b (downregulated in OA) directly targets MMP-13 expression (Stone et al., 2011); miR-22 (upregulated in OA) directly regulates PPARA and BMP-7 expression in cartilage; miR-9 inhibits MMP13 secretion in isolated human chondrocytes; and miR-146a is highly expressed in early OA cartilage and has been shown to control knee joint homeostasis and OA -associated algesia by balancing inflammatory responses in the cartilage and synovium. [score:22]
They suggested miR-22 and miR-125 as possible master regulators, and miR-344-5p/484 and miR-488 as possible master coregulators that may influence the genes involved in one-carbon metabolism. [score:3]
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[+] score: 21
Other miRNAs from this paper: mmu-mir-150, mmu-mir-196b, mmu-mir-495
Moreover, we reported previously that TET1 can recruit polycomb proteins to the promoter region of the mir-22 gene and suppress the primary transcription of this critical tumor-suppressor microRNA, and such transcriptional suppression is independent from TET1’s enzymatic activity [46]. [score:7]
and repressing expression of tumor-suppressor targets (e. g., miR-22) 18, 19, 46. [score:7]
, and the upregulation of negative targets, e. g., miR-22 [46], in MONOMAC-6 cells (Fig.   5a, b). [score:6]
Jiang X miR-22 has a potent anti-tumour role with therapeutic potential in acute myeloid leukaemiaNat. [score:1]
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19
[+] score: 19
For example, miR-208, miR-9, let-7a, 7b, and miR-22* were found to be up-regulated in transformed IEC-6 cells, whereas miR-539, miR-181d, and miR-146a were down-regulated. [score:7]
Increased miR-22 was found in erythropoiesis, and it was predicted to target genes involved in cell development and differentiation [34]. [score:4]
Among these differentially expressed miRNAs, we verified the alteration of miR-208 and miR-22*. [score:3]
So the expression of miR208 and miR22* was chosen to be validated. [score:3]
miR-22* and miR-22 are the alternative mature type of their primary precursors. [score:1]
Our result showed miR-22* was increased, but not miR-22. [score:1]
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20
[+] score: 18
DEGs expression heat map was shown in Figure  4. Table 1 One hundred and thirty‐one differentially expressed genes (DEGs) were identified between IR + NS and IR + Zymosan‐A groups Up‐regulated gene Down‐regulated gene Stfa2 Ecm1 Egr1 Herpud1 Ccrl2 Zc3h12a Ier3 Irak2 Hbb‐b1 Stfa3 Mir5109 Atf3 Gramd1a Xcl1 Socs3 Lfng H2‐K1 Beta‐s BC100530 F630028O10Rik Ptafr Lpl Bpgm Ier5 Cyth1 Cxcl2 Slc4a1 BC117090 Gstm1 Bcl3 Ptgs2 H2‐Q4 Tnf Niacr1 Tnfsf13b Mir21 2010005H15Rik Ear1 Rasal3 Phf1 H2‐Q5 Erdr1 Txnip Mir22 Hba‐a2 Stfa1 Mt1 Smox Skil Rasl11b Nfkbia H2‐Ab1 H2‐Eb1 Hba‐a1 Gm5483 Rn45s Amica1 Cd74 Fmnl2 Mir24‐2 H2‐T22 Zfp36 Hbb‐b2 Stfa2 l1 Ear12 Neurl3 Nfkbid Cables1 Relb Nfkbiz Nfkb2 Hbb‐bt Saa3 Ear3 Ier2 Hmox1 Mir1901 Tnfaip3 H2‐T9 Ppp1r15a Mirlet7i Mt2 Ear7 5430421N21Rik Klf2 Tmcc2 Fn1 Junb Smim5 Gpnmb Marco Ear6 Bbc3 Jund H2‐Q6 H2‐Q10 Phlda1 Gabbr1 Mir146b Ggt1 Acvrl1 Irg1 H2‐Aa H2‐Q8 Thbs1 Gm15441 Mir1198 Prok2 Ceacam10 Rnf167 Tgif1 H2‐Q9 Nfkbie Jun Dusp2 Lars2 Ctsg Pik3ap1 Tgm2 H2‐Q7 Gadd45b Zmpste24 Antxr2 Steap4 Ear2 Sh2b2 Sertad1 Alas2 Ptger4 Basp1 Ninj1 John Wiley & Sons, Ltd Figure 4 Identification of differentially expressed genes (DEGs) between IR + NS and IR + Zymosan‐A groups. [score:9]
DEGs expression heat map was shown in Figure  4. Table 1 One hundred and thirty‐one differentially expressed genes (DEGs) were identified between IR + NS and IR + Zymosan‐A groups Up‐regulated gene Down‐regulated gene Stfa2 Ecm1 Egr1 Herpud1 Ccrl2 Zc3h12a Ier3 Irak2 Hbb‐b1 Stfa3 Mir5109 Atf3 Gramd1a Xcl1 Socs3 Lfng H2‐K1 Beta‐s BC100530 F630028O10Rik Ptafr Lpl Bpgm Ier5 Cyth1 Cxcl2 Slc4a1 BC117090 Gstm1 Bcl3 Ptgs2 H2‐Q4 Tnf Niacr1 Tnfsf13b Mir21 2010005H15Rik Ear1 Rasal3 Phf1 H2‐Q5 Erdr1 Txnip Mir22 Hba‐a2 Stfa1 Mt1 Smox Skil Rasl11b Nfkbia H2‐Ab1 H2‐Eb1 Hba‐a1 Gm5483 Rn45s Amica1 Cd74 Fmnl2 Mir24‐2 H2‐T22 Zfp36 Hbb‐b2 Stfa2 l1 Ear12 Neurl3 Nfkbid Cables1 Relb Nfkbiz Nfkb2 Hbb‐bt Saa3 Ear3 Ier2 Hmox1 Mir1901 Tnfaip3 H2‐T9 Ppp1r15a Mirlet7i Mt2 Ear7 5430421N21Rik Klf2 Tmcc2 Fn1 Junb Smim5 Gpnmb Marco Ear6 Bbc3 Jund H2‐Q6 H2‐Q10 Phlda1 Gabbr1 Mir146b Ggt1 Acvrl1 Irg1 H2‐Aa H2‐Q8 Thbs1 Gm15441 Mir1198 Prok2 Ceacam10 Rnf167 Tgif1 H2‐Q9 Nfkbie Jun Dusp2 Lars2 Ctsg Pik3ap1 Tgm2 H2‐Q7 Gadd45b Zmpste24 Antxr2 Steap4 Ear2 Sh2b2 Sertad1 Alas2 Ptger4 Basp1 Ninj1 John Wiley & Sons, Ltd Figure 4 Identification of differentially expressed genes (DEGs) between IR + NS and IR + Zymosan‐A groups. [score:9]
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21
[+] score: 17
MicroRNA-22 targets and regulates HDAC4, REST corepressor1, and G-protein signaling 2 (Rgs2) and reduces caspase activation related to its other targets of proapoptotic MAPK14/p38 and Tp53inp1, and its overexpression inhibited neurodegeneration in primary striatal and cortical cultures exposed to the mutant Htt171-82Q fragment [97]. [score:9]
Based on these findings, upregulation of miR-9, miR-9*, miR-22, miR-34b, miR-125b, miR-137, miR-146a, miR148a, miR-150, miR-196a, and miR-214 may have therapeutic potential against mutant HTT, REST, HDAC4, apoptosis, and other pathobiological factors in HD. [score:4]
These functional data support some (miR-22, miR-125b, miR-146a, miR-150) and contradict other (miR-34b, miR-148a, and miR-214) Table 2 miRNA targets. [score:3]
The effects of psychotropics on the other miRNAs listed in Table 2, particularly miR-9, miR-9*, miR-22, miR-34b, miR-125b, miR-137, miR-146a, miR148a, miR-150, miR-196a, and miR-214, as well as on REST, deserve study in HD mo dels. [score:1]
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22
[+] score: 16
Interestingly, the predicted targets of miR-22* are significantly enriched for genes functioning in cardiovascular development, function and disease. [score:6]
This is similar to mature miR-22, although their predicted targets are different, suggesting both miRNAs regulate similar processes through different targets. [score:6]
Notable examples of highly expressed miRNAs with unexpected strand bias in HL-1 cells and also in the heart, but having very different strand bias in other tissues [22] are the abundant miR-22*, -322*, -872*, and let-7d*, as well as a marked-5p bias for miR-151-5p. [score:3]
One important example already mentioned above is miR-22, which is involved in the cardiac hypertrophic response [34] and has an abundant miR* in HL-1 cells and the heart (58% and 40% of tags from hairpin respectively, Figure 2C). [score:1]
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[+] score: 15
In their study, miR-22 overexpression can also increase the expression of the anti-apoptosis gene Bcl-2 and decrease the pro-apoptosis gene Bax, which attributed to a reduction in apoptosis. [score:5]
In addition, they also found that miR-22 overexpression resulted in a reduction in inflammatory cytokines, such as TNF-α, IL-6, COX-2, and iNOS [22]. [score:3]
Yu H. Wu M. Zhao P. Huang Y. Wang W. Yin W. Neuroprotective effects of viral overexpression of microRNA-22 in rat and cell mo dels of cerebral ischemia-reperfusion injury J. Cell. [score:3]
Researchers also found that caspase-3 activity was inhibited by miR-22 in cerebral ischemic/reperfusion injury [22]. [score:3]
As the inflammatory cascade reaction is the main cause of aggravation of cerebral injury, the anti-inflammatory effect might also be one of the mechanisms underlying miR-22 mediated neuroprotection. [score:1]
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24
[+] score: 15
On one hand, when the original miRNA expression dataset was combined with other mRNA expression datasets miR-22 was radically repositioned relative to its targets and their expression profiles. [score:9]
Moving forward, miR-22 was shown to be involved in age-related cardiac fibrosis, whose overexpression contributed to cellular senescence and migration of cardiac fibroblasts [26]. [score:3]
On the contrary, we suggest that miR-22 has not substantial impact on heart longevity as proposed recently. [score:1]
Huang ZP Chen J Seok HY Zhang Z Kataoka M Hu X MicroRNA-22 regulates cardiac hypertrophy and remo deling in response to stressCirc Res. [score:1]
Further, miR-22 was suggested as cardiac aging biomarker by the work of Jazbutyte et al. [26]. [score:1]
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25
[+] score: 15
For example, miR-29b specifically targets HDAC4 to epigenetically regulate multiple myeloma cell growth and survival [1], miR-22 targets and inhibits HDAC4 in antigen-presenting cells and plays a critical role in emphysema and TH17 responses [7], miR-125a-5p targets HDAC4 to suppress breast tumorigenesis [3], and miR-140 and miR-365 target HDAC4 and participate in cartilage and bone development [20, 21]. [score:15]
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26
[+] score: 13
Interestingly, p53 has been shown to suppress the expression of miR-125b and miR-22 [56], indicating that it could repress its negative regulators to increase its expression. [score:8]
Besides, miR-150 and miR-22 are predicted to inhibit the expression of p53 [Table 3]. [score:5]
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27
[+] score: 13
We found that 3 miRNAs (mmu-miR-125a-5p, mmu-miR-146a, and mmu-miR-141) were downregulated and another three (mmu-miR-188-5p, mmu-miR-223 and mmu-miR-22) were upregulated in UVB irradiated mice compared with untreated mice. [score:6]
In the present study, it is clear that mmu-miR-188-5p, mmu-miR-223 and mmu-miR-22 were upregulated after UVB irradiation. [score:4]
Six miRNAs (mmu-miR-188-5p, mmu-miR-223, mmu-miR-22, mmu-miR-125a-5p, mmu-miR-146a and mmu-miR-141) were found to be differentially expressed in the control group compared with the UVB treatment group (P < 0.05, Table S1). [score:2]
However, little is known about the function of miR-188-5p and miR-22. [score:1]
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[+] score: 13
Members of the miR-99 family (miR99a, and miR100, the fourth and seventh most abundant mouse sRNAs) are miRNAs that have been shown to co-enrich with polyribosomes in mammalian neurons, and regulate the mammalian target of rapamycin (mTOR) pathway 46. miR22, the eighth most abundant mouse sRNA, is important for cerebellar development, and in adults has been shown to protect neurons from neurodegeneration, and is down regulated in both Huntington’s and Alzheimer’s disease 47. miR127, along with a cluster of miRNAs found on chromosome14q32, is maternally expressed, and the down regulation of miRNAs within this cluster (including miR127) has been linked to schizophrenia 48. [score:11]
The most abundant sequences of sRNAs isolated and sequenced were over 30 nt; however, we did isolate and sequence miRNAs in the 20–21 nt range, including miR128, miR99a, miR100, miR22, and miR127. [score:1]
The third, fourth, seventh, eighth and ninth mapped to neuronal associated microRNAs, including miR128, miR99, miR100, miR22, and miR127 (21–22 nt). [score:1]
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29
[+] score: 12
Other miRNAs from this paper: hsa-let-7a-1, hsa-let-7a-2, hsa-let-7a-3, hsa-let-7b, hsa-let-7c, hsa-let-7d, hsa-let-7e, hsa-let-7f-1, hsa-let-7f-2, hsa-mir-15a, hsa-mir-16-1, hsa-mir-17, hsa-mir-18a, hsa-mir-19a, hsa-mir-19b-1, hsa-mir-20a, hsa-mir-22, hsa-mir-26a-1, hsa-mir-26b, hsa-mir-98, hsa-mir-101-1, hsa-mir-16-2, mmu-let-7g, mmu-let-7i, mmu-mir-1a-1, mmu-mir-15b, mmu-mir-101a, mmu-mir-126a, mmu-mir-130a, mmu-mir-133a-1, mmu-mir-142a, mmu-mir-181a-2, mmu-mir-194-1, hsa-mir-208a, hsa-mir-30c-2, mmu-mir-122, mmu-mir-143, hsa-mir-181a-2, hsa-mir-181b-1, hsa-mir-181c, hsa-mir-181a-1, mmu-let-7d, hsa-let-7g, hsa-let-7i, hsa-mir-1-2, hsa-mir-15b, hsa-mir-122, hsa-mir-130a, hsa-mir-133a-1, hsa-mir-133a-2, hsa-mir-142, hsa-mir-143, hsa-mir-126, hsa-mir-194-1, mmu-mir-30c-1, mmu-mir-30c-2, mmu-mir-208a, mmu-let-7a-1, mmu-let-7a-2, mmu-let-7b, mmu-let-7c-1, mmu-let-7c-2, mmu-let-7e, mmu-let-7f-1, mmu-let-7f-2, mmu-mir-15a, mmu-mir-16-1, mmu-mir-16-2, mmu-mir-18a, mmu-mir-20a, mmu-mir-26a-1, mmu-mir-26b, mmu-mir-29c, mmu-mir-98, mmu-mir-326, rno-mir-326, rno-let-7d, rno-mir-20a, rno-mir-101b, mmu-mir-101b, hsa-mir-1-1, mmu-mir-1a-2, hsa-mir-181b-2, mmu-mir-17, mmu-mir-19a, mmu-mir-181a-1, mmu-mir-26a-2, mmu-mir-19b-1, mmu-mir-181b-1, mmu-mir-181c, hsa-mir-194-2, mmu-mir-194-2, hsa-mir-29c, hsa-mir-30c-1, hsa-mir-101-2, hsa-mir-26a-2, hsa-mir-378a, mmu-mir-378a, hsa-mir-326, mmu-mir-133a-2, mmu-mir-133b, hsa-mir-133b, mmu-mir-181b-2, rno-let-7a-1, rno-let-7a-2, rno-let-7b, rno-let-7c-1, rno-let-7c-2, rno-let-7e, rno-let-7f-1, rno-let-7f-2, rno-let-7i, rno-mir-15b, rno-mir-16, rno-mir-17-1, rno-mir-18a, rno-mir-19b-1, rno-mir-19a, rno-mir-22, rno-mir-26a, rno-mir-26b, rno-mir-29c-1, rno-mir-30c-1, rno-mir-30c-2, rno-mir-98, rno-mir-101a, rno-mir-122, rno-mir-126a, rno-mir-130a, rno-mir-133a, rno-mir-142, rno-mir-143, rno-mir-181c, rno-mir-181a-2, rno-mir-181b-1, rno-mir-181b-2, rno-mir-194-1, rno-mir-194-2, rno-mir-208a, rno-mir-181a-1, hsa-mir-423, hsa-mir-18b, hsa-mir-20b, hsa-mir-451a, mmu-mir-451a, rno-mir-451, ssc-mir-122, ssc-mir-15b, ssc-mir-181b-2, ssc-mir-19a, ssc-mir-20a, ssc-mir-26a, ssc-mir-326, ssc-mir-181c, ssc-let-7c, ssc-let-7f-1, ssc-let-7i, ssc-mir-18a, ssc-mir-29c, ssc-mir-30c-2, hsa-mir-484, hsa-mir-181d, hsa-mir-499a, rno-mir-1, rno-mir-133b, mmu-mir-484, mmu-mir-20b, rno-mir-20b, rno-mir-378a, rno-mir-499, hsa-mir-378d-2, mmu-mir-423, mmu-mir-499, mmu-mir-181d, mmu-mir-18b, mmu-mir-208b, hsa-mir-208b, rno-mir-17-2, rno-mir-181d, rno-mir-423, rno-mir-484, mmu-mir-1b, ssc-mir-15a, ssc-mir-16-2, ssc-mir-16-1, ssc-mir-17, ssc-mir-130a, ssc-mir-101-1, ssc-mir-101-2, ssc-mir-133a-1, ssc-mir-1, ssc-mir-181a-1, ssc-let-7a-1, ssc-let-7e, ssc-let-7g, ssc-mir-378-1, ssc-mir-133b, ssc-mir-499, ssc-mir-143, ssc-mir-423, ssc-mir-181a-2, ssc-mir-181b-1, ssc-mir-181d, ssc-mir-98, ssc-mir-208b, ssc-mir-142, ssc-mir-19b-1, hsa-mir-378b, ssc-mir-22, rno-mir-126b, rno-mir-208b, rno-mir-133c, hsa-mir-378c, ssc-mir-194b, ssc-mir-133a-2, ssc-mir-484, ssc-mir-30c-1, ssc-mir-126, ssc-mir-378-2, ssc-mir-451, hsa-mir-378d-1, hsa-mir-378e, hsa-mir-378f, hsa-mir-378g, hsa-mir-378h, hsa-mir-378i, mmu-mir-378b, mmu-mir-101c, hsa-mir-451b, hsa-mir-499b, ssc-let-7a-2, ssc-mir-18b, hsa-mir-378j, rno-mir-378b, mmu-mir-133c, mmu-let-7j, mmu-mir-378c, mmu-mir-378d, mmu-mir-451b, ssc-let-7d, ssc-let-7f-2, ssc-mir-20b-1, ssc-mir-20b-2, ssc-mir-194a, mmu-let-7k, mmu-mir-126b, mmu-mir-142b, rno-let-7g, rno-mir-15a, ssc-mir-378b, rno-mir-29c-2, rno-mir-1b, ssc-mir-26b
miR-22, miR-26b, miR-29c, miR-30c and miR-126 exhibited almost similar expression patterns in all tissues examined (Figure 3B). [score:3]
Additionally, many other miRNAs, such as let-7, miR-98, miR-16, miR22, miR-26b, miR-29c, miR-30c and miR126, were also expressed abundantly in thymus (Figure 3). [score:3]
miR-22, miR-26b, miR-29c and miR-30c showed ubiquitous expression in diverse tissues. [score:3]
The observation that miR-22, miR-26b, miR-126, miR-29c and miR-30c are ubiquitously expressed in 14 different tissues of pig is interesting. [score:3]
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[+] score: 11
For example, miR-22 that was upregulated in the Sgcg -null mouse in the Exiqon screen (FC = 3.48, p≤0.05, table 2), was also significantly upregulated in the same screen in the Sgca -null and the mdx mouse mo dels. [score:7]
However in these two latter mo dels miR-22 was not upregulated in the AB screening and therefore was not a double positive candidate and absent from table 2 for the Sgca -null and the mdx mo dels. [score:4]
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[+] score: 10
Of the seven upregulated miRNAs, three (miR-680, miR-320 and miR-22) were confirmed to be upregulated by qRT-PCR analysis (Supplemental Figure 2A). [score:7]
MiR-22, miR-519, miR-152 and miR-181a, among others, were recently identified as inducers of cellular senescence [16- 18]. [score:1]
We analyzed the levels of 13 miRNAs confirmed to be dysregulated in P7 Ercc1 [−/−] MEFs compared to P3 Ercc1 [−/−] MEFs (miR-680, miR-320, miR-22, miR-449a, miR-455*, miR-675-3p, miR-128, miR-497, miR-543, miR-450b-3p, miR-872, miR-369-5p and miR-10b) in RNA samples prepared from the livers of WT young (20 weeks), the progeroid Ercc1 [−/Δ] mice, and WT old mice (30 months). [score:1]
Three miRNAs (miR-680, miR-320, and miR-22) which were upregulated in P7 compared to P3 Ercc1 [−/−] MEFs (Table 4) as measured by microarray did not show upregulation in livers from progeroid and WT old mice compared to young WT controls as measured by qRT-PCR (data not shown). [score:1]
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[+] score: 10
Interestingly, a group of miRNAs, including miR-221/222, miR-206, miR-18a, and miR-22, have been reported to be involved in the regulation of ERα at either the transcriptional or post-transcriptional level [10, 11], thereby presenting attractive targets for therapeutic intervention in ERα -negative breast cancer. [score:4]
miR-22 has previously been shown to be over-expressed in progenitor cells [45]. [score:3]
miR-22 was found to be primarily expressed in MMTV- Wnt1 tumors. [score:3]
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[+] score: 10
Besides, Gomafu could upregulate DAPK2 expression by sponging miR-22−3p, which consequently led to cardiomyocyte apoptosis in a rat mo del of diabetic cardiomyopathy [15]. [score:6]
Zhou X lncRNA MIAT functions as a competing endogenous RNA to upregulate DAPK2 by sponging miR-22-3p in diabetic cardiomyopathyCell Death Dis. [score:4]
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[+] score: 10
Hepatic expression of tumor suppressive miRNAs, miR-26a, miR-26a-1, miR-192, miR-122, miR-22 and miR-125b, and tumor promoting miRNAs, miR-10b and miR-99b in NASH-HCC mo del male and female mice. [score:5]
As shown in Fig. 4, the tumor suppressive miRNAs, miR-26a, miR-26a-1, miR-192, miR-122, miR-22, and miR-125b were lower, whereas the tumor-promoting miRNAs, miR-10b and miR-99b were higher in males than in females in both the STZ-HFD group and the control group. [score:3]
We also observed that tumor-suppressive miRNAs, miR-26a, miR-26a-1, miR-192, miR-122, miR-22, and miR-125b were significantly decreased in STZ-HFD mice compared to controls with significantly lower levels in males than in females. [score:2]
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[+] score: 10
In cerebellar development, VEGF is co-expressed with late-expressed miR-125, whereas E-cadherin and P21 are either not significantly changed or are co-expressed with late miR-9 and miR-22, respectively, in another series (personal communication with J. M. Lee). [score:8]
For synaptic transmission, miR-128, miR-27b, miR-133, miR-206, miR-152 and miR-9 are shared between development and tumor using picTar prediction; miR-128, miR-140, miR-27b, miR-22, miR-133, miR-223 and miR-152 are shared using PITA prediction. [score:2]
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[+] score: 10
Other miRNAs from this paper: hsa-let-7a-1, hsa-let-7a-2, hsa-let-7a-3, hsa-let-7b, hsa-let-7c, hsa-let-7d, hsa-let-7e, hsa-let-7f-1, hsa-let-7f-2, hsa-mir-21, hsa-mir-22, hsa-mir-25, hsa-mir-33a, hsa-mir-96, mmu-let-7g, mmu-let-7i, mmu-mir-1a-1, mmu-mir-125a, mmu-mir-125b-2, mmu-mir-9-2, mmu-mir-133a-1, mmu-mir-141, mmu-mir-155, mmu-mir-10b, mmu-mir-129-1, mmu-mir-181a-2, mmu-mir-183, mmu-mir-184, hsa-mir-192, mmu-mir-200b, hsa-mir-129-1, mmu-mir-122, hsa-mir-7-1, hsa-mir-7-2, hsa-mir-7-3, hsa-mir-10a, hsa-mir-10b, hsa-mir-34a, hsa-mir-181a-2, hsa-mir-183, hsa-mir-210, hsa-mir-181a-1, hsa-mir-216a, hsa-mir-217, hsa-mir-223, hsa-mir-200b, mmu-mir-34c, mmu-mir-34b, mmu-let-7d, hsa-let-7g, hsa-let-7i, hsa-mir-1-2, hsa-mir-122, hsa-mir-125b-1, hsa-mir-133a-1, hsa-mir-133a-2, hsa-mir-141, hsa-mir-9-1, hsa-mir-9-2, hsa-mir-9-3, hsa-mir-125a, hsa-mir-125b-2, hsa-mir-129-2, hsa-mir-184, mmu-mir-192, mmu-mir-200a, mmu-let-7a-1, mmu-let-7a-2, mmu-let-7b, mmu-let-7c-1, mmu-let-7c-2, mmu-let-7e, mmu-let-7f-1, mmu-let-7f-2, mmu-mir-21a, mmu-mir-96, mmu-mir-34a, mmu-mir-129-2, hsa-mir-1-1, mmu-mir-1a-2, hsa-mir-155, mmu-mir-10a, mmu-mir-25, mmu-mir-210, mmu-mir-181a-1, mmu-mir-216a, mmu-mir-223, mmu-mir-33, mmu-mir-9-1, mmu-mir-9-3, mmu-mir-125b-1, mmu-mir-7a-1, mmu-mir-7a-2, mmu-mir-7b, mmu-mir-217, hsa-mir-200a, hsa-mir-34b, hsa-mir-34c, hsa-mir-375, mmu-mir-375, mmu-mir-133a-2, mmu-mir-133b, hsa-mir-133b, hsa-mir-33b, mmu-mir-216b, hsa-mir-216b, mmu-mir-1b, mmu-mir-133c, mmu-mir-21b, mmu-let-7j, mmu-mir-21c, mmu-let-7k, mmu-mir-129b, mmu-mir-216c, bbe-let-7a-1, bbe-let-7a-2, bbe-mir-10a, bbe-mir-10b, bbe-mir-10c, bbe-mir-125a, bbe-mir-125b, bbe-mir-129a, bbe-mir-129b, bbe-mir-133, bbe-mir-1, bbe-mir-183, bbe-mir-184, bbe-mir-200a, bbe-mir-200b, bbe-mir-210, bbe-mir-216, bbe-mir-217, bbe-mir-22, bbe-mir-252a, bbe-mir-252b, bbe-mir-278, bbe-mir-281, bbe-mir-33-1, bbe-mir-33-2, bbe-mir-34a, bbe-mir-34b, bbe-mir-34c, bbe-mir-34d, bbe-mir-34f, bbe-mir-375, bbe-mir-7, bbe-mir-71, bbe-mir-9, bbe-mir-96, bbe-mir-34g, bbe-mir-34h, mmu-mir-9b-2, mmu-mir-9b-1, mmu-mir-9b-3
The sequencing frequency of the four most abundantly expressed miRNAs (miR-22, miR-1, let-7a and miR-25) constituted 78.82% of the total miRNA sequencing reads, suggesting that they might be ubiquitously expressed in amphioxus. [score:5]
As shown in the figure, bbe-miR-1, bbe-let-7, bbe-miR-25, bbe-miR-22, and so on were clearly expressed in amphioxus. [score:3]
Based on the available nematode, fruitfly, zebrafish, frog, chicken, mouse, rat and human miRNA information [18], 45 conserved amphioxus miRNAs could be classified into three distinct groups: 23 miRNAs (let-7a, miR-1, miR-7, miR-9, and so on) were conserved throughout the Bilateria; 5 miRNAs (miR-252a, miR-252b, miR-278, miR-281 and miR-71) were homologous to invertebrate miRNAs; and 17 miRNAs (miR-141, miR-200a, miR-200b, miR-183, miR-216, miR-217, miR-25, miR-22, miR-96, and so on) were present both in chordates and vertebrates (Table S9 in). [score:1]
In contrast, many phylogenetically conserved miRNAs, as well as miRNAs present in both chordates and vertebrates (for example, miR-216, miR-217, miR-22, miR-25, and miR-96), could be reliably traced back to B. belcheri (Gray). [score:1]
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[+] score: 9
Other miRNAs from this paper: mmu-mir-21a, mmu-mir-29a, mmu-mir-211, mmu-mir-21b, mmu-mir-21c
A previous study also confirmed that miR-22 could inhibit cell proliferation by targetting the 3′-UTR of SIRT1 in glioblastoma could inhibit cell proliferation and miR-22-SIRT1 pathway was a potential target for glioblastoma treatment [43]. [score:9]
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[+] score: 9
We chose to profile the ubiquitously expressed miR-16, five ESC-specific miRNAs (miR-290, miR-291-3p, miR-292-3p, miR-294, and miR-295) [23], [24], and two miRNAs that are upregulated in ESCs undergoing differentiation (miR-21 and miR-22) [23], [24]. [score:6]
RNU6b is significantly less abundant than all miRNAs tested except for miR-22, miR-290, and miR-291. [score:1]
The miRNAs tested include miR-16 (lane 1), miR-21 (lane 2), miR-22 (lane 3), miR-290 (lane 4), miR-291-3p (lane 5), miR-292-3p (lane 6), miR-294 (lane 7), miR-295 (lane 8), and the small nuclear RNA, RNU6b (lane 9). [score:1]
Thus, based on the 95 [th] percentile confidence interval, it appears that RNU6b is significantly less abundant than several of the miRNAs tested except miR-22, miR-290, and miR-291. [score:1]
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[+] score: 9
Profiling of miRNAs expression was also performed in the YAC128 and R6/2 mice, showing that nine miRNAs (miR-22, miR-29c, miR-128, miR-132, miR-138, miR-218, miR-222, miR-344, and miR-674*) are commonly down-regulated in 12-month-old YAC128 mice and 10-week-old R6/2 mice (100). [score:6]
Rescuing miR-22 expression in in vitro HD mo dels, protected against Exp-Htt -induced neurotoxicity (106). [score:3]
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[+] score: 9
The HDACIs upregulated well-known tumor suppressive miRNAs including miR-16, miR-22, miR-192-194-215 cluster, and miR-320 family. [score:6]
Furthermore, miR-22 was also demonstrated as a tumor suppressive factor in CTCL pathogenesis [42]. [score:3]
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[+] score: 8
We then noticed that the expression of Vash1 in ECs is downregulated with aging due to an increase in the expression of a certain microRNA, namely, miR-22 [17]. [score:8]
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[+] score: 8
The oncogenic microRNA miR-22 targets the TET2 tumor suppressor to promote hematopoietic stem cell self-renewal and transformation. [score:5]
Recently, overexpression of miR-22 in hematopoietic cells has been shown to lead to MDS (Song et al., 2013). [score:3]
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[+] score: 8
Meanwhile, miR-22 is a well-studied neuroprotective molecule [101] and its observed downregulation may have detrimental consequences for cells. [score:4]
MiR-409-3p and miR-22-3p were down-regulated in the PFC tissues of the PR+BC untreated and crizotinib -treated PR+BC animals. [score:4]
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[+] score: 8
The oncogenic microRNA miR-22 targets the TET2 tumor suppressor to promote hematopoietic stem cell self-renewal and transformation. [score:5]
Targeted deletion of microRNA-22 promotes stress -induced cardiac dilation and contractile dysfunction. [score:3]
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[+] score: 8
66, 67 Blood miR-22 is upregulated by chronic antidepressant treatment in depressed subjects, [68] being therefore suggested as a molecular signature. [score:4]
[63] Max is also directly targeted and repressed by the miR-22, 64, 65 a microRNA recently implicated in the pathogenesis of psychiatry disorders. [score:4]
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[+] score: 7
Other miRNAs from this paper: hsa-let-7a-1, hsa-let-7a-2, hsa-let-7a-3, hsa-let-7b, hsa-let-7c, hsa-let-7d, hsa-let-7e, hsa-let-7f-1, hsa-let-7f-2, hsa-mir-21, hsa-mir-22, hsa-mir-24-1, hsa-mir-24-2, hsa-mir-25, hsa-mir-26a-1, hsa-mir-92a-1, hsa-mir-92a-2, hsa-mir-99a, mmu-let-7g, mmu-let-7i, mmu-mir-27b, mmu-mir-99a, mmu-mir-140, mmu-mir-10b, mmu-mir-181a-2, mmu-mir-24-1, mmu-mir-191, hsa-mir-192, hsa-mir-148a, hsa-mir-30d, mmu-mir-122, hsa-mir-10b, hsa-mir-181a-2, hsa-mir-181a-1, mmu-let-7d, hsa-let-7g, hsa-let-7i, hsa-mir-27b, hsa-mir-122, hsa-mir-140, hsa-mir-191, hsa-mir-320a, mmu-mir-30d, mmu-mir-148a, mmu-mir-192, mmu-let-7a-1, mmu-let-7a-2, mmu-let-7b, mmu-let-7c-1, mmu-let-7c-2, mmu-let-7e, mmu-let-7f-1, mmu-let-7f-2, mmu-mir-21a, mmu-mir-24-2, mmu-mir-26a-1, mmu-mir-92a-2, mmu-mir-25, mmu-mir-181a-1, mmu-mir-26a-2, mmu-mir-92a-1, hsa-mir-26a-2, hsa-mir-423, hsa-mir-451a, mmu-mir-451a, hsa-mir-486-1, mmu-mir-486a, mmu-mir-423, bta-mir-26a-2, bta-let-7f-2, bta-mir-148a, bta-mir-21, bta-mir-30d, bta-mir-320a-2, bta-mir-99a, bta-mir-181a-2, bta-mir-27b, bta-mir-140, bta-mir-92a-2, bta-let-7d, bta-mir-191, bta-mir-192, bta-mir-22, bta-mir-423, bta-let-7g, bta-mir-10b, bta-mir-24-2, bta-let-7a-1, bta-let-7f-1, bta-mir-122, bta-let-7i, bta-mir-25, bta-let-7a-2, bta-let-7a-3, bta-let-7b, bta-let-7c, bta-let-7e, hsa-mir-1246, bta-mir-24-1, bta-mir-26a-1, bta-mir-451, bta-mir-486, bta-mir-92a-1, bta-mir-181a-1, bta-mir-320a-1, mmu-mir-486b, hsa-mir-451b, bta-mir-1246, mmu-mir-21b, mmu-let-7j, mmu-mir-21c, mmu-mir-451b, mmu-let-7k, hsa-mir-486-2
In the present study, bta-miR-22-3p was upregulated as the animals grew older. [score:4]
Bta-miR-22-3p may be a critical micro RNA associated with development of cattle. [score:2]
Bta-miR-22-3p and bta-miR-24-3p had the fewest number of copies in summer, 2013, an intermediate number of sequences in fall, 2013, and the greatest number in spring, 2014 (P< 0.0001). [score:1]
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[+] score: 7
Among miRs identified in OA, miR-22 targets BMP7, a factor inducing chondrocyte terminal differentiation [18]; miR-140 targets HDAC4, a histone deacetylase inducer of chondrocyte terminal differentiation [19, 20]; and miR-27b targets MMP13, a key remo deling enzyme in hypertrophic terminally differentiated chondrocyte [21]. [score:7]
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[+] score: 7
The other miRNAs involved in regulation of CSE are miR-30 that directly inhibits CSE [47], and miR-22 that inhibits SP1 [49]. [score:7]
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49
[+] score: 7
However, previous studies on hMSCs-Ad undergoing adipogenesis reported that miR-21 13, miR-22 14, miR-196 15, miR-27b 20, and miR-138 31 were either upregulated or downregulated, and miR-148a was not reported in hMSCs-Ad. [score:7]
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[+] score: 7
Of the 20 miRNAs downregulated in crypts, 8 showed a >4.0 fold difference (miR-142-5p, miR-16-5p, miR-22-3p, miR-194-3p, miR-33-5p, miR-223-3p, miR-32-5p, miR-140-5p; Fig. 4a1, blue spots), whereas, of the 15 miRNAs upregulated in crypts, 2 showed a >3.0 fold difference (miR-192-5p, miR-98-5p) (Fig. 4a2, blue spots). [score:7]
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[+] score: 7
Previous studies have found that miR-22 and miR-124 affect cortical neuron migration by targeting components of the coREST/REST complex, indirectly regulating DCX expression (Volvert et al., 2014). [score:7]
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52
[+] score: 6
Other miRNAs from this paper: hsa-let-7a-1, hsa-let-7a-2, hsa-let-7a-3, hsa-let-7b, hsa-let-7c, hsa-let-7d, hsa-let-7e, hsa-let-7f-1, hsa-let-7f-2, hsa-mir-16-1, hsa-mir-17, hsa-mir-21, hsa-mir-22, hsa-mir-28, hsa-mir-29b-1, hsa-mir-16-2, mmu-let-7g, mmu-let-7i, mmu-mir-1a-1, mmu-mir-29b-1, mmu-mir-124-3, mmu-mir-9-2, mmu-mir-133a-1, mmu-mir-145a, mmu-mir-150, mmu-mir-10b, mmu-mir-195a, mmu-mir-199a-1, hsa-mir-199a-1, mmu-mir-200b, mmu-mir-206, mmu-mir-143, hsa-mir-10a, hsa-mir-10b, hsa-mir-199a-2, hsa-mir-217, hsa-mir-218-1, hsa-mir-223, hsa-mir-200b, mmu-let-7d, hsa-let-7g, hsa-let-7i, hsa-mir-1-2, hsa-mir-124-1, hsa-mir-124-2, hsa-mir-124-3, hsa-mir-133a-1, hsa-mir-133a-2, hsa-mir-143, hsa-mir-145, hsa-mir-9-1, hsa-mir-9-2, hsa-mir-9-3, hsa-mir-150, hsa-mir-195, hsa-mir-206, mmu-mir-200a, mmu-let-7a-1, mmu-let-7a-2, mmu-let-7b, mmu-let-7c-1, mmu-let-7c-2, mmu-let-7e, mmu-let-7f-1, mmu-let-7f-2, mmu-mir-16-1, mmu-mir-16-2, mmu-mir-21a, mmu-mir-29c, rno-let-7d, rno-mir-329, mmu-mir-329, rno-mir-331, mmu-mir-331, rno-mir-148b, mmu-mir-148b, rno-mir-135b, mmu-mir-135b, hsa-mir-200c, hsa-mir-1-1, mmu-mir-1a-2, mmu-mir-10a, mmu-mir-17, mmu-mir-28a, mmu-mir-200c, mmu-mir-218-1, mmu-mir-223, mmu-mir-199a-2, mmu-mir-124-1, mmu-mir-124-2, mmu-mir-9-1, mmu-mir-9-3, mmu-mir-7b, mmu-mir-217, hsa-mir-29c, hsa-mir-200a, hsa-mir-365a, mmu-mir-365-1, hsa-mir-365b, hsa-mir-135b, hsa-mir-148b, hsa-mir-331, mmu-mir-133a-2, mmu-mir-133b, hsa-mir-133b, rno-let-7a-1, rno-let-7a-2, rno-let-7b, rno-let-7c-1, rno-let-7c-2, rno-let-7e, rno-let-7f-1, rno-let-7f-2, rno-let-7i, rno-mir-7b, rno-mir-9a-1, rno-mir-9a-3, rno-mir-9a-2, rno-mir-10a, rno-mir-10b, rno-mir-16, rno-mir-17-1, rno-mir-21, rno-mir-22, rno-mir-28, rno-mir-29b-1, rno-mir-29c-1, rno-mir-124-3, rno-mir-124-1, rno-mir-124-2, rno-mir-133a, rno-mir-143, rno-mir-145, rno-mir-150, rno-mir-195, rno-mir-199a, rno-mir-200c, rno-mir-200a, rno-mir-200b, rno-mir-206, rno-mir-217, rno-mir-223, dre-mir-7b, dre-mir-10a, dre-mir-10b-1, dre-mir-217, dre-mir-223, hsa-mir-429, mmu-mir-429, rno-mir-429, mmu-mir-365-2, rno-mir-365, dre-mir-429a, hsa-mir-329-1, hsa-mir-329-2, hsa-mir-451a, mmu-mir-451a, rno-mir-451, dre-mir-451, dre-let-7a-1, dre-let-7a-2, dre-let-7a-3, dre-let-7a-4, dre-let-7a-5, dre-let-7a-6, dre-let-7b, dre-let-7c-1, dre-let-7c-2, dre-let-7d-1, dre-let-7d-2, dre-let-7e, dre-let-7f, dre-let-7g-1, dre-let-7g-2, dre-let-7h, dre-let-7i, dre-mir-1-2, dre-mir-1-1, dre-mir-9-1, dre-mir-9-2, dre-mir-9-4, dre-mir-9-3, dre-mir-9-5, dre-mir-9-6, dre-mir-9-7, dre-mir-10b-2, dre-mir-16a, dre-mir-16b, dre-mir-16c, dre-mir-17a-1, dre-mir-17a-2, dre-mir-21-1, dre-mir-21-2, dre-mir-22a, dre-mir-22b, dre-mir-29b-1, dre-mir-124-1, dre-mir-124-2, dre-mir-124-3, dre-mir-124-4, dre-mir-124-5, dre-mir-124-6, dre-mir-133a-2, dre-mir-133a-1, dre-mir-133b, dre-mir-133c, dre-mir-143, dre-mir-145, dre-mir-150, dre-mir-200a, dre-mir-200b, dre-mir-200c, dre-mir-206-1, dre-mir-206-2, dre-mir-365-1, dre-mir-365-2, dre-mir-365-3, dre-let-7j, dre-mir-135b, rno-mir-1, rno-mir-133b, rno-mir-17-2, mmu-mir-1b, dre-mir-429b, rno-mir-9b-3, rno-mir-9b-1, rno-mir-9b-2, rno-mir-133c, mmu-mir-28c, mmu-mir-28b, hsa-mir-451b, mmu-mir-195b, mmu-mir-133c, mmu-mir-145b, mmu-mir-21b, mmu-let-7j, mmu-mir-21c, mmu-mir-451b, mmu-let-7k, rno-let-7g, rno-mir-29c-2, mmu-mir-9b-2, mmu-mir-124b, mmu-mir-9b-1, mmu-mir-9b-3
Furthermore, there were seven miRNAs that were only expressed at high levels in one neural tissue, for example let-7b, miR-16, miR-22, miR-206, and miR-143 specifically expressed in olfactory bulb (Fig. 3b). [score:5]
Olfactory bulb let-7b, let-7c-1, let-7c-2, miR-10a, miR-16, miR-17, miR-21, miR-22, miR-28, miR-29c, miR-124a-1, miR-124a-3, miR-128a, miR-135b, miR-143, miR-148b, miR-150, miR-199a, miR-206, miR-217, miR-223, miR-29b-1, miR-329, miR-331, miR-429, miR-451. [score:1]
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53
[+] score: 6
miR-22*, -34c* and -200b* were upregulated against all the injuries whereas expression of miR-191* was repressed by all the injury types. [score:6]
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54
[+] score: 6
Ma HL Inhibition of Endometrial Tiam1/Rac1 Signals Induced by miR-22 Up-Regulation Leads to the Failure of Embryo Implantation During the Implantation Window in Pregnant MiceBiol. [score:6]
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55
[+] score: 6
Other miRNAs from this paper: hsa-mir-22, mmu-mir-200b, hsa-mir-200b
Tang H. Kong Y. Guo J. Tang Y. Xie X. Yang L. Su Q. Xie X. Diallyl disulfide suppresses proliferation and induces apoptosis in human gastric cancer through Wnt-1 signaling pathway by up-regulation of miR-200b and miR-22 Cancer Lett. [score:6]
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56
[+] score: 6
Furthermore, miR-22 has been shown to inhibit estrogen signaling by directly targeting estrogen receptor-α mRNA [46]. [score:6]
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57
[+] score: 5
Other miRNAs from this paper: hsa-mir-22
We also showed that this activation was associated with decreased expression of PTEN, a result consistent with a recent report that CD40 stimulation results in a specific induction of microRNA-22, a cellular inhibitor of PTEN, which subsequently leads to AKT activation in CLL cells [48]. [score:5]
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58
[+] score: 5
Other studies have demonstrated that miR-22 overexpression leads to a reduction of ERα level, at least in part by inducing mRNA degradation, and compromises estrogen signaling, as exemplified by its inhibitory impact on the ERα -dependent proliferation of breast cancer cells [31], [32]. [score:5]
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59
[+] score: 5
Of the 113 miRNAs with significantly aberrant expressions after RDX exposure, the expression levels of 10 miRNAs were significantly increased in both mouse liver and brain (p < 0.01): miR-99a, miR-30a, miR-30d, miR-30e, miR-22, miR-194, miR-195, miR-15a, miR-139-5p, and miR-101b. [score:5]
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60
[+] score: 5
Although miRNA expression among these samples was highly correlated overall, such as in the case of miR-22-3p or miR-24-1-3p (Fig. 3A), several miRNAs appeared to be specifically or preferentially expressed in either the MIN6 cells or human beta cells/islets (Fig. 3A). [score:5]
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61
[+] score: 5
Together with miR-21, miR-22 could regulate targets such as transforming growth factor-β -induced gene (TGFBi) [27], [28]. [score:4]
An example of these 18 miRNAs is miR-22, which was recognized as one of the miRNAs, which increase dramatically during differentiation. [score:1]
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62
[+] score: 4
For example, a microRNA identified as a regulator of p53 expression could be considered a senescence marker but there are reports that p53 can be regulated by microRNA-20 (miR-20) [13], miR-106a [14], miR-22 [15], miR-33 [16] and miR-29 [17]. [score:4]
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63
[+] score: 4
Other miRNAs from this paper: hsa-mir-22, dre-mir-22a, dre-mir-22b
A conserved binding site for miR-22/22-3p conserved among species is located in position 837–843 nts, as predicted by TargetScan webtool. [score:3]
Interestingly, p21 mRNA 3′UTR contains an evolutionarily conserved binding site for miR-22 100 nts upstream of the G-quadruplex motif (Figure S3). [score:1]
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64
[+] score: 4
Other miRNAs from this paper: hsa-mir-22, rno-mir-22, gga-mir-22, ssc-mir-22
However, the role of the syntenic locus in humans has been controversial, and more recent analyses have revealed mir-22 as a regulator of not only HTR2C mRNA expression, but also of other candidate genes for panic disorder [12]. [score:4]
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65
[+] score: 4
MiR-145, miR-22, miR-125b-5p, miR-27a and miR-1 appeared to be most highly expressed in the bladder muscle layer, and their knockdown level ranged between 68 and 99% (Table S1). [score:4]
[1 to 20 of 1 sentences]
66
[+] score: 4
MiRNA-22 exerts suppressive effect on cysteine-rich protein 61 expression which plays vital roles in mediating the joint inflammation and damage in arthritis [18]. [score:4]
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67
[+] score: 4
Other miRNAs from this paper: mmu-let-7g, mmu-let-7i, mmu-mir-23b, mmu-mir-29b-1, mmu-mir-30b, mmu-mir-99a, mmu-mir-126a, mmu-mir-132, mmu-mir-141, mmu-mir-181a-2, mmu-mir-185, mmu-mir-193a, mmu-mir-199a-1, mmu-mir-200b, mmu-mir-34c, mmu-let-7d, mmu-mir-196a-1, mmu-mir-196a-2, mmu-mir-200a, mmu-let-7a-1, mmu-let-7a-2, mmu-let-7b, mmu-let-7c-1, mmu-let-7c-2, mmu-let-7e, mmu-let-7f-1, mmu-let-7f-2, mmu-mir-16-1, mmu-mir-16-2, mmu-mir-20a, mmu-mir-23a, mmu-mir-26a-1, mmu-mir-26b, mmu-mir-34a, mmu-mir-200c, mmu-mir-212, mmu-mir-181a-1, mmu-mir-26a-2, mmu-mir-29b-2, mmu-mir-199a-2, mmu-mir-199b, mmu-mir-378a, mmu-mir-451a, mmu-mir-674, mmu-mir-423, mmu-mir-146b, bta-mir-26a-2, bta-let-7f-2, bta-mir-16b, bta-mir-20a, bta-mir-26b, bta-mir-99a, bta-mir-126, bta-mir-181a-2, bta-mir-199a-1, bta-mir-30b, bta-mir-193a, bta-let-7d, bta-mir-132, bta-mir-199b, bta-mir-200a, bta-mir-200c, bta-mir-22, bta-mir-23a, bta-mir-29b-2, bta-mir-423, bta-let-7g, bta-mir-200b, bta-let-7a-1, bta-let-7f-1, bta-let-7i, bta-mir-23b, bta-mir-34c, bta-let-7a-2, bta-let-7a-3, bta-let-7b, bta-let-7c, bta-let-7e, bta-mir-34a, bta-mir-141, bta-mir-146b, bta-mir-16a, bta-mir-185, bta-mir-196a-2, bta-mir-196a-1, bta-mir-199a-2, bta-mir-212, bta-mir-26a-1, bta-mir-29b-1, bta-mir-181a-1, bta-mir-2284i, bta-mir-2284s, bta-mir-2284l, bta-mir-2284j, bta-mir-2284t, bta-mir-2284d, bta-mir-2284n, bta-mir-2284g, bta-mir-2284p, bta-mir-2284u, bta-mir-2284f, bta-mir-2284a, bta-mir-2284k, bta-mir-2284c, bta-mir-2284v, bta-mir-2284q, bta-mir-2284m, bta-mir-2284b, bta-mir-2284r, bta-mir-2284h, bta-mir-2284o, bta-mir-2284e, bta-mir-2284w, bta-mir-2284x, bta-mir-2284y-1, mmu-let-7j, bta-mir-2284y-2, bta-mir-2284y-3, bta-mir-2284y-4, bta-mir-2284y-5, bta-mir-2284y-6, bta-mir-2284y-7, bta-mir-2284z-1, bta-mir-2284aa-1, bta-mir-2284z-3, bta-mir-2284aa-2, bta-mir-2284aa-3, bta-mir-2284z-4, bta-mir-2284z-5, bta-mir-2284z-6, bta-mir-2284z-7, bta-mir-2284aa-4, bta-mir-2285t, bta-mir-2284z-2, mmu-let-7k, mmu-mir-126b, bta-mir-2284ab, bta-mir-2284ac
The expression of the seven miRNA detected in the top 30 of epithelial tissues and the two miRNA expressed only in mammary gland (miR-22-3p and miR-141-3p) were compared with those on published non-lactating mammary gland miRNomes generated from several species (bovine [40], caprine [38], [39], [41] and human [59]) using the same NGS technology. [score:4]
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68
[+] score: 4
It has been demonstrated that upregulation of miR-22 contributes to M-I/R injury by interfering with the mitochondrial function [24]. [score:4]
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69
[+] score: 4
HF diet -associated miRNA up- (miR-22, miR-342-3p, miR-142-3p and others) and down-regulations (miR-200b, miR-200c, miR-204 and others) were observed in the adipose tissues of C57BL/6J mice [76]. [score:4]
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70
[+] score: 4
Ischemic preconditioning potentiates the protective effect of stem cells through secretion of exosomes by targeting Mecp2 via miR-22. [score:3]
EVs from mesenchymal stem cells (MSCs) following ischemic preconditioning were abundant with miR-22 and reduced cardiomyocytes apoptosis and cardiac fibrosis after AMI (Feng et al., 2014). [score:1]
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71
[+] score: 4
Other miRNAs from this paper: mmu-mir-19b-2, mmu-mir-19a, mmu-mir-19b-1
As a control, miR-22 could not be detected in the pull-down products precipitated by the anti-TIA1 mRNA probes (Fig.   3h), since miR-22 was not supposed to bind TIA1 according to the target prediction software. [score:3]
g Quantitative RT-PCR analysis of TIA1 and GAPDH mRNA levels in SW480 after pulling down with control probe or miR-19a probe; h Quantitative RT-PCR analysis of miR-19a and miR-22 levels in SW480 after pulling down with control probes or two TIA1 mRNA probes; i The relative luciferase activities in SW480 transfected with wild type or mutant TIA1 3’-UTR. [score:1]
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72
[+] score: 4
The 10 most upregulated miRNAs were miR-146b, miR-297b, miR-34a, miR-469, miR-139-3p, miR-21, miR-466E-5p, miR22*, miR-324, and miR-143. [score:4]
[1 to 20 of 1 sentences]
73
[+] score: 4
Among the current candidates, we can cite miR-22 that is induced by vitamin D and acts as an antiproliferative and antimigratory agent in cancer cells [21] or miR-125b that regulates the expression of human vitamin D receptor and abolishes the anti-proliferative action of calcitriol [22]. [score:4]
[1 to 20 of 1 sentences]
74
[+] score: 4
Interestingly, the loss of miR-22 (which targets HDAC4) led to the development of dilated cardiomyopathy under stress conditions [29]. [score:4]
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75
[+] score: 4
miR-34a and miR-22 were also reported to regulate VSMCs differentiation from stem cells by targeting sirtuin 1 and Methyl CpG–Binding Protein, respectively [22, 23]. [score:4]
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76
[+] score: 4
Other miRNAs from this paper: hsa-let-7a-1, hsa-let-7a-2, hsa-let-7a-3, hsa-let-7b, hsa-let-7c, hsa-let-7d, hsa-let-7e, hsa-let-7f-1, hsa-let-7f-2, hsa-mir-22, hsa-mir-29a, hsa-mir-30a, hsa-mir-29b-1, hsa-mir-29b-2, mmu-let-7g, mmu-let-7i, mmu-mir-1a-1, mmu-mir-29b-1, mmu-mir-30a, mmu-mir-127, mmu-mir-132, mmu-mir-133a-1, mmu-mir-136, mmu-mir-144, mmu-mir-146a, mmu-mir-152, mmu-mir-155, mmu-mir-10b, mmu-mir-185, mmu-mir-190a, mmu-mir-193a, mmu-mir-203, mmu-mir-206, hsa-mir-148a, mmu-mir-143, hsa-mir-10b, hsa-mir-34a, hsa-mir-203a, hsa-mir-215, mmu-mir-34c, mmu-mir-34b, mmu-let-7d, hsa-let-7g, hsa-let-7i, hsa-mir-1-2, hsa-mir-132, hsa-mir-133a-1, hsa-mir-133a-2, hsa-mir-143, hsa-mir-144, hsa-mir-152, hsa-mir-127, hsa-mir-136, hsa-mir-146a, hsa-mir-185, hsa-mir-190a, hsa-mir-193a, hsa-mir-206, mmu-mir-148a, mmu-let-7a-1, mmu-let-7a-2, mmu-let-7b, mmu-let-7c-1, mmu-let-7c-2, mmu-let-7e, mmu-let-7f-1, mmu-let-7f-2, mmu-mir-29a, mmu-mir-29c, mmu-mir-34a, mmu-mir-337, hsa-mir-1-1, mmu-mir-1a-2, hsa-mir-155, mmu-mir-29b-2, hsa-mir-29c, hsa-mir-34b, hsa-mir-34c, hsa-mir-378a, mmu-mir-378a, hsa-mir-337, mmu-mir-133a-2, mmu-mir-133b, hsa-mir-133b, mmu-mir-215, mmu-mir-411, mmu-mir-434, hsa-mir-486-1, hsa-mir-146b, hsa-mir-193b, mmu-mir-486a, mmu-mir-540, hsa-mir-92b, hsa-mir-411, hsa-mir-378d-2, mmu-mir-146b, mmu-mir-193b, mmu-mir-92b, mmu-mir-872, mmu-mir-1b, mmu-mir-3071, mmu-mir-486b, hsa-mir-378b, hsa-mir-378c, hsa-mir-378d-1, hsa-mir-378e, hsa-mir-378f, hsa-mir-378g, hsa-mir-378h, hsa-mir-378i, mmu-mir-378b, hsa-mir-203b, mmu-mir-3544, hsa-mir-378j, mmu-mir-133c, mmu-let-7j, mmu-mir-378c, mmu-mir-378d, mmu-let-7k, hsa-mir-486-2
Recently, miR-22 was identified as a cardiac- and skeletal muscle-enriched miRNA that is up-regulated during myocyte differentiation and cardiomyocyte hypertrophy [21]. [score:4]
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77
[+] score: 3
Other miRNAs from this paper: mmu-mir-214, mmu-mir-675
Increased hepatic miR-22-3p hepatic levels promote hepatic gluconeogenesis and glucose output and in vivo inhibition of this miRNA improves hyperglycemia, glucose and pyruvate tolerance [33]. [score:3]
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78
[+] score: 3
Here, by sequence matching using bioinformatics analyses, we found quite a few of candidate miRNAs that target Bcl-2, including miR-429, miR-30, miR-22, miR-25, miR-32, miR-92, miR-363, miR-367, miR-99, miR-27, miR-128, etc. [score:3]
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79
[+] score: 3
On the other hand, miR-22 and miR-205, which were reported to be highly expressed in mammary progenitor cells [38], seemed to be enriched during gestation and again during late involution. [score:3]
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80
[+] score: 3
In addition, other miRNAs including miR-22, -31, and -301a were also shown to increase significantly in expression regardless of the irritant status of the TDI dose (data not shown). [score:3]
[1 to 20 of 1 sentences]
81
[+] score: 3
Other miRNAs from this paper: hsa-let-7a-1, hsa-let-7a-2, hsa-let-7a-3, hsa-let-7b, hsa-let-7c, hsa-let-7d, hsa-let-7e, hsa-let-7f-1, hsa-let-7f-2, hsa-mir-18a, hsa-mir-22, hsa-mir-29a, hsa-mir-30a, hsa-mir-93, hsa-mir-100, hsa-mir-29b-1, hsa-mir-29b-2, mmu-let-7g, mmu-let-7i, mmu-mir-1a-1, mmu-mir-29b-1, mmu-mir-30a, mmu-mir-30b, mmu-mir-124-3, mmu-mir-126a, mmu-mir-9-2, mmu-mir-133a-1, mmu-mir-146a, mmu-mir-200b, mmu-mir-203, mmu-mir-204, mmu-mir-205, hsa-mir-148a, hsa-mir-30c-2, hsa-mir-30d, mmu-mir-30e, hsa-mir-10a, hsa-mir-34a, hsa-mir-203a, hsa-mir-204, hsa-mir-205, hsa-mir-218-1, hsa-mir-218-2, hsa-mir-221, hsa-mir-222, hsa-mir-200b, mmu-mir-34c, mmu-mir-34b, mmu-let-7d, hsa-let-7g, hsa-let-7i, hsa-mir-1-2, hsa-mir-30b, hsa-mir-124-1, hsa-mir-124-2, hsa-mir-124-3, hsa-mir-133a-1, hsa-mir-133a-2, hsa-mir-9-1, hsa-mir-9-2, hsa-mir-9-3, hsa-mir-126, hsa-mir-146a, mmu-mir-30c-1, mmu-mir-30c-2, mmu-mir-30d, mmu-mir-148a, mmu-mir-200a, mmu-let-7a-1, mmu-let-7a-2, mmu-let-7b, mmu-let-7c-1, mmu-let-7c-2, mmu-let-7e, mmu-let-7f-1, mmu-let-7f-2, mmu-mir-18a, mmu-mir-29a, mmu-mir-29c, mmu-mir-93, mmu-mir-34a, hsa-mir-200c, hsa-mir-1-1, mmu-mir-1a-2, mmu-mir-10a, mmu-mir-100, mmu-mir-200c, mmu-mir-218-1, mmu-mir-218-2, mmu-mir-221, mmu-mir-222, mmu-mir-29b-2, mmu-mir-124-1, mmu-mir-124-2, mmu-mir-9-1, mmu-mir-9-3, hsa-mir-29c, hsa-mir-30c-1, hsa-mir-200a, hsa-mir-34b, hsa-mir-34c, hsa-mir-30e, hsa-mir-375, mmu-mir-375, hsa-mir-335, mmu-mir-335, mmu-mir-133a-2, hsa-mir-424, hsa-mir-193b, hsa-mir-512-1, hsa-mir-512-2, hsa-mir-515-1, hsa-mir-515-2, hsa-mir-518f, hsa-mir-518b, hsa-mir-517a, hsa-mir-519d, hsa-mir-516b-2, hsa-mir-516b-1, hsa-mir-517c, hsa-mir-519a-1, hsa-mir-516a-1, hsa-mir-516a-2, hsa-mir-519a-2, hsa-mir-503, mmu-mir-503, hsa-mir-642a, mmu-mir-190b, mmu-mir-193b, hsa-mir-190b, mmu-mir-1b, hsa-mir-203b, mmu-let-7j, mmu-mir-30f, mmu-let-7k, mmu-mir-126b, mmu-mir-9b-2, mmu-mir-124b, mmu-mir-9b-1, mmu-mir-9b-3
In the mouse mammary epithelial cell line, Comma-Dβ [19], the expression of miR-205 and miR-22 but not let-7 and miR-93 was linked to progenitor-like properties, while miR-200c appears to function within the basal cell compartment of normal breast tissue [20]. [score:3]
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82
[+] score: 3
Other miRNAs from this paper: mmu-mir-223
MaxSuppressor In Vivo RNA-LANCEr II (NLE) (Bioscientific, Austin, TX, USA) was used according to the manufacturer’s instructions to administer 100  μg/kg/day mmu-miR-22 mimics intravenously. [score:3]
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83
[+] score: 3
In a mouse mo del of emphysema, HDAC4 was targeted by miR-22 to promote a Th17 response in antigen presenting cells (APCs) [45]. [score:3]
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84
[+] score: 3
Genes associated with ubiquitin -mediated proteolysis, cell cycle, NF-kB and insulin signalling, as well as miRs miR-132, miR-122, miR-499, miR-128 and miR-22 formed central nodes in the network of miRNA:target interactions disrupted during ageing (Fig. S2). [score:3]
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85
[+] score: 3
As shown in Fig. 2A, LPS induced expression of a sizable subset of miRNAs such as miR-21, miR-22, miR-29 family, miR-99b, miR-146a-b, and miR-155 in RAW264.7 cells. [score:3]
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86
[+] score: 3
Neuroprotective effects of viral overexpression of microRNA-22 in rat and cell mo dels of cerebral ischemia-reperfusion injury. [score:3]
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87
[+] score: 3
AGS [GR] cells transfected with a chemically synthesised miR-222 mimic showed a dose dependent decrease in p27 mRNA and protein expression (Figure 5B and 5D); this was significant at miR-22 mimic concentrations > 50 nM. [score:3]
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88
[+] score: 3
In cells with an activated MAPK/ERK pathway, the expression levels of let-7a, miR-10, miR-22, miR-26, miR-34, and miR-125a were lower, and those of miR-20, miR-25, and miR-135b, were higher (Supplementary Table 1). [score:3]
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89
[+] score: 3
In human cancers, is frequently targeted by miRNAs such as miR21, miR22, miRN214 and miR221 [150]. [score:3]
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90
[+] score: 3
However, some miRNAs, like miR-720, miR-22, and miR-145, were substantially more highly expressed in the 14 DIV MG. [score:3]
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91
[+] score: 3
In addition, miR 142–3p, miR-15a, miR-29b, miR-22, miR-32, and miR-34c, also known to be pro-apoptotic, are downregulated in the galactosemic lenses as compared to the normals. [score:3]
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92
[+] score: 3
Ming et al. found that nicotinamide phosphoribosyltransferase (NAMPT) inhibited EPC senescence through a sirtuin 1 (SIRT1) antisense long noncoding RNA (AS lncRNA)/miR-22/SIRT1 pathway and promoted EPC proliferation and migration [23]. [score:3]
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93
[+] score: 3
Among these 77 dysregulated miRs, we identified 12 altered miRNAs that were 1.5 fold regulated by DMCs and average intensity >100, including miR-23a-3p, miR-3069-5p, miR-26a-5p, miR-142-3p, miR-21a-5p, miR-223-3p, miR-16-5p, miR-22-3p, let-7g-5p, let-7b-5p, miR-878-3p, miR-489-3p. [score:3]
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94
[+] score: 3
However, the expression of the remaining 9 miRNAs (miR-411, miR-434-3p, miR-299*, miR-193, miR-146b, miR-379, miR-193b, miR-22, and miR-223) has not been verified. [score:3]
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95
[+] score: 2
In them, 7 miRNAs (miR-378d, miR-29c-3p, miR-20a-5p, miR-335-5p, miR-22-3p, miR-21a-5p and miR-223-3p) had been shown to be related with diabetes or glucose metabolism. [score:1]
It is reported that miR-22 is involved in renal fibrosis and glucose metabolism [38, 39]. [score:1]
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96
[+] score: 2
In total, the 3′UTR of Creb1 contains eight predicted binding sites for miR-17 (three sites), miR-144 (one site), miR-22 (two sites), and miR-181a (two sites) (Fig. 1b). [score:1]
Since binding of miR-181a could not be proven (Fig. 2a), and miR-22 and could not be confirmed by qRT-PCR, we excluded both miRNAs from further analysis. [score:1]
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97
[+] score: 2
Other miRNAs from this paper: mmu-mir-132, mmu-mir-19b-2, mmu-mir-19a, mmu-mir-19b-1
37, 38, 39 In addition, we performed an analysis of miRNA binding sites in the 3′ UTR of MECP2, using a number of bioinformatic tools, 40, 41, 42 and incorporated a compact sequence containing the binding sites of three highly conserved miRNAs known to be involved in regulation of MeCP2 in the brain; miR-22, [32] miR-19, [33] and miR-132. [score:2]
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98
[+] score: 2
Notably, the miR-290_295 cluster, miR-127 and miR-22 contribute collectively to more than 65% of all cellular miRNAs of undifferentiated ES cells, and their respective abundance consistently decreases during early differentiation. [score:1]
This would also explain why miR-22 -which we cloned at a high frequency specifically in both male and female undifferentiated samples- was not overrepresented in their study. [score:1]
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99
[+] score: 2
old 3xTg-AD mice, we identified a particular group of miRNAs integrated by miR-132, miR-138, miR-146a, miR-146b, miR-22, miR-24, miR-29a, miR-29c, and miR-34a which show significant differences in plasma levels only in the transgenic group, raising the possibility of age-related changes that specifically occur in the 3xTg-AD mice (Figure 3, Supplementary Table 3). [score:1]
age-matched WT mice, we detected a significant lower abundance of miR-132, miR-138, miR-139, miR-146a, miR-146b, miR-22, miR-24, miR-29a, and miR-29c as well as a higher abundance of miR-346 (Figure 4, Supplementary Table 4). [score:1]
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100
[+] score: 2
Aside from the established dystromiRs, the four most differentially abundant miRNAs were miR-22, miR-30a, miR-193b and miR-378 (Figure 2A). [score:1]
Although these miRNAs were generally elevated in the mdx samples, for miR-22, miR-30a and miR-193b, the serum miRNA levels dropped below C57Bl/10 levels at the 32-week time point (Supplementary Figure S2A–C). [score:1]
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