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190 publications mentioning hsa-mir-135b (showing top 100)

Open access articles that are associated with the species Homo sapiens and mention the gene name mir-135b. Click the [+] symbols to view sentences that include the gene name, or the word cloud on the right for a summary.

1
[+] score: 363
By directly targeting the 3′-UTR, miR-135b suppressed BMAL1 expression and thereby disturbed the entire molecular clockwork inside the exocrine pancreas, leading to impaired circadian control of tumour suppression. [score:10]
Also, we found that the level of miR-135b was significantly upregulated by YY1 overexpression and was downregulated by YY1 silencing (Fig.   7g). [score:9]
Here, we showed that miR-135b overexpression in MIA PaCa-2 cells significantly altered the expression of clock-controlled cell cycle checkpoints (Supplementary Fig.   S3a), the clock-controlled DNA repair system (Supplementary Fig.   S3b) and clock-controlled apoptosis (Supplementary Fig.   S3c), leading to enhanced cell cycle progression and the inhibition of cell apoptosis; however, the restoration of BMAL1 expression largely reversed these changes by rescuing the local circadian gating control. [score:9]
We then manipulated the miR-135b level using expression or knockdown vectors and we found that overexpressing miR-135b in HPDE6c7 cells significantly dampened the rhythms of PER1 and PER2 by shortening their amplitudes, and caused arrhythmic expression of BMAL1, CLOCK, CRY1/2, NR1D1, RORA and SIRT1 (Fig.   3a). [score:8]
miR-135b upregulation markedly altered the expression of clock-controlled cell cycle checkpoints, DNA repair regulators and apoptotic mediators, resulting in tumourigenic transformation at both the molecular and cellular levels, whereas the restoration of BMAL1 partially reversed these changes. [score:7]
d GSEA used to identify the differential gene profiles between BMAL1 high -expression group and low -expression group of patients in the GSE19650 PC cohort Further, MIA PaCa-2 and Panc-1 cells with manipulated miR-135b and/or BMAL1 expressions were used in in vitro gain-of-function and loss-of-function studies (Supplementary Fig.   S4 shows the transfection efficiency). [score:7]
Moreover, GEM -based treatment resulted in an objective response rate (ORR) of 16.2% and a disease control rate (DCR) of 62.2%; high miR-135b/low BMAL1/high YY1 expression facilitated GEM resistance, whereas those patients with low miR-135b/high BMAL1/low YY1 -expressing tumours had relatively higher chemosensitivity (Supplementary Table  S10). [score:7]
Moreover, the expression of YY1 and its targets Snail [29] and VEGF [30] aligned with that of miR-135b but was the opposite of BMAL1 expression. [score:7]
CCK-8 assays revealed that miR-135b overexpression increased the proliferation of MIA PaCa-2 cells, and this effect was remarkably antagonised by BMAL1 (Fig.   5a); however, knocking-down BMAL1 expression significantly increased the proliferation rate of Panc-1 cells, which was suppressed by miR-135b depletion (Fig.   5b). [score:7]
To generate miR-135b expression or knockdown (Anti-miR-135b) vectors, oligonucleotides encoding precursors or inhibitors of miR-135b were synthesised and subcloned into the BamHI and XhoI restrictive sites of pPG/miR/EGFP/blasticidin plasmid or pGCMV/EGFP/miR/blasticidin plasmid (GenePharma), and then verified by DNA sequencing. [score:6]
The circadian parameters including period, phase, and amplitude were analysed by the JTK_CYCLE algorithm and were shown in Supplementary Table  S6 a, b Temporal expression patterns of nine core circadian genes were determined by qRT-PCR in HPDE6c7 cells transfected with miR-135b expression vectors/empty vectors (NCs) (a) and in Panc-1 cells transfected with miR-135b knockdown vectors/NCs (b). [score:6]
Ectopic miR-135b expression impaired the operation of the pancreatic oscillator, and miR-135b downregulation is essential for cellular clock realignment. [score:6]
In contrast, silencing BMAL1 in Panc-1 cells markedly attenuated the inhibitory effect of miR-135b downregulation on cell migration and invasion (Fig.   5d, f). [score:6]
d GSEA used to identify the differential gene profiles between BMAL1 high -expression group and low -expression group of patients in the GSE19650 PC cohort As the circadian clock targets CCGs to regulate cellular processes, we next investigated the influence of miR-135b on cancer-related CCGs 12, 26. [score:6]
Fig. 3 a, b Temporal expression patterns of nine core circadian genes were determined by qRT-PCR in HPDE6c7 cells transfected with miR-135b expression vectors/empty vectors (NCs) (a) and in Panc-1 cells transfected with miR-135b knockdown vectors/NCs (b). [score:6]
Here, we showed that miR-135b was significantly upregulated and was negatively correlated with BMAL1 expression in PC tissues. [score:6]
Here, we showed that overexpressing miR-135b significantly facilitated GEM resistance in PC cells, whereas BMAL1 upregulation restored GEM -induced apoptosis and sensitised the pancreatic xenograft tumours to GEM treatment. [score:6]
d GSEA used to identify the differential gene profiles between BMAL1 high -expression group and low -expression group of patients in the GSE19650 PC cohortAs the circadian clock targets CCGs to regulate cellular processes, we next investigated the influence of miR-135b on cancer-related CCGs 12, 26. [score:6]
After a 72 h-exposure to GEM, cleaved caspase-3 and PARP were significantly increased in BMAL1 -upregulated MIA PaCa-2 cells and in miR-135b -downregulated Panc-1 cells, compared with their respective controls, which presented with mainly full-length and inactivated caspase-3 and PARP proteins (Fig.   6j). [score:6]
Data are shown as the means ± SEM for at least three independent experiments Subsequently, RT-PCR and western blotting revealed that miR-135b mimics markedly reduced the mRNA and protein levels of BMAL1, whereas miR-135b inhibitors increased BMAL1 expression in PC cells (Fig.   2e). [score:5]
As expected, miR-135b mimics significantly inhibited the luciferase activity of the BMAL1 3′-UTR in a dose -dependent manner, whereas miR-135b inhibitors induced a drastic increase in luciferase activity (Fig.   2b). [score:5]
a, b GSEA comparing PC patients with high miR-135b expression (red) against patients with low miR-135b expression (blue) in TCGA data set (median split, n = 178). [score:5]
Data are shown as the means ± SEM for at least three independent experimentsSubsequently, RT-PCR and western blotting revealed that miR-135b mimics markedly reduced the mRNA and protein levels of BMAL1, whereas miR-135b inhibitors increased BMAL1 expression in PC cells (Fig.   2e). [score:5]
We found that compared with a significant reduction in the activity of the wild-type controls, miR-135b upregulation in HEK 293T cells or PC cells did not affect the activity of mutant BMAL1 3′-UTR (Fig.   2d) that demonstrated the specificity of this inhibition. [score:5]
As BMAL1 depletion is associated with uncontrolled cell division and proliferation [33], we explored the mechanism by which BMAL1 is downregulated in PC, and we identified that hsa-miR-135b directly binds to the 3′-UTR of BMAL1. [score:5]
Fig. 4 a, b GSEA comparing PC patients with high miR-135b expression (red) against patients with low miR-135b expression (blue) in TCGA data set (median split, n = 178). [score:5]
Hua K miR-135b, upregulated in breast cancer, promotes cell growth and disrupts the cell cycle by regulating LATS2Int. [score:5]
Collectively, these results validated that BMAL1 suppresses miR-135b-regulated PC progression. [score:4]
Dysregulation of the miR-135b–BMAL1 axis impairs clock-controlled tumour suppression. [score:4]
We found that ectopic YY1 expression significantly increased the luciferase activity of the wild-type miR-135b promoter; however, when mutations were present in binding site 1 or site 2, this enhancement was abrogated (Fig.   7f). [score:4]
Additional qRT-PCR analysis showed that miR-135b was the only upregulated miRNA in cohort 1 PC tissues (Supplementary Fig.   S1). [score:4]
Meanwhile, the downregulation of miR-135b in Panc-1 cells rescued the diurnal fluctuations of BMAL1, PER1/2, CRY1/2 and RORA (Fig.   3b). [score:4]
Intriguingly, we observed that the transcription factor Yin Yang 1 (YY1) directly activated the promoter of miR-135b and formed a ‘miR-135b–BMAL1–YY1’ loop, whose expression was related to the clinicopathological factors, survival outcomes and chemoresponsiveness in patients with PC. [score:4]
Further, MIA PaCa-2 and Panc-1 cells with manipulated miR-135b and/or BMAL1 expressions were used in in vitro gain-of-function and loss-of-function studies (Supplementary Fig.   S4 shows the transfection efficiency). [score:3]
Notably, the pancreatic expression of miR-135b rhythmically oscillated and was roughly in anti-phase with that of BMAL1. [score:3]
We subsequently explored why miR-135b was aberrantly overexpressed in PC. [score:3]
As anticipated, miR-135b overexpression promoted the growth of subcutaneous xenografts generated by MIA PaCa-2 cells, whereas BMAL1 reintroduction sensitised the cell response to GEM therapy and substantially reduced the sizes and weights of tumours (Fig.   6c, d). [score:3]
These data demonstrated that miR-135b -mediated BMAL1 suppression markedly facilitates GEM resistance in PC cells. [score:3]
Importantly, the PC gene set was also correlated with high miR-135b -expressing patients (Fig.   4a, b). [score:3]
In addition, we identified YY1 as both an upstream activator of miR-135b and a downstream target of BMAL1. [score:3]
Pearson Correlation analysis was used to determine the relationship between the expression levels of miR-135b, BMAL1 and YY1. [score:3]
We then transfected miR-135b mimics/inhibitors with BMAL1 luciferase reporter constructs into MIA PaCa-2 and Panc-1 cells, which presented with the relatively lowest and highest levels of miR-135b, respectively, among the PC cell lines (Supplementary Fig.   S2). [score:3]
Collectively, these findings confirmed that miR-135b is a BMAL1 -targeting miRNA in PC. [score:3]
b Kaplan–Meier analysis of the correlation between miR-135b/BMAL1/YY1 expressions (mean split) and the OS times of 141 patients from TCGA cohort. [score:3]
f, g Correlation analysis of miR-135b and BMAL1 mRNA expressions in PC tissues from cohort 1 (55 cases, f) or TCGA cohort (178 cases, g). [score:3]
The Kaplan–Meier analysis revealed that patients with high miR-135b/low BMAL1/ high YY1 -expressing tumours had significantly shorter overall survival (OS) times (Fig.   8b; Supplementary Table  S8). [score:3]
These findings pave the way for the future use of miR-135b–BMAL1–YY1 signalling as a predictive biomarker for PC inception and progression, as a prognostic factor for patient survival outcome, and as a therapeutic target for the modulation of GEM sensitivity. [score:3]
Enrichment plots of GSEA showed that the gene signatures of cell proliferation, cell cycle, DNA replication and cycling genes, which are responsible for PC growth, and the gene signatures of cell migration, metastasis and epithelial–mesenchymal–transition (EMT), which are crucial for PC progression, were enriched in patients with high miR-135b expression. [score:3]
Data are shown as the means ± SEM for at least three independent experiments Having shown the direct regulation of BMAL1 by miR-135b, we next examined the influence of miR-135b on central circadian TTFLs within normal and malignant pancreatic epithelial cells. [score:3]
The percentage of miR-135b -expressing cells in three high-power fields of each individual sample was analysed. [score:3]
These observations clearly demonstrated the effects of miR-135b -mediated loss of circadian homoeostasis and gave convincing proof that a well-functioning time-keeping system is crucial for tumour suppression. [score:3]
g The level of miR-135b in PC cells transfected with YY1 expression vectors, shYY1 vectors or NCs was detected by qRT-PCR. [score:3]
The OS and progression-free survival (PFS) curves showed that high miR-135b and low BMAL1 expression were significantly correlated with poor survival outcomes (Fig.   8d). [score:3]
In conclusion, this study identifies the miR-135b–BMAL1–YY1 loop as a determinant of pancreatic circadian homoeostasis, and we propose that targeting this signalling pathway may be useful for PC management. [score:3]
Patients with high miR-135b/low BMAL1/high YY1 -expressing tumours presented with significantly shorter OS and PFS times and relatively unfavourable responses to GEM therapy. [score:3]
Luciferase constructs were generated by ligating oligonucleotides containing the wild-type or mutated putative target site of the BMAL1 3′-UTR into the pmirGLO vector (Promega) downstream of the luciferase gene; and the hsa-miR-135b promoter sequence with wild-type or mutated putative YY1 -binding sites was amplified from human genomic DNA and cloned into the pGL3 vector (Promega). [score:3]
f Relative luciferase activity of the wild-type or mutant putative binding sites of hsa-miR-135b promoter in MIA PaCa-2 and Panc-1 cells with (grey) or without (black) ectopic YY1 expression. [score:3]
e The mRNA and protein levels of BMAL1 in miR-135b mimics (70 nM)/inhibitors (100 nM)- or their respective controls -transfected PC cells. [score:3]
Strikingly, the gene signatures related to PC growth and metastasis were generally enriched in patients with high miR-135b and low BMAL1 expression. [score:3]
Specifically, the modulation of BMAL1 expression was found to be effective against this miR-135b -mediated anti-apoptotic activity (Fig.   6g–i). [score:3]
β-actin was used as internal control protein We subsequently explored why miR-135b was aberrantly overexpressed in PC. [score:3]
By targeting this core clock gene, miR-135b significantly enhanced PC cell proliferation and invasion. [score:3]
Having shown the direct regulation of BMAL1 by miR-135b, we next examined the influence of miR-135b on central circadian TTFLs within normal and malignant pancreatic epithelial cells. [score:3]
In situ hybridisation (ISH) analysis showed that miR-135b staining was significantly stronger in PC tissues than in normal controls and was positively correlated with AJCC stage, T classification, histological grade and the level of CA19-9. Meanwhile, IHC analysis showed that BMAL1 was negatively associated with miR-135b expression and aggressive parameters of PC, whereas the YY1 level was positively related to pT stage and tumour differentiation (Fig.   8a; Supplementary Table  S7). [score:3]
h Quantitative RT-PCR analysis of miR-135b and BMAL1 expressions in HPDE6c7 and Panc-1 cells at 4 h intervals over a 24-h period. [score:3]
The expression sequence of miR-135b was as follows: 5′-TATGGCTTTTCATTCCTATGTGA-3′. [score:3]
The expression levels of miR-135b and BMAL1 in cohort 1 were negatively correlated (55 cases, Pearson r = –0.481, P < 0.001; Fig.   2f), and this result was further validated by bioinformatics analysis using high throughput RNA-sequencing data from The Cancer Genome Atlas (TCGA) PC cohort (178 cases, Pearson r = –0.251, P < 0.001; Fig.   2g, Supplementary Table  S5). [score:3]
Finally, we established the translational potential of the miR-135b–BMAL1–YY1 loop. [score:3]
Multivariate Cox regression analysis adjusted for AJCC stage, T and N classifications, histological grade, tumour location, gender and age of patients consistently confirmed that the expression level of the miR-135b–BMAL1–YY1 loop was a prognostic indicator for OS in PC patients (Fig.   8c). [score:3]
In PC samples from two independent cohorts of patients, similar results were obtained showing that YY1 was positively correlated with miR-135b expression (cohort 1: 55 cases, Pearson r = 0.502, P < 0.001; Fig.   7h; TCGA cohort: 178 cases, Pearson r = 0.173, P = 0.021; Fig.   7i). [score:3]
High levels of miR-135b and YY1 are correlated with advanced TNM stage and poor histological differentiation, whereas low BMAL1 expression is linked to the aggressive features of PC. [score:3]
Identification of miR-135b as a negative regulator of BMAL1. [score:2]
The role of miR-135b in regulating the pancreatic epithelial clockwork. [score:2]
Overall, our findings demonstrated that dysregulation of the miR-135b–BMAL1 axis confers GEM resistance to PC cells. [score:2]
Then, wound-healing and transwell assays were conducted, and we found that the ectopic expression of miR-135b in MIA PaCa-2 cells led to significantly faster wound closure and higher invasive activity than these parameters in the control cells; however, these enhancements were partially reversed after BMAL1 restoration (Fig.   5c, e). [score:2]
miR-135b–BMAL1 deregulation promotes PC tumourigenesis and chemoresistance. [score:2]
These observations clearly suggested that miR-135b is an important regulator of the pancreatic time-keeping system. [score:2]
These data indicated that YY1 activated miR-135b by directly binding to its promoter. [score:2]
YY1 forms a regulatory loop with miR-135b and BMAL1. [score:2]
Identification of hsa-miR-135b as a negative regulator of BMAL1. [score:2]
Thus, on the basis of the above findings, we speculated that identifying miR-135b–BMAL1–YY1 signalling activity may be useful for predicting GEM responsiveness. [score:1]
The intensity of miR-135b staining was scored according to the following standards: 0–1 (no staining), 1–2 (weak staining), 2–3 (medium staining) and 3–4 (strong staining). [score:1]
d Schematic diagram illustrating two putative YY1 -binding sites and the respective mutants in the hsa-miR-135b promoter. [score:1]
Kaplan–Meier survival curves with log-rank test were used for prognostic evaluation in patients stratified by miR-135b/BMAL1/YY1 expression levels. [score:1]
Clinical significance of the miR-135b–BMAL1–YY1 loop in human PC. [score:1]
miR-135b serves as an oncomiR in various cancers; 34– 37 however, there is currently a lack of data on its role in PC. [score:1]
As shown in Fig.   2h, in both the synchronised normal and malignant pancreatic cells, the relative abundance of miR-135b was marked by rhythmic variations (P < 0.05) that were roughly in anti-phase with those of BMAL1. [score:1]
Then, PGL3 vectors containing the wild-type or mutant putative binding sites of the miR-135b promoter were constructed and transfected into MIA PaCa-2 and Panc-1 cells. [score:1]
d Relative luciferase activity of the wild-type or mutant BMAL1 3′-UTR in HEK 293T cells (left) and in human PC cells (right) transfected with miR-135b mimics or NCs. [score:1]
Thus, miR-135b, BMAL1 and YY1 form a feedback loop that modulates the pancreatic clockwork and, when desynchronized, may drive and exacerbate local circadian disturbance. [score:1]
The circadian parameters including period, phase, and amplitude were analysed by the JTK_CYCLE algorithm and were shown in Supplementary Table  S6 To probe the miR-135b–BMAL1 axis -associated biological pathways in an unbiased manner, we performed a gene set enrichment analysis (GSEA) in the TCGA PC cohort. [score:1]
Meanwhile, the IC [50] values for GEM in Panc-1/Vector/Scramble, Panc-1/Vector/shBMAL1, Panc-1/Anti-miR-135b/Scramble and Panc-1/Anti-miR-135b/shBMAL1 cells were 8.61, 24.37, 2.12 and 8.56 μM, respectively (Fig.   6b). [score:1]
Then, the in vivo relevance of miR-135b–BMAL1 to chemotherapy was tested using xenograft mo dels. [score:1]
a Representative ISH anaysis of miR-135b and IHC analyses of BMAL1 and YY1 in normal pancreas and in PC tissues with different histological grades. [score:1]
As the BMAL1 gene oscillates rhythmically in vivo, we explored whether miR-135b also harbours self-sustained oscillation by assessing its temporal pattern in HPDE6c7 and Panc-1 cells at 4-h intervals over a 24-h period. [score:1]
Effects of the miR-135b–BMAL1 axis on PC cell proliferation, migration and invasion. [score:1]
Our bioinformatics analyses unravelled an altered network of intracellular biological pathways associated with miR-135b–BMAL1 misalignment. [score:1]
Co-transfection of the predicted miRNA mimics with luciferase reporter constructs containing wild-type BMAL1 3′-UTR into HEK 293T cells revealed that miR-142, miR-448, miR-135a and miR-135b significantly reduced luciferase activity (Fig.   2a). [score:1]
c A human BMAL1 3′-UTR fragment containing the wild-type or mutant miR-135b -binding sequence was cloned downstream to the luciferase reporter gene. [score:1]
We first evaluated the expression levels of miR-135b, BMAL1 and YY1 in the cohort 1 samples. [score:1]
YY1 forms a feedback loop with miR-135b and BMAL1. [score:1]
GSEA was performed to gain insight into the biological pathways involved in PC pathogenesis through the miR-135b–BMAL1 axis. [score:1]
Equal amounts of miR-135b and/or BMAL1-manipulated MIA PaCa-2 cells (c, d) or Panc-1 cells (e, f) were subcutaneously implanted on the back-side of each nude mouse. [score:1]
These bioinformatics results consistently demonstrated that the miR-135b–BMAL1 axis has an important role in PC pathogenesis. [score:1]
miR-135b perturbs the clock machinery in pancreatic duct epithelial cells. [score:1]
Effects of the miR-135b–BMAL1 axis on chemoresistance of PC cells. [score:1]
Sensitivity enhanced ISH kits (MK10301, Boster Biological Technology, Wuhan, China), and LNA -modified and DIG -labelled miR-135b probes (miRCURY LNA Detection probe, Exiqon) were used. [score:1]
The silencing sequence of miR-135b was as follows: 5′-TCACATAGGAATGAAAAGCCATA-3′. [score:1]
analysis revealed that miR-135b significantly reduced the fraction of apoptotic MIA PaCa-2 cells during GEM treatment, whereas silencing miR-135b in Panc-1 cells led to a sharp increase in programmed cell death. [score:1]
Biological implications of the miR-135b–BMAL1 axis in PC. [score:1]
Fig. 8 a Representative ISH anaysis of miR-135b and IHC analyses of BMAL1 and YY1 in normal pancreas and in PC tissues with different histological grades. [score:1]
The miR-135b–BMAL1–YY1 loop holds predictive and prognostic values in patients with PC. [score:1]
As shown in Fig.   6a, the IC [50] values of MIA PaCa-2/Vector/pcDNA and MIA PaCa-2/miR-135b/pcDNA cells towards GEM were 1.11 and 9.79 μM, respectively, and were sharply reduced to 0.34 (MIA PaCa-2/Vector/Lv-BMAL1) and 3.05 (MIA PaCa-2/miR-135b/Lv-BMAL1) μM, respectively after BMAL1 restoration. [score:1]
Taken together, these findings suggested that YY1 transcriptionally activates miR-135b and forms a feedback loop with miR-135b–BMAL1 signalling. [score:1]
c– f Xenograft mo dels were used to test the in vivo relevance of the miR-135b–BMAL1 axis and GEM resistance. [score:1]
In this study, we identified hsa-miR-135b as an oncogenic miRNA that promotes tumourigenesis and chemoresistance in human PC. [score:1]
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[+] score: 241
Other miRNAs from this paper: mmu-mir-135b
Here, we demonstrated that miR-135b-5p expression was downregulated in human osteoblastoma tissues, which was associated with Ppm1e upregulation.-5p silenced Ppm1e and potently inhibited osteoblastoma cell proliferation in vitro and in vivo. [score:11]
If Ppm1e is the direct target of miR-135b-5p, knockdown of Ppm1e shall also inhibit osteoblastoma cell proliferation. [score:7]
miR-135b-5p upregulation correlates with Ppm1e upregulation and AMPKα1 de-phosphorylation in human osteoblastoma tissues. [score:7]
miR-135b-5p was upregulated in Vec-miR-135b -expressing tumors (Figure 6F). [score:6]
Therefore, miR-135b-5p expression was in-effective when Ppm1e was depleted, suggesting that Ppm1e is the direct target of this Anti-oncomir. [score:6]
On the other hand, miR-135b-5p's target, Ppm1e mRNA, was upregulated in osteoblastoma tissues (Figure 1B). [score:6]
qRT-PCR results in Figure 2A demonstrated that expression level of miR-135b-5p was indeed significantly upregulated in the stable cells (“L1/L2/L3”). [score:6]
As demonstrated, miR-135b-5p expression level was significantly downregulated in osteoblastoma tissues (“Tumor”, n = 10), as compared to that in the surrounding normal bone tissues (“Normal”, n = 10) (Figure 1A). [score:5]
Stable MG-63 cells (A– C) or U2OS cells (D– F), expressing miR-135b vector (“Vec-miR-135b”, three lines each, “L1/L2/L3”), microRNA control (“mi-C”) vector or the empty vector (“Vec”, pSuper-puro), were subjected to qRT-PCR assay to test expression of miR-135b-5p (A and D) and Ppm1e mRNA (B and E); Listed proteins in above cells were tested by Western blot assay, Ppm1e protein expression (vs. [score:5]
Figure 2Stable MG-63 cells (A– C) or U2OS cells (D– F), expressing miR-135b vector (“Vec-miR-135b”, three lines each, “L1/L2/L3”), microRNA control (“mi-C”) vector or the empty vector (“Vec”, pSuper-puro), were subjected to qRT-PCR assay to test expression of miR-135b-5p (A and D) and Ppm1e mRNA (B and E); Listed proteins in above cells were tested by Western blot assay, Ppm1e protein expression (vs. [score:5]
Remarkably, miR-135b-5p -induced MG-63 cell proliferation inhibition was almost reversed by AMPKα1 knockdown or mutation (Figure 5C and 5D). [score:5]
Intriguingly, we here proposed that Ppm1e is the primary target of miR-135b in mediating its inhibition against osteoblastoma cells. [score:5]
First, we tested expression of miR-135b-5p, the Ppm1e -targeting miRNA [19, 20], in human osteoblastoma tissues. [score:5]
Above results showed that forced -expression of miR-135b-5p activated AMPK signaling and inhibited osteoblastoma cell proliferation. [score:5]
Above results have shown that forced -expression of miR-135b-5p silenced Ppm1e and inhibited osteoblastoma cell proliferation. [score:5]
Yet, unlike control cells (See Figure 3), forced -expression of miR-135b-5p failed to further inhibit the proliferation of Ppm1e-silneced cells (Figure 4G). [score:5]
As shown in Figure 5A, AMPKα1 shRNA knockdown or T172A mutation almost completely blocked AMPK activation (p-AMPKα1 at Thr-172) in vec-miR-135b -expressing cells. [score:5]
Tumor growth curve results in Figure 6A demonstrated that growth of U2OS tumors was largely inhibited after expressing Ppm1e shRNA or Vec-miR-135b. [score:5]
U2OS tumor growth in SCID mice is inhibited after expressing Ppm1e shRNA or miR-135b-5p. [score:5]
Remarkably, forced -expression of miR-135b-5p failed to further inhibit the proliferation of Ppm1e-silneced cells. [score:5]
These results demonstrate that forced miR-135b-5p expression inhibits osteoblastoma cell proliferation. [score:5]
In the current study, we showed that miR-135b-5p expression silences Ppm1e, which activates AMPK to inhibit osteoblastoma cell proliferation. [score:5]
These results together imply that Ppm1e is the direct and primary target of miR-135b-5p in mediating its actions in osteoblastoma cells. [score:4]
In order to block AMPK activation, AMPKα1 shRNA [20, 27] or a dominant negative mutation of AMPKα1 (T172A, Flag-tagged) [20, 27] was introduced to vec-miR-135b -expressing MG-63 cells (“L1”, see Figure 2). [score:4]
shRNA -mediated knockdown of Ppm1e mimicked miR-135b-5p's actions, and similarly induced AMPK activation and inhibited osteoblastoma cell proliferation. [score:4]
Expressions of miR-135b-5p and Ppm1e were examined. [score:3]
AMPKα1 shRNA knockdown or mutation abolishes miR-135b-5p's actions against osteoblastoma cells. [score:3]
Expression of miR-135b-5p, as expected, was unchanged in Ppm1e-silenced cells (Figure 4C). [score:3]
Recent studies have identified a Ppm1e -targeting miRNA: miR-135b-5p [19, 20]. [score:3]
Above results confirmed significant AMPK activation in miR-135b-expressed cells. [score:3]
Forced -expression of miR-135b. [score:3]
As shown in Figure 4F, the level of miR-135b-5p was again elevated after expression of vector. [score:3]
Estimated daily tumor growth (in mm [3] per day) was also significantly lower in Ppm1e shRNA- or Vec-miR-135b -expressing tumors (Figure 6B). [score:3]
As demonstrated, Ppm1e mRNA was indeed depleted in Ppm1e shRNA- or Vec-miR-135b -expressing tumors (Figure 6E). [score:3]
These results suggest that activation of AMPK is required for miR-135b-5p -induced MG-63 cell proliferation inhibition. [score:3]
Thus, we therefore exogenously expressed miR-135b vector in the two MG-63 lines with Ppm1e shRNA (“shPpm1e-1” and “shPpm1e-1”). [score:3]
Stable MG-63 cells with miR-135b vector (“Vec-miR-135b”, “L1”) or the empty vector (“Vec”, pSuper-puro) were further constructed with AMPKα1 shRNA (“shAMPKα1”), scramble control shRNA (“sh-C”) or a dominant negative mutation of AMPKα1 (T172A, Flag-tagged, ““dnAMPKα1”), expressions of listed proteins were shown (A); miR-135b-5p mRNA expression was tested by qRT-PCR assay (B); Cell proliferation was tested by the CCK-8 assay (C) and BrdU ELISA assay (D). [score:3]
Further, forced -expression of miR-135b-5p in MG-63 cells also dramatically decreased the number of colonies (Figure 3B). [score:3]
In cultured human osteoblastoma cells (MG-63 and U2OS lines), forced -expression of miR-135b depleted Ppm1e, leading to profound AMPK activation (AMPKα1 phosphorylation at Thr-172). [score:3]
In the three lines (“L1/L2/L3”) of miR-135b-5p -expressing U2OS cells, CCK-8 OD (Figure 3D), colony formation (Figure 3E) and BrdU incorporation ELISA OD (Figure 3F) were all decreased. [score:3]
Next, a miR-135b expression vector (“Vec-miR-135b”, a gift from Dr. [score:3]
Figure 5Stable MG-63 cells with miR-135b vector (“Vec-miR-135b”, “L1”) or the empty vector (“Vec”, pSuper-puro) were further constructed with AMPKα1 shRNA (“shAMPKα1”), scramble control shRNA (“sh-C”) or a dominant negative mutation of AMPKα1 (T172A, Flag-tagged, ““dnAMPKα1”), expressions of listed proteins were shown (A); miR-135b-5p mRNA expression was tested by qRT-PCR assay (B); Cell proliferation was tested by the CCK-8 assay (C) and BrdU ELISA assay (D). [score:3]
Ppm1e expression (Figure 5A) and miR-135b-5p level (Figure 5B) were unchanged in AMPKα1-silenced or -mutant cells. [score:3]
BrdU ELISA OD in these miR-135b-5p -expressing cells was also decreased (Figure 3C). [score:3]
The scramble shRNA control (“sh-C”) didn't change Ppm1e expression, miR-135b-5p level, AMPK activation and MG-63 cell proliferation (Figure 4A–4E). [score:3]
U2OS cells, stably expressing Ppm1e shRNA (“-1”, see Figure 4), Vec-miR-135b (“L1”, see Figure 2) or empty vector (“Vec”, see Figure 2), were inoculated into the severe combined immunodeficient (SCID) mice via s. c. injection. [score:3]
Importantly, AMPKα1 shRNA knockdown or dominant negative mutation almost abolished miR-135b-5p -induced actions in osteoblastoma cells. [score:3]
Once again, forced -expression of miR-135b-5p in three U2OS cell lines (“L1/L2/L3”) (Figure 2D) led to Ppm1e depletion (Figure 2E and 2F) and significant AMPK activation (Figure 2F). [score:3]
Introduction of the non-sense microRNA control (“mi-C”) showed no effect on expressions of miR-135b, Ppm1e and p-AMPKα1 (Figure 2A–2F). [score:3]
We conclude that miR-135b silences Ppm1e to provoke AMPK activation and inhibit osteoblastoma cell proliferation. [score:3]
Via selection by puromycin, a total of three stable MG-63 cell lines (“L1/L2/L3”) expressing Vec-miR-135b were established. [score:3]
Collectively, miR-135b-5p expression causes Ppm1e silence and AMPK activation in human osteoblastoma cells. [score:3]
The expression of mature miR-135b was tested by the TaqMan microRNA assay as described [47]. [score:2]
miR-135b-5p expression in the resulting stable cells was tested by qRT-PCR assay. [score:2]
Figure 4Stable MG-63 cells with listed Ppm1e shRNA (“shPpm1e-1” or “shPpm1e-1”) or scramble shRNA control (“sh-C”), as well as the parental control MG-63 cells (“Ctrl”) were subjected to qRT-PCR assay to test expression of Ppm1e mRNA (A) and miR-135b-5p (C); Listed proteins in above cells were also tested, and blot data were quantified (B). [score:2]
MG-63 cells with listed Ppm1e shRNA (“shPpm1e-1” or “shPpm1e-1”) were also transfected with miR-135b vector (“Vec-miR-135b”), expression of miR-135b-5p was tested afterwards (F); Cell proliferation was examined by CCK-8 assay (G). [score:2]
Stable MG-63 cells with listed Ppm1e shRNA (“shPpm1e-1” or “shPpm1e-1”) or scramble shRNA control (“sh-C”), as well as the parental control MG-63 cells (“Ctrl”) were subjected to qRT-PCR assay to test expression of Ppm1e mRNA (A) and miR-135b-5p (C); Listed proteins in above cells were also tested, and blot data were quantified (B). [score:2]
The potential effect of miR-135b-5p on osteoblastoma cell growth in vivo was tested. [score:1]
Therefore, further studies will be needed to explore the downstream signalings of AMPK that mediate miR-135b's actions in osteoblastoma cells. [score:1]
Remarkably, we imply that AMPK activation could be responsible for miR-135b-5p -mediated anti-osteoblastoma cell activity. [score:1]
Cell Counting Kit-8 (CCK-8) cell proliferation assay results in Figure 3A clearly showed that proliferation of MG-63 cells with miR-135b vector (three lines, “L1/L2/L3”, see Figure 2) was significantly inhibited, as compared to cells with non-sense microRNA control (“mi-C”) or empty vector (Figure 3A). [score:1]
Three million of U2OS cells (per mouse), with Ppm1e shRNA or “Vec-miR-135b”, were inoculated subcutaneously (s. c. ) into the flanks of the mice. [score:1]
The miR-135b pSuper-puro-GFP vector (“Vec-miR-135b”) and miR-control (“miR-C”) vector were provided by Dr. [score:1]
On the other hand, miR-135b-3p level in above cells was quite low (Data not shown). [score:1]
Expressions of miR-135b-5p (A, qRT-PCR assay), Ppm1e mRNA (B, qRT-PCR assay) and listed proteins (C–D,) in ten (10) different human osteoblastoma tissues (“Tumor”) and surrounding normal bone tissues (“Normal”) were tested. [score:1]
Stable U2OS cells, with Ppm1e shRNA (“-1”), Vec-miR-135b (“L1”) or empty vector (“Vec”), were inoculated into the SCID mice via s. c. injection. [score:1]
These results imply that miR-135b-5p could possibly be a novel anti-cancer microRNA (“anti-oncomir”) in osteoblastoma. [score:1]
Figure 6Stable U2OS cells, with Ppm1e shRNA (“-1”), Vec-miR-135b (“L1”) or empty vector (“Vec”), were inoculated into the SCID mice via s. c. injection. [score:1]
Figure 1Expressions of miR-135b-5p (A, qRT-PCR assay), Ppm1e mRNA (B, qRT-PCR assay) and listed proteins (C–D,) in ten (10) different human osteoblastoma tissues (“Tumor”) and surrounding normal bone tissues (“Normal”) were tested. [score:1]
At the end of the experiments (Week-7), the weight of tumors with Ppm1e shRNA or Vec-miR-135b was also much lower than “Vec” control tumors (Figure 6C). [score:1]
Based on the results above, we speculated that miR-135b-5p could possibly be invalid in Ppm1e -depleted cells. [score:1]
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3
[+] score: 225
For example, the targets of the mir-135 family, a family that was up-regulated in the vestibule, were enriched in a set of proteins down-regulated in this tissue; and the targets of mir-205, a miRNA that exhibited a higher expression in the cochlea, were depleted in a set of proteins also up-regulated in the cochlea. [score:16]
We noted that targets of mir-135 were marginally enriched in the set of all proteins up-regulated in the cochlea (P = 0.075), and a statistically significant enrichment was found only when considering genes up-regulated in the cochlea only on the protein level (i. e., genes without significant mRNA changes between the two tissues, P = 0.047). [score:9]
Thus, for six miRNA families – mir-135, mir-205, mir-142-3p, mir-15/16, mir-218 and mir-24 - we obtained evidence for their functional relevance in the inner ear on two levels: (a) the miRNAs were differentially expressed between the two tissues; and (b) their predicted targets were differentially expressed in a manner consistent with the currently accepted mo del of miRNA regulation. [score:8]
miR-135b regulates PSIP1-P75 expression by inhibition of translation. [score:8]
miR-135b down-regulates PSIP1-P75 (red) expression in the vestibular hair cells while its expression remains relatively high in the cochlear hair cells. [score:8]
miR-135b was up-regulated 4-fold in the vestibule and miR-124a was up-regulated 8-fold in the cochlea (Figure 1C). [score:7]
analysis revealed a reduction in miR-135b expression and similar Psip1 mRNA expression level in both the cells transfected with the shRNA targeting miR-135b and transfected with the anti-miR negative control (Figure 4D; n = 3, P = 0.66; Student's t-test). [score:7]
The most notable miRNA for which we identified translationally repressed targets was miR-135b, the miRNA with the highest differential expression in our dataset. [score:7]
The miRNAs with the greatest differential expression were miR-135b (expressed 2.5 times higher in the vestibule) and miR-124a (expressed 4 times higher in the cochlea). [score:7]
These results indicate that miR-135b down-regulates the expression of PSIP1-P75 protein but does not affect the mRNA levels. [score:6]
miR-135b down-regulates PSIP1-P75 protein expression. [score:6]
Transient co -expression of this vector with a miR-135b expressing vector revealed that miR-135b reduced luciferase expression levels by approximately 40% (Figure 4E; as compared to a mutated Luc- Psip1-P75-3′UTR control. [score:6]
The overall effect of miR-135b in the inner ear is summarized in Figure 5. In this scheme, we propose a unique mechanism by which miR-135b down-regulates PSIP1-P75 expression in the vestibular hair cells, whereas it remains relatively high in the cochlea. [score:6]
For further study, we selected miR-135b and miR-205, for which miRNA target enrichment or depletion, respectively, were detected only at the protein expression level and therefore would not have been identified by analyzing transcript data alone. [score:5]
We chose to focus on miR-135b due to its intriguing cell specific expression pattern and its high differential expression between the vestibule and cochlea. [score:5]
miR-135b (blue) is expressed in the vestibular hair cells, whereas no expression is detected in the cochlear hair cells. [score:5]
shRNA targeting miR-135b (X-miR-135b, oligoengine) or an anti-miR negative control were transfected to Cal51 cells that naturally express miR-135b. [score:5]
The P52 isoform of PSIP1 does not have a target site within its 3′UTR and is therefore not a potential target of miR-135b. [score:5]
0018195.g005 Figure 5 miR-135b (blue) is expressed in the vestibular hair cells, whereas no expression is detected in the cochlear hair cells. [score:5]
miR-135b and miR-124a, the miRNAs with the highest differential expression in the array, exhibited significant differential expression between the cochlear and vestibular sensory epithelia in the validation (4-fold and 8-fold, respectively). [score:5]
Cal51 cells were transfected with either a plasmid expressing shRNA targeting miR-135b or an anti-miR negative control. [score:5]
Semi-quantitative western blot analysis exhibited a 10-fold increase in PSIP1-P75 protein abundance in the cells expressing shRNA targeting miR-135b (Figure 4E; as compared to transfection with an anti-miR negative control. [score:4]
Furthermore, our data predict that miR-135b regulates three targets in the vestibule, PSIP1-P75 (also called LEDGF) and PC4, two interacting transcriptional coactivators [25], [26] and ARCN1, a subunit of the coat protein I (COPI) complex required for intracellular trafficking [27]. [score:4]
Furthermore, we demonstrated the translational regulation of PC4 and SFRS1 interacting protein 1 (PSIP1), a transcriptional coactivator previously unknown to function in the inner ear, by miR-135b. [score:4]
The distinct expression pattern of miR-135b most probably points to a specific regulation mechanism that exists in the vestibular hair cells but not in the cochlear hair cells. [score:4]
Significantly, the identification of a bona-fide miRNA-target pair, miR-135b and PSIP1-P75, predicts a role for this pair in inner ear cell survival, protection against stress, differentiation, cell fate determination and development, and may explain differences in regeneration of vestibular vs. [score:4]
Each of the targets contains a single sequence complementary to the miR-135b seed within their 3′ UTR. [score:3]
Interestingly, the efficiency by which miR-135b silences PSIP1-P75, as identified by our in vitro analysis, is much higher than previously expected for targets with only a single binding site for a miRNA seed [2]. [score:3]
Expression patterns for miR-135b (C) and miR-205 (D) were consistent with the miRNA array analysis. [score:3]
Briefly, MCF-7 cells were grown in 24-well plates and transfected using JetPEI reagent (Polyplus transfection™) with either 5 ng of Luc- Psip1-P75-3′UTR or a mutated control, 5 ng Renilla and 0.5 µg of miR-135b (miRNA expression vector obtained as a gift from Reuven Agami, [61]). [score:3]
Of the two, only P75 contains a sequence within its 3′ UTR with the potential of being targeted by miR-135b. [score:3]
Consistent with the miRNA microarray results, miR-135b exhibited specific expression in vestibular organs hair cells. [score:3]
In situ hybridization demonstrated specific expression of miR-135b in vestibular hair cells. [score:3]
The spatial expression pattern of miR-135b and miR-205 in the inner ear of P0 mice was determined using in situ hybridization (ISH; Figure 3), and suggested differences in miRNA function across the cochlea and vestibular organs. [score:3]
Of the three putative targets of miR-135b, we chose to further validate the interaction with the P75 isoform of PSIP1. [score:3]
For miR-135b inhibitor treatment, Cal51 cells were transfected using JetPEI reagent (Polyplus transfection™) with a pSUPER-GFP plasmid encoding either shRNAs against mouse miR-135b or negative control shRNA (Oligoengine). [score:3]
Therefore, it is likely that miR-135b is transcribed as part of Lemd1, leading to a similar expression pattern. [score:3]
Cal51, breast carcinoma, cells were found to express high levels of miR-135b, and relatively low levels of PSIP1-P75. [score:3]
For two miRNAs, miR-135b and miR-205, we localized their cell specific expression in the inner ear using in situ hybridization. [score:3]
Unlike miR-135b, these miRNAs are expressed both in the cochlear and vestibular hair cells. [score:3]
To better understand miR-135b function in the inner ear, we studied its spatial expression. [score:3]
Distinct spatial expression patterns of miR-135b and miR-205 in the newborn mouse inner ear. [score:3]
For miR-135b regulation analysis in shRNA transfected Cal51 cells, transfected cells were lysed and frozen at -80°C. [score:2]
Taken together, our results demonstrate the regulation of PSIP1-P75 by miR-135b in vestibular hair cells. [score:2]
By this means, miR-135b might serve as a cellular effector, involved in regulating the differences between the cochlear and vestibular hair cells and thus contributes to their distinct cell identities and maintaining their specific functions. [score:2]
We hypothesize that PSIP1-P75 and miR-135b might play a role in regulating these processes in the cochlear hair cells, whereas in vestibular hair cells they are modulated by other miRNA. [score:2]
For miR-135b regulation analysis in shRNA transfected Cal51 cells, transfected cells were spun-down and frozen at -80°C. [score:2]
Due to the similarity between miR-135b and miR-135a, we predict that miR-135a also regulates PSIP1-P75 in the vestibular system. [score:2]
miR-135b is located within the first intron of the LEM domain containing 1 (Lemd1) gene. [score:1]
In addition, miR-135b was detected in the neurons of the vestibular and spiral ganglia. [score:1]
Schematic representation of a possible role of miR-135b in the inner ear. [score:1]
In vitro analysis further proved an interaction between miR-135b and PSIP1-P75. [score:1]
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4
[+] score: 197
Further, forced -expression of miR-135b-5p downregulates Ppm1e to activate AMPK signaling, which subsequently inhibits LPS -induced TNFα production in human monocytes. [score:8]
Intriguingly, mRNA and protein expressions of Ppm1e were sharply downregulated following miR-135b-5p expression (Figure 1C). [score:8]
Together, these results demonstrate that miR-135b-5p targets and downregulates Ppm1e in human macrophages. [score:6]
The results of this study showing AMPK activation by miR-135b-5p via downregulating Ppm1e provide a new strategy to activate AMPK and to inhibit LPS inflammatory responses. [score:6]
Expression of miR-135b-5p downregulates Ppm1e in human macrophages. [score:6]
Collectively, these results indicate that miR-135b-5p activates AMPK to inhibit LPS -induced ROS production, NFκB activation and TNFα mRNA expression. [score:5]
2”) or scramble control shRNA (“sh-C”), and stably cells were established; Expressions of listed proteins in these cells were tested by Western blot assay A. ; Cells were treated with LPS (100 ng/mL) for 24 hours, TNFα production was tested B. miR-135b-5p expressing U937 cells were constructed with dominant negative AMPKα (T172A, “dnAMPKα”, GFP-tagged) or empty vector (“pSuper-puro”), stably cells were established; Expressions of listed proteins in these cells were tested by Western blot assay C. ; LPS -induced TNFα production was also examined D. Experiments in this figure were repeated for three times, and similar results were obtained. [score:5]
We found that microRNA-135b-5p (“miR-135b-5p”) selectively targets Ppm1e's untranslated regions (UTRs, 3′). [score:5]
Thus, we propose that miR-135b-5p activates AMPK to attenuate LPS -induced ROS production, and subsequent NFκB activation, which then inhibit TNFα mRNA expression and production. [score:5]
We thus expressed miR-135b-5p in Ppm1e-shRNA expressing U937 cells. [score:5]
miR-135b-5p inhibits LPS -induced ROS production, NFκB activation and TNFα mRNA expression. [score:5]
Importantly, miR-135b-5p expression failed to further inhibit LPS -induced TNFα production in the Ppm1e-silenced cells (p > 0.05, Figure 3F). [score:5]
Significantly, ELISA results in Figure 4D showed that AMPKα mutation almost nullified miR-135b's inhibition on TNFα production by LPS. [score:4]
2”) were utilized to knockdown AMPKα in miR-135b-5p -expressing U937 cells (Figure 4A). [score:4]
ELISA assay results in Figure 2B showed that LPS -induced TNFα protein secretion was largely inhibited in miR-135b-5p -expressing U937 cells. [score:4]
Above results showed that miR-135b-5p downregulated this phosphatase in human macrophages. [score:4]
If AMPK activation is the primary reason of miR-135b-5p -induced action against TNFα production by LPS, AMPK inhibition should then abolish miR-135b's activity. [score:3]
This could be one key reason of TNFα inhibition by miR-135b-5p. [score:3]
These results indicate that Ppm1e is likely the primary target of miR-135b-5p in mediating its actions against LPS. [score:3]
Such effects by miR-135b-5p were again almost abolished with AMPKα knockdown or mutation (Figure 5B-5D). [score:3]
Lipofectamine 2000 was applied to transfect mutant AMPKα or the vector to miR-135b -expressing U937 cells. [score:3]
As a result, miR-135b-5p -induced AMPK activation, or AMPKα/ACC phosphorylation, was dramatically inhibited (Figure 4A). [score:3]
If, as we proposed, Ppm1e is the primary target of miR-135b-5p in mediating its actions in monocytes, miR-135b-5p should possibly be invalid in Ppm1e -depleted cells. [score:3]
Net, we introduced a dominant -negative mutant of AMPKα (T172A) into miR-135b-5p -expressing U937 cells [26]. [score:3]
Figure 1 A. miR-135b-5p complements Ppm1e's 3′ untranslated regions (UTRs, position 517-524) (A). [score:3]
In the present study, we showed that miR-135b-5p activated AMPK signaling to inhibit LPS -induced ROS production and subsequent NFκB activation. [score:3]
Notably, the non-sense control mi -RNA (“miR-C”) showed no effect on expression of miR-135b-5p (Figure 1B and 1D) or Ppm1e (Figure 1C and 1E). [score:3]
As shown in Figure 2A, the level of phosphorylated (“p”) AMPKα (Thr-172) and its major downstream acetyl-CoA carboxylase (ACC, Ser-79) was significantly increased in miR-135b-5p -expressing U937 cells, indicating profound AMPK activation. [score:3]
As shown in Figure 5A, treatment of LPS in U937 cells induced significant ROS production, which was largely attenuated with miR-135b-5p expression (Figure 5A). [score:3]
Expression of miR-135b-5p B and D. and Ppm1e mRNA (C and E., left panels) were tested by quantitative real-time PCR (“RT-qPCR”) assay; Ppm1e protein expression was examined by Western blot assay (C, right panels). [score:3]
miR-135b-5p activates AMPK signaling and inhibits LPS -induced TNFα production in human macrophages. [score:3]
A. miR-135b-5p complements Ppm1e's 3′ untranslated regions (UTRs, position 517-524) (A). [score:3]
miR-135b-5p activates AMPK and inhibits LPS -induced TNFα production in human macrophages. [score:3]
Such effects by miR-135b-5p were almost abolished with AMPK inhibition. [score:3]
Remarkably, AMPKα shRNAs almost abolished miR-135b-5p -induced inhibition of TNFα production (Figure 4B). [score:3]
miR-135b-5p expressing U937 cells were constructed with scramble control shRNA (“sh-C”), AMPKα shRNA (“shAMPKα”, No. [score:3]
Forced miR-135b-5p expression. [score:3]
Intriguingly, LPS -induced NFκB activation, tested by Western blot assay of pIKKα/β (Ser176/180) (Figure 5B) and p65 DNA -binding assay (Figure 5C) [9], was significantly inhibited with miR-135b-5p expression. [score:3]
The experiments were also repeated in another human macrophage cell line: THP-1. Two stably THP-1 cell lines (“Line-1” and “Line-2”) expressing miR-135b-5p (Figure 1D) were established. [score:3]
As described, an expression vector (“pSuper-neo”) integrating miR-135b-5p [25] was transfected to U937 macrophages. [score:3]
These two sets of results clearly indicate that miR-135b-5p inhibits LPS -induced TNFα production through activating AMPK. [score:3]
Similar results were also obtained in THP-1 macrophages, where miR-135b-5p induced significant AMPK activation and inhibited LPS -induced TNFα production (Data not shown). [score:3]
We therefore analyzed ROS level and NFκB signaling in human macrophages with/our miR-135b-5p expression. [score:3]
Notably, Ppm1e shRNA didn't change miR-135b-5p expression (Figure 3B). [score:3]
miR-135b-5p expressing U937 cells were constructed with AMPKα shRNA (“shAMPKα-No. [score:3]
AMPK activation is required for miR-135b-5p's inhibition on LPS -induced TNFα production. [score:3]
Real-time qPCR (“RT-qPCR”) assay analyzing miR-135b-5p level confirmed the phenotype of two stably cell lines, with high level of miR-135b-5p expression (Figure 1B). [score:2]
AMPKα or mutation almost abolished miR-135b-5p's ROS scavenging activity (Figure 5A). [score:2]
RT-qPCR assay results confirmed miR-135b-5p over -expression (Figure 3D) in the Ppm1e-silence U937 cells (Figure 3E). [score:2]
miR-135b-5p expression in the stable cells was tested by the RT-qPCR assay. [score:2]
Figure 3 in human macrophagesStably U937 cells expressing Ppm1e shRNA (“shPpm1e-1” or “shPpm1e-2”, with non-overlapping sequences) or scramble control shRNA (“sh-C”) were subjected to Western blot assay of listed proteins A. or RT-qPCR assay of miR-135b-5p and Ppm1e mRNA B. Above cells were treated with LPS (100 ng/mL) or medium control (“C”) for 24 hours, TNFα production was tested by ELISA assay C. U937 cells with shPpm1e-1 were also transfected with miR-135b-5p construct, and stably cells were again established; miR-135b-5p D. and Ppm1e mRNA E. expressions were tested by RT-qPCR assay. [score:1]
Intriguingly, miR-135b-5p -induced anti-oxidant function also relies on AMPK activation (Figure 5A). [score:1]
In line with these findings, we show that AMPK activation by miR-135b-5p decreased LPS -induced ROS production and NFκB activation. [score:1]
U937 or THP-1 cells were transfected with miR-135b-5p construct (0.10 μg/mL of each well) through the Lipofectamine 2000 protocol (Invitrogen, Shanghai, China) for 24 hours. [score:1]
Stably U937 cells expressing Ppm1e shRNA (“shPpm1e-1” or “shPpm1e-2”, with non-overlapping sequences) or scramble control shRNA (“sh-C”) were subjected to Western blot assay of listed proteins A. or RT-qPCR assay of miR-135b-5p and Ppm1e mRNA B. Above cells were treated with LPS (100 ng/mL) or medium control (“C”) for 24 hours, TNFα production was tested by ELISA assay C. U937 cells with shPpm1e-1 were also transfected with miR-135b-5p construct, and stably cells were again established; miR-135b-5p D. and Ppm1e mRNA E. expressions were tested by RT-qPCR assay. [score:1]
In another words, miR-135b-5p was in-effective against TNFα production in AMPKα -depleted cells (Figure 4B). [score:1]
Therefore, the potential effect of miR-135b-5p on LPS -induced TNFα protein was then tested. [score:1]
Via neomycin selection, two stably U937 lines (“Line-1” and “Line-2”) with miR-135b-5p were established. [score:1]
First, miR-135b-5p indeed complements UTRs (position 517-524) of Ppm1e (Figure 1A, which is also seen in the recent study [25]). [score:1]
Above results suggest that AMPK activation is required for miR-135b-5p -induced actions in monocytes. [score:1]
Human U937 or THP-1 macrophages were transfected with miR-135b-5p construct or non-sense control microRNA (“miR-C”), and stable cells were established via neomycin selection. [score:1]
miR-135b-5p resulted in over 60% reduction of TNFα production (Figure 2B). [score:1]
Stably U937 macrophages expressing miR-135b-5p (two lines, “Line-1/-2”) or non-sense control microRNA (“miR-C”) were subjected to Western blot assay of phosphorylated- (“p”) and regular AMPKα and ACC A. Above cells were treated with LPS (100 ng/mL) or medium control (“C”) for 24 hours, TNFα content in conditional medium was tested by ELISA assay B. Experiments in this figure were repeated for three times, and similar results were obtained. [score:1]
Figure 2Stably U937 macrophages expressing miR-135b-5p (two lines, “Line-1/-2”) or non-sense control microRNA (“miR-C”) were subjected to Western blot assay of phosphorylated- (“p”) and regular AMPKα and ACC A. Above cells were treated with LPS (100 ng/mL) or medium control (“C”) for 24 hours, TNFα content in conditional medium was tested by ELISA assay B. Experiments in this figure were repeated for three times, and similar results were obtained. [score:1]
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5
[+] score: 196
Here we showed that miR-135b expression increased NADPH activity and inhibited Dex -induced oxidative stress in osteoblastic cells, and such effects were almost reversed by AMPK knockdown or mutation. [score:7]
miR-135b expressing OB-6/hFOB1.19 cells cells were constructed with AMPKα shRNA, dominant negative AMPKα (“dn-AMPKα-flag”, T172A) or the scramble control shRNA (“Scr shRNA”), expressions of listed proteins in these cells were tested by Western blots (A, for OB-6 cells); miR-135b and Ppm1e mRNA expressions were also tested (B, qRT-PCR assay, for OB-6 cells). [score:6]
Forced expression of microRNA-135b downregulates Ppm1e but activates AMPK signaling in human osteoblastic cells. [score:6]
Ppm1e shRNA (“-1”) -expressing OB-6 cells were transfected with miR-135b expressing construct, expressions of miR-135b E. and Ppm1e mRNA F. were tested by qRT-PCR assay, these cells were also treated with or without Dex (1 μM) for 24 hours, cell viability G. and apoptosis H. were shown. [score:6]
We showed that miR-135b expression downregulated Ppm1e to activate AMPK, which protects osteoblastic cells from Dex. [score:6]
In summary, our preclinical results indicate that miR-135b expression downregulates Ppm1e to activate AMPK signaling and protect osteoblastic cells from Dex. [score:6]
Figure 4miR-135b expressing OB-6/hFOB1.19 cells cells were constructed with AMPKα shRNA, dominant negative AMPKα (“dn-AMPKα-flag”, T172A) or the scramble control shRNA (“Scr shRNA”), expressions of listed proteins in these cells were tested by Western blots (A, for OB-6 cells); miR-135b and Ppm1e mRNA expressions were also tested (B, qRT-PCR assay, for OB-6 cells). [score:6]
Importantly, AMPK knockdown or dominant negative mutation almost blocked AMPK activation (p-AMPK/p-ACC) in miR-135b -expressing OB-6 cells (Figure 4A). [score:5]
Through searching miRNA databases, we found that microRNA-135b (“miR-135b”) targets the 3' untranslated regions (UTRs) of Ppm1e. [score:5]
Figure 1 A. microRNA-135b (“miR-135b”) targets the 3' untranslated regions (UTRs, position 517-524) of human Ppm1e (Figure 1A). [score:5]
A. microRNA-135b (“miR-135b”) targets the 3' untranslated regions (UTRs, position 517-524) of human Ppm1e (Figure 1A). [score:5]
First, through searching multiple microRNA database, we found that microRNA-135b (“miR-135b”) targets the 3' untranslated regions (UTRs, Position 517-524) of human Ppm1e (Figure 1A). [score:5]
Here we showed that miR-135b selectively targets the AMPK phosphatase Ppm1e [21], whose expression induced a profound AMPK activation in osteoblastic cells. [score:5]
Such an effect by Dex was largely inhibited by expression of miR-135b (Figure 4G). [score:5]
These results indicate that miR-135b upregulation and Ppm1e depletion could be the reason of AMPK activation in patients' necrotic femoral head tissues. [score:4]
Upregulation of miR-135b in patients' osteonecrosis tissues. [score:4]
Significantly, miR-135b expression or Ppm1e shRNA knockdown, which also activated AMPK signalings, significantly protected osteoblastic cells from Dex. [score:4]
Expressions of miR-135b (B and E) and Ppm1e mRNA (C and F) were tested by quantitative real-time PCR (“qRT-PCR”) assay; Expression of listed proteins in these cells were tested by (D and G). [score:4]
Significantly, miR-135b level was increased in human necrotic femoral head tissues, which was correlated with Ppm1e downregulation and AMPK activation. [score:4]
AMPK knockdown or mutation abolishes miR-135b -induced cytoprotection in osteoblastic cells. [score:3]
We also expressed miR-135b in the Ppm1e-silenced OB-6 cells. [score:3]
Significantly, expression of miR-135b failed to further offer cytoprotection against Dex in the Ppm1e-silenced cells (Figure 3G and 3H). [score:3]
The results above demonstrated that AMPK was activated in miR-135b -expressing osteoblastic cells. [score:3]
qRT-PCR results in Figure 3E confirmed miR-135b over -expression in Ppm1e-shRNA (“-1”)-containing OB-6 cells. [score:3]
Expression of miR-135b-5p was also significantly increased (Data not shown). [score:3]
AMPKα shRNA or a dominant negative AMPKα (dn-AMPKα, T172A) was introduced to the miR-135b -expressing OB-6 cells. [score:3]
In another words, OB-6 cells with miR-135b expression were resistant to Dex (Figure 2A-2C). [score:3]
Similarly, stable hFOB1.19 cells expressing miR-135b (Figure 1E) showed depleted Ppm1e (Figure 1F and 1G) but increased AMPK activation (p-AMPKα/p-ACC, Figure 1G). [score:3]
Additionally, we showed that AMPK knockdown or mutation abolished miR-135b -induced cytoprotection against Dex in osteoblastic cells, supporting a critical function of AMPK activation in miR-135b's actions in osteoblastic cells. [score:3]
Significantly, AMPK knockdown or dominant negative mutation almost completely abolished miR-135b -induced anti-oxidant ability (Figure 4G). [score:3]
Forced miR-135b expression. [score:3]
These results suggest that forced expression of miR-135b indeed protects osteoblastic cells from Dex. [score:3]
Thus, miR-135b activates AMPK-NADPH signaling to possibly inhibit Dex -induced oxidative stress and osteoblastic cell death. [score:3]
Forced expression of microRNA-135b protects osteoblastic cells from Dex. [score:3]
Together, these results suggest that forced expression of miR-135b decreases Ppm1e, but activates AMPK signaling in cultured human osteoblastic cells. [score:3]
These results suggest that Ppm1e is likely the primary target of miR-135b in mediating its cytoprotective effect in osteoblastic cells. [score:3]
Remarkably, expression of miR-135b significantly attenuated above cytotoxic effects by Dex in OB-6 cells (Figure 2A-2C). [score:3]
We next established a miR-135b expressing construct (see Methods) and stably transfected it into osteoblastic cells. [score:3]
Pre-miR-135b (see its sequence in studies [33, 34]) was sub-cloned into pSuper-neo (OligoEngine, Seattle, WA) to generate miR-135b expression vector. [score:3]
We wanted to know if Ppm1e is the primary target of miR-135b in mediating its cytoprotective effect in osteoblastic cells. [score:3]
AMPK shRNA knockdown or dominant negative mutation almost completely blocked NADPH activity increase by miR-135b (Figure 4H). [score:3]
Therefore, Ppm1e could be the primary target of miR-135b in mediating its cytoprotective effect. [score:3]
Expectably, miR-135b or Ppm1e mRNA expression was not changed in these cells (Figure 4B). [score:3]
qRT-PCR assay results in Figure 1B showed that miR-135b was indeed over-expressed in the stable OB-6 cells after transfection. [score:2]
miR-135b and Ppm1e mRNA levels were tested (A, qRT-PCR assay), Ppm1e protein expression and AMPK activation (p-AMPK/p-ACC) were also tested (B,). [score:2]
Similar in hFOB1.19 cells, AMPKα shRNA or dominant negative mutation largely attenuated miR-135b -induced cytoprotection against Dex (Figure 4E and 4F). [score:2]
Expressions of miR-135b B. and Ppm1e mRNA C. were also shown (qRT-PCR assay) in above tissues. [score:2]
miR-135b expression in the resulting stable cells was tested by the qRT-PCR assay. [score:2]
As compared to control cells, hFOB1.19 cells expressing miR-135b were protected from Dex, showing improved viability (Figure 2D), decreased cell apoptosis (Figure 2E) and cell death (Figure 2F). [score:2]
Based on these results, we conclude that AMPK activation mediates miR-135b -induced cytoprotection against Dex in osteoblastic cells. [score:1]
The miR-135b construct (0.10 μg/mL of each well) was transfected to the osteoblastic cells via Lipofectamine 2000 protocol (Invitrogen, Shanghai, China). [score:1]
Intriguingly, after Ppm1e was silenced, miR-135b was not able to further protect osteoblastic cells from Dex. [score:1]
In another words, miR-135b was no longer cytoprotective in AMPK -depleted or AMPK-mutated cells. [score:1]
Therefore, we suggest that miR-135b activates AMPK to exert anti-oxidant activity and to protect osteoblastic cells from Dex. [score:1]
Next, we wanted to know if AMPK activation was the reason of miR-135b-meidated cytoprotection in osteoblastic cells. [score:1]
Interestingly, in the necrotic tissues, the level of miR-135b was also increased (Figure 5B), and the Ppm1e (protein and mRNA) level was decreased (Figure 5C and 5D). [score:1]
Here we found that miR-135b attenuated Dex -induced osteoblastic cell death and apoptosis. [score:1]
Importantly, p-AMPKα (Thr-172) and p-acetyl-CoA carboxylase (p-ACC, Ser-79) levels were largely enhanced in the miR-135b-expresising OB-6 cells (Figure 1D), indicating AMPK signaling activation. [score:1]
Human osteoblastic OB-6 cells B-D. or hFOB1.19 cells E-G. were transfected with microRNA-135b (“miR-135b”) or non-sense control microRNA (“miR-C”), and stable cells were established. [score:1]
Here, we found that miR-135b -induced NADPH activity increase required AMPK activation (Figure 4H). [score:1]
Consequently, miR-135b -induced cytoprotection against Dex was almost nullified in OB-6 cells (Figure 4C and 4D). [score:1]
Thus, it will be interesting to test the possible effect of miR-135b against GC -induced osteoporosis and/or osteonecrosis in vivo. [score:1]
We also repeated those experiments in hFOB1.19 cells, and similar anti-Dex effects by miR-135b were noticed (Figure 2D-2F). [score:1]
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6
[+] score: 161
As the mechanism responsible of miR-135b in human GBM cells, we found whose mRNA and protein expression is downregulated in U87R cells with endogenous upregulation of miR-135b expression. [score:11]
Here, we demonstrated miR-135b could direct suppress GSK3β expression at mRNA and protein level in human GBM cells. [score:6]
In addition, we examined the expression levels of miR-135b and GSK3β in human GBM specimens and found that miR-135b was significantly upregulated in primary GBM tissues. [score:6]
As for mechanism, we found GSK3β is a direct target of miR-135b, and ectopic GSK3β expression significantly reverses radioresistance in U87R cells. [score:6]
To analyze the molecular mechanisms of miR-135b involvement in radioresistance of human GBM cells, online softwares TargetScan was used to search for potential miR-135b target genes. [score:5]
The ability of miR-135b to target multiple tumour suppressors indicates an indiscriminate ability to promote tumour progression and metastasis. [score:5]
The correlation analysis showed that the expression of miR-135b was negatively correlated with the expression of GSK3β proteins in normal brain and GBM tissues (p = 0.07, Figure 5D). [score:5]
It's shown that addition of in vitro-produced miR-135b suppressed the luciferase activity of the 3′-UTR of GSK3β upon co-transfection of the luciferase vector (wild-type, mutant) with the in vitro-produced microRNAs (miR-135b mimic or scramble control) into U87 cells and vitro-produced microRNAs (miR-135b inhibitor or scramble control) into U87R cells (Figure 3F). [score:5]
In the present study, compared to its parental cell line U87, we show miR-135b is upregulated in radioresistant human GBM cell line U87R, which targets Glycogen synthase kinase 3 beta (GSK3β). [score:5]
A miR-135b antagomir (Antago-135), which is able to functionally suppress miR-135b, effectively reduced metastasis and tumour burden, which suggests the potential for the development of miR-135b antagonists for lung cancer therapy [12]. [score:4]
miR-135b is upregulated in U87R cells and contributes radioresistance in U87 cells. [score:4]
miR-135b directly targets GSK3β. [score:4]
GSK3β is a direct target of miR-135b in U87R cells. [score:4]
To determine whether the association of miR-135b or GSK3β expression with IR resistance is clinically relevant, we examined the expression levels of miR-135b or GSK3β in a cohort of 30 GBM tissues and 30 normal brain tissues using qRT-PCR (miR-135b and GSK3β) and immunohistochemistry (GSK3β) assays. [score:4]
In order to explore the mechanisms responsible for radioresistance of human GBM, we established a radioresistant human GBM cell line U87R and found miR-135b was upregulated in U87R cells. [score:4]
To assess whether GSK3β is a direct target of miR-135b, we subcloned the full-length 3′-UTR of GSK3β into the luciferase reporter vector. [score:4]
The association of miR-135b or GSK3β expression with IR resistance is clinically relevant. [score:3]
miR-135b has also been reported to induce Wnt signaling pathway by the suppression of APC in colorectal cancers [26] and lung cancer [12]. [score:3]
More importantly, we found that elevated expression of miR-135b and GSK3β are associated with recurrent GBM patients who underwent IR therapy. [score:3]
These results strongly demonstrated the specificity of miR-135 targeting GSK3β. [score:3]
This inhibition was abolished when the seed sequences of the miR-135b were mutated in the Luc-mut vector. [score:3]
Furthermore, we examined the miR-135b or mRNA expression of GSK3β in tumor tissues from patients who received IR treatment. [score:3]
Figure S1 qRT-PCR measured the miR-135 expression levels in U87 cells transfected with miR-135b mimics as well as U87R cells transfected with miR-26a inhibitors. [score:3]
qRT-PCR data showed that miR-135b was dramatically elevated in the recurrent tumors compared to the primary tumors after IR treatment, but the mRNA expression of GSK3β was dramatically declined in the recurrent tumors compared to the primary tumors after IR treatment (p<0.01, Figure 5E, F), indicating that the glioma cells with high expression of miR-135b or GSK3β were more resistant to the IR and more susceptible to death, whereas the glioma cells with low miR-135b or GSK3β levels were more sensitive to IR. [score:3]
So we inhibited miR-135b function with miR-135b specific inhibitor in U87R cells to further characterize its biological function (Figure 2B). [score:3]
Moreover, GSK3β protein level in U87R cells significantly increased after miR-135b inhibitor transfection. [score:3]
Conversely, the ectopic expression of miR-135b in U87 cells was achieved by miR-135b mimics transfection (Figure 2C). [score:3]
miR-135b mimics, miR-135b inhibitor and relative controls were purchased from Ambion. [score:3]
Figure S2 Micro-photographs after 48 h of transfection with miR-135b inhibitor and the corresponding controls. [score:3]
Using miRNA specific RT-qPCR, we found miR-135b expression was about 5.17 fold higher in U87R cells than that in U87 cells (Figure 2A). [score:3]
However, miR-135b overexpression obviously enhanced the radioresistance of U87 cells. [score:3]
measured the LZTS1 protein (a target gene of miR-135b) expression levels in U87 cells transfected with miR-135b mimics. [score:3]
A predict potential target of miR-135b, and GSK3β with critically conserved binding site was selected for further molecular and functional confirmation (Figure 3A). [score:3]
miR-135b targets GSK3β. [score:3]
But miR-135b was found to be significantly upregulated in these GBM specimens compared with normal brain tissues (p<0.01, Figure 5C). [score:3]
Previous evidence has indicated that miR-135b is overexpressed in lung [12], colon [19], [20], breast [21] and prostate [22] cancers, which strongly suggests a general role in different types of cancers. [score:3]
0108810.g002 Figure 2 (A) miR-135b expression increases in U87R cells, compared to U87 cells. [score:2]
Expectedly, miR-135b knockdown significantly increased the radiosensitivity of U87R cells. [score:2]
A Luc-mut vector in which the first seven nucleotides complementary to the miR-135b seed-region were mutated by site-directed mutagenesis (Stratagene) served as a mutant control. [score:2]
miR-135b contributes to radioresistance in U87 cells. [score:1]
Other researchers have found that miR-135b may also contribute to mediate NPM-ALKassociated oncogenicity in large-cell lymphomas [23]. [score:1]
In this study, we show, for the first time, that miR-135b functions as a novel mediator of IR resistance in glioma cells. [score:1]
Our findings suggest that miR-135b and GSK3β are potential biomarkers to estimate the sensitivity of human GBM to radiotherapy and help to developing rational therapeutic strategies. [score:1]
Together, these results suggest that miR-135b or GSK3β is of clinical significance as a mediator of IR resistance. [score:1]
miR-135b enhances radioresistance of U87 cells. [score:1]
Luc-wt, Luc-mut, and Luc-ctrl were co -transfected within vitro-produced miR-135b into U87 cells. [score:1]
Here, we firstly demonstrate miR-135b is involved in the radioresistance in human GBM cells. [score:1]
Conversely, GSK3β protein level in U87 cells decreased after miR-135b mimics transfection (Figure 3D, E). [score:1]
To investigate the co-relation between miR-135b and GSK3β, the expression of GSK3β at mRNA and protein levels were detected in U87 and U87R cells. [score:1]
0108810.g003 Figure 3 (A) Schematic of predicted miR-135b site in the 3′UTR of GSK3β mRNA, which broadly conserved among vertebrates. [score:1]
Thus, our findings suggest miR-135b-GSK3β axis will be valuable biomarkers for the radiosensitivity and related interference will be worthy therapeutic strategies for human GBM patients. [score:1]
To the best of our knowledge, we will explore the detailed mechanism responsible for miR-135b-GSK3β axis in modulating radiosensitivity in human GBM cells. [score:1]
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7
[+] score: 64
The results indicate that miR-95 was up-regulated by P [4] and reached maximal levels with E [2]+P [4], while miR-96 and miR-135b were both down-regulated by E [2] or P [4] (Figure 1A). [score:7]
Moreover, the overexpression of miR-96 or miR-135b individually or combine, two downregulated miRNAs during endometrial decidualization, has an impact on IGFBP-1 secretion, suggesting that precise and coordinated miRNA regulation is required for a correct decidualization response. [score:7]
It has been previously demonstrated that miR-96 and miR-135b regulate the expression of their target genes, FOXO1 and HOXA10 [26], although their role in this particular process has not been studied. [score:6]
Interestingly, the transcription factor HOXA10, which is essential for female fertility and decidualization, at least in mice [41], [42], is a validated target of miR-135b [43], one of the miRNAs which was down-regulated during our in vitro decidualization assay. [score:5]
miR-96 and miR-135b Regulates FOXO and HOXA10 Expression and IGFBP-1 Secretion. [score:4]
Remarkably, HOXA10 mutant mice are infertile and show a diminished decidualization response, while low HOXA10 levels in humans are associated with endometriosis, which is partly due to an up-regulation in miR-135b levels [41], [43], [60]. [score:4]
Next, we examined the effect of individual ovarian steroids on the regulation of miR-95, this being the most up-regulated miRNA in our in vitro decidualization assay, as well as miR-135 b and miR-96. [score:4]
Noteworthily, some of the differentially expressed miRNAs identified in our study during decidualization have been found to be misregulated in endometriosis (e. g., miR-9, miR-135b and miR-141) [56], [17], [43], preeclampsia (e. g., miR-155, miR-183 and miR-181b) [18], [19], [57] or endometrial cancer (e. g., the miR-200 family and miR-96) [54], [58], [59]. [score:4]
Increased levels of miR-96 and miR-135b using miRNAs mimics in hESCs under the decidualization treatment reduced the expression of FOXO1 and HOXA10, respectively and decrease IGFPB-1 secretion levels (Figure 2A and B). [score:3]
miRNA Mimic Transfection and in vitro Decidualization To overexpress miR-96 and miR-135 b we used the corresponding miRNA mimics and control sequences from SABiosciences. [score:3]
0041080.g001 Figure 1 A, miR-95, miR-135b and miR-96 expression levels by quantitative PCR in hESCs treated with 17β-estradiol (E), progesterone (P), or both (E+P), for 9 days. [score:3]
A, miR-95, miR-135b and miR-96 expression levels by quantitative PCR in hESCs treated with 17β-estradiol (E), progesterone (P), or both (E+P), for 9 days. [score:3]
Moreover, our results indicate that HOXA10 is regulated by miR-135b and its levels are significantly lower after Dicer knockdown in decidualized hESCs. [score:3]
To overexpress miR-96 and miR-135 b we used the corresponding miRNA mimics and control sequences from SABiosciences. [score:3]
We have selected miR-96 and miR-135b, two miRNAs that decrease their expression during stromal differentiation (Table 1), to evaluate in more detail their function during endometrial decidualization. [score:1]
A, Relative FOXO1 and HOXA10 mRNA levels quantified by RT-qPCR in control or miR-96 and miR-135b transfected mimics in decidualized hESCs 48 h and 72 h after decidual treatment. [score:1]
miR-96 and miR-135b role during endometrial decidualization. [score:1]
The efficiency of miRNA overexpression (more than 100 fold change compared to control, data not shown) was confirmed by RT-qPCR using specific miR-96 and miR-135 b primers from SABiosciences. [score:1]
0041080.g002 Figure 2 A, Relative FOXO1 and HOXA10 mRNA levels quantified by RT-qPCR in control or miR-96 and miR-135b transfected mimics in decidualized hESCs 48 h and 72 h after decidual treatment. [score:1]
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8
[+] score: 62
Remarkably, exogenous expression of miR-135b-5p induced Ppm1E downregulation, AMPK activation, and proliferation inhibition in AGC cells. [score:8]
Forced miR-135b-5p expression similarly induced AMPK activation (p-AMPKα1, Thr-172) and mTORC1 (p-S6K1) inhibition (Figure 5E, results were quantified). [score:5]
Exogenous expression of miR-135b-5p leads to Ppm1E depletion, AMPK activation, and proliferation inhibition in AGC cells. [score:5]
Together, we show that exogenous expression of miR-135b-5p causes Ppm1E depletion, AMPK activation, and proliferation inhibition in AGC cells. [score:5]
Exogenous expression of miR-135b-5p causes Ppm1E depletion, AMPK activation, and proliferation inhibition in AGC cells. [score:5]
Remarkably, as shown in Figure 5A, miR-135b-5p level was dramatically downregulated in human gastric cancer tissues. [score:4]
Meanwhile, miR-135b-5p expression also inhibited AGC cell survival and proliferation, which were again tested by the (Figure 5F) and BrdU ELISA assay (Figure 5G), respectively. [score:4]
Here we found that miR-135b-5p was significantly downregulated in human gastric cancer tissues and cell lines. [score:4]
Expression of miRNA-135b-5p and Ppm1E in above cells was always tested. [score:3]
AGC cells, expressing miR-135b-vector or the miR-control vector (“miR-Ctrl”) were subjected to qRT-PCR assay testing expression of miR-135b-5p (C) and Ppm1E mRNA (D) Listed proteins were also tested by, and blot data were quantiifed (E) Cells were also subjected to (F) and BrdU ELISA assay (G). [score:3]
Next, a miR-135b -expressing vector (a gift from Dr. [score:3]
miRNA-135b expression vector and non-sense miRNA-control (“miR-Ctrl”) vector were gifts from Dr. [score:3]
qRT-PCR assay results showed that AGS cells with miR-135b vector showed significantly increased miR-135b-5p expression (Figure 5C). [score:2]
The fresh human gastric cancer tissues (“Tumor”, n = 12) and the surrounding normal gastric tissues (“Normal”, n = 12), as well as gastric cancer cells (AGS, HGC-27, and SNU601) or GES-1 epithelial cells were subjected to qRT-PCR assay of microRNA-135b-5p (“miR-135b-5p”) expression (A and B). [score:2]
Figure 5The fresh human gastric cancer tissues (“Tumor”, n = 12) and the surrounding normal gastric tissues (“Normal”, n = 12), as well as gastric cancer cells (AGS, HGC-27, and SNU601) or GES-1 epithelial cells were subjected to qRT-PCR assay of microRNA-135b-5p (“miR-135b-5p”) expression (A and B). [score:2]
Very recent studies have characterized miR-135b-5p as the Ppm1E -targeting miRNA. [score:1]
microRNA-135b (miRNA-135b) transfection. [score:1]
Several very recent studies have characterized a Ppm1E -targeting miRNA: namely microRNA-135b-5p (“miR-135b-5p”) [34, 35]. [score:1]
Therefore, miR-135b-5p depletion could be the cause of/cells. [score:1]
[1 to 20 of 19 sentences]
9
[+] score: 44
In multiple human cancers, PTEN expressions are downregulated by miRNAs, which are shown in Table 1. Table 1 miRNA Locus Expression status Tumor type Reference MiR-21 17q23.1 Upregulated Colorectal, bladder, and hepatocellular cancer[112– 114] MiR-19a 13q31.3 Upregulated Lymphoma and CLL[87, 115] MiR-19b Xq26.2 Upregulated Lymphoma[87] MiR-22 17p13.3 Upregulated Prostate cancer and CLL[116, 117] MiR-32 9q31.3 Upregulated Hepatocellular carcinoma[118] MiR-93 7q22.1 Upregulated Hepatocellular carcinoma[119] MiR-494 14q32.31 Upregulated Cervical cancer[120] MiR-130b 22q11.21 Upregulated Esophageal carcinoma[121] MiR-135b 1q32.1 Upregulated Colorectal cancer[122] MiR-214 1q24.3 Upregulated Ovarian cancer[123] MiR-26a3p22.2 (MIR26A1)12q14.1(MIR26A2) Upregulated Prostate cancer[113] MiR-23b 9q22.32 Upregulated Prostate cancer[114] Abbreviations: CLL, chronic lymphocytic leukemia. [score:44]
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10
[+] score: 43
In order to explore the miR-21-5p, miR-135b target genes and their biological function, we explored target scan signatures using IPA, and constructed a miRNA-gene network which included miR-21-5p, miR-135b and pivotal target genes in Wnt and Hippo pathway. [score:7]
In the present study, we also identified several microRNAs (e. g. miR-21-5p, miR-135b, miR-34a-5p, miR-212-3p, miR-302b-3p and miR-302c-3p) which proved by previous studies of heart disease with consistently aberrant expression in ARVC patients. [score:5]
Potential targets for miR-21-5p and miR-135b were searched from Targetscan (http://www. [score:5]
was carried out on ABI StepOne Plus thermal cycler at the following conditions: 95 °C for 3 min, followed by 40 cycles of 95 °C for 10 s and 60 °C for 30 s. Reactions were performed in triplicate In order to identify miR-21-5p, miR-135b on Wnt pathway and Hippo pathway putative targets, the software Targetscan (http://www. [score:5]
Two target genes BMPR2 and TGFBR2 were noticed, which were regulated by miR-21 and miR-135b in common. [score:4]
Our analysis results suggested that both miR-21 and miR-135b and their target genes BMPR2, TGFBR2 and genes related to Wnt and Hippo pathway in the coordinate regulation of pathology of ARVC. [score:4]
Furthermore, we identify the putative targets of miR-21-5p and miR-135b and construct the network of these genes on Wnt and Hippo pathway. [score:3]
The most important finding of this study was that 21 significantly changed microRNAs were identified independently in diseased myocardium, miRNA-gene network of miR-21-5p and miR-135b involved in Wnt and Hippo pathway was established. [score:3]
In summary, we identified the signatures of 21 microRNAs in the heart tissue of ARVC patients with precise quantification, miR-21-5p and miR-135b may play important roles in the regulation of genes in Wnt and Hippo signal pathway resulting in the manifestation and phenotype of ARVC. [score:2]
By contrast, 10 of 11 significantly decreased microRNAs got optimal AUC, the AUC of these microRNAs were 0.936, 0.758, 0.946, 0.991, 0.992, 0.970, 0.837, 0.922, 0.838, 0.966 for miR-135b, miR-138-5p, miR-193b-3p, miR-302b-3p, miR-302c-3p, miR-338-3p, miR-491-3P, miR-575, miR-4254 and miR-4643 respectively (Fig. 6). [score:1]
Green circular nodes represent genes, and yellow circular nodes represent miR-21-5p or miR-135b. [score:1]
Green circular nodes represent genes, and yellow circular nodes indicate miR-21-5p and miR-135b. [score:1]
Among those microRNAs screened in our study, miR-21-5p and miR-135b have been reported to be involved in Wnt and Hippo pathway 28 29. [score:1]
The miRNA-gene network indicated the relationship between miR-21-5p/miR-135b and Wnt/Hippo pathway was built using the software Cytoscape. [score:1]
[1 to 20 of 14 sentences]
11
[+] score: 43
Besides these associations, published data also suggest a possible role in angiogenesis as shown for exosomal miR-135b derived from myeloma cells which enhances angiogenesis by targeting factor-inhibiting HIF-1 [49], or myeloma bone disease, with miR-135b, being upregulated in mesenchymal stromal cells from myeloma patients, being involved in an impaired osteogenic differentiation process [21]. [score:10]
Target gene signatures for miR-135a, miR-135b, miR-200a, and miR-200b significantly predict for EFS and OS with a high “target risk-score” delineating a group with inferior survival (Figure 3B, 3C). [score:5]
For miRNA-135b and miR-596, samples with a high expression were significantly more frequent in the particular high-risk group. [score:3]
Expression of three survival relevant miRNAs (miR-135a, miR-135b, and miR-596) was validated in ten cell lines and nine primary myeloma cell samples using qRT-PCR (miQPCR). [score:3]
In an ANOVA-mo del including the target risk-scores of miR-135a, miR-135b, miR-200a, miR-200b and the UAMS-score, the score of miR-200a remains significant (P =. [score:3]
Indeed, a high expression of miR-135a, miR-135b, and miR-596 is significantly associated with a t(4;14), miR-596 also with del13q14. [score:3]
B, C. By using miRWalk, predicted target genes for miR-135a, miR-135b, miR-200a, and miR-200b are significantly associated with (B1,C1) event-free survival (miR-135a, P <. [score:3]
Those remaining significant after correction for multiple testing, i. e. miR-135a, miR-135b, miR-200a, miR-200b, and miR-596, have recently been published to play a role in solid tumors and hematologic cancers, respectively, e. g. functioning as either oncogenes or tumor-suppressors and prognostic markers [44– 48]. [score:3]
Samples with a high miR-135b -expression were significantly more frequently classified as being high-risk. [score:3]
Corrected for multiple testing, five miRNAs remained significantly associated with EFS as continuous variable, i. e. miR-135a, miR-135b, miR-200a, miR-200b, and miR-596, and, but for miR-200b, also with OS (Figure 2). [score:1]
001; miR-135b, P =. [score:1]
Four miRNAs are significantly positively associated and correlate with the University of Medical Sciences (UAMS) 70-gene risk-score, i. e. miR-135b, miR-432*, miR-583, and miR-596 (Supplementary Table S4, S5). [score:1]
02), miR-135b (P =. [score:1]
001; miR-135b, P = ns (. [score:1]
02), miR-135b (P =. [score:1]
For the UAMS-score, miR-135b (P =. [score:1]
[1 to 20 of 16 sentences]
12
[+] score: 40
Of interest was the expression profile of the miR-96, miR-182 and miR-183 clusters as well as miR-135b, which were up-regulated in embryonic stem cells and whose expression decreased following differentiation. [score:8]
It has recently been shown that increased levels of miR-135a/b lead directly to decreased protein expression of the CC tumor suppressor APC via a direct binding interaction between miR-135b and APC mRNA 3' UTR [40]. [score:7]
Decreases in PDRM5 expression levels lead to increased expression of miR-135b presumably due to loss of recruitment of this chromatin-remo deling complex. [score:5]
Our analyses show that miR-135b was highly up-regulated in colon tumors. [score:4]
Mechanistically, PRDM5 recruits HDAC1 and G9a to the miR-135b promoter, and this chromatin remo deling results in decreased miR-135b expression. [score:3]
Tumor specimens showed highly significant and large fold change differential expression of the levels of 39 miRNAs including miR-135b, miR-96, miR-182, miR-183, miR-1, and miR-133a, relative to normal colon tissue. [score:3]
Although APC mutations are found in a majority of CC, deregulation of miR-135b may have an adverse effect on APC in the remainder of cases. [score:3]
Six of the miRNAs identified as highly significant to tumors (HS-29, miR-135b, miR-32, miR-33, miR-542-5p and miR-96) displayed higher expression in pMMR stage IV as compared to stage II tumors (p < 0.05 and fold change > 1.5) (Figure 3C). [score:2]
), miRNAs reported involved in colon tumorigenesis (miR-21 and miR-143) and miRNAs we observed to be altered in tumor specimens (miR-31, miR-135b, miR-30a-3p). [score:1]
Of interest, PDRM5 has been shown to bind to the promoter of miR-135b and PDRM5 silencing leads to increased levels of miR-135b. [score:1]
In this analysis, highly significant increases were observed in miR-135b in CC and the interaction between miR-135b and APC was identified as relevant. [score:1]
Figures Array data was validated by by qRT-PCR for 10 miRNAs (mir-1, miR-10b, miR-135b, miR-147, miR-31, miR-33, miR-503, miR-552, miR-592, miR-622). [score:1]
Importantly, miR-135b displayed the largest average change, a 4.55-fold increase. [score:1]
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[+] score: 36
In mice, mutations in the canonical CRC tumor suppressors Pten or Trp53 in the context of Apc loss greatly enhance the upregulation of miR-135b, with phosphoinositide 3-kinase (PI3K) and downstream FOXO1 and FOXO3A transcription factors confirmed as regulators of miR-135b (Valeri et al., 2014). [score:8]
In addition, given that the inhibition of miR-135b by specific antagomiRs greatly represses tumorigenesis in multiple mouse mo dels (Lin et al., 2013; Valeri et al., 2014), miR-135b might drive tumorigenesis by inhibiting multiple tumor suppressors (besides APC), such as TGFBR2 (Valeri et al., 2014). [score:7]
In the PI3K pathway, which is negatively regulated by PTEN, miR-135b is augmented by PI3K inhibition of FoxO transcription factors (FOXO1 and FOXO3A), which represses cell cycle progression. [score:4]
miR-135b- and miR-146b -dependent silencing of calcium-sensing receptor expression in colorectal tumors. [score:3]
MicroRNA-135b promotes lung cancer metastasis by regulating multiple targets in the Hippo pathway and LZTS1. [score:3]
SFRP4 and miR-135 expression is inversely correlated in multiple types of cancer (Jacobsen et al., 2013). [score:3]
The Wnt pathway is augmented by miR-135b, miR-21 and miR-155, and inhibited by miR-34a, miR-29b/c. [score:3]
Regulation of the adenomatous polyposis coli gene by the miR-135 family in colorectal cancer. [score:2]
In a likely positive feedback loop, miR-135b is transcriptionally activated by TCF4/β-catenin, and is dramatically increased in colonic tumors in mice with inactivated Apc and in sporadic human CRC (Valeri et al., 2014). [score:1]
The TGF-β pathway, which is important for repressing cellular proliferation and cell cycle progression is also antagonized by several miRNAs, including miR-17/106, miR-135b, and miR-20a through effects on TGFBR2 and SMAD4. [score:1]
The mechanism of TP53 -mediated repression of miR-135b, however, has yet to be explored. [score:1]
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[+] score: 34
Moreover, miR-135b suppressed the T-helper (Th) 2 master regulators STAT6 and GATA3, and inhibition of miR-135b suppressed the production of a Th17 pro-inflammatory cytokine, IL-17, by NPM/ALK cells. [score:8]
When analyzing the differences of miRNA regulation in ALK(+) versus ALK(−) cells following inactivation of STAT3 by shRNA -mediated ALK or STAT3 knockdown, miR-135b expression was most prominently altered, with a significant upregulation in ALK(+) ALCL cell lines and human primary ALK(+) ALCL samples compared to ALK(−) ALCL cells [30, 43]. [score:7]
MiR-135b targets the FOXO1 transcription factor in ALK(+) ALCL cell lines, which is critical as FOXO1 can promote the expression of the cell cycle inhibitors p21 and p27. [score:6]
Compared to ALK(−) ALCLs, miR-203, miR-135b, miR-886-5p/3p, miR-20b, miR-106a and miR-183 were significantly upregulated in ALK(+) ALCLs while others (miR-155, miR-181a, miR-210, miR-29a/b, miR-342-5p/3p, miR-369-3p miR-374a/b, miR-423-5p, miR-625, miR-205, miR-146a and miR-26a) were down-regulated (Table 1). [score:6]
This indicates that miR-135b -mediated Th2 suppression may lead to the ALCL immunophenotype overlapping with Th17 cells [30]. [score:3]
In accordance with the pro-angiogenic function of IL-17, miR-135b inhibition also reduced tumor angiogenesis and growth in vivo (Table 3). [score:3]
2.2.2. miR-135b. [score:1]
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[+] score: 34
Recently, Nezu et al. [27] identified miR-135b as a key regulator in myxoid liposarcoma, the overexpression of which would favor neoplastic invasion and metastasis through the direct suppression of thrombospondin 2 (THBS2), a protein that mediates cell-extracellular matrix interactions. [score:7]
When analyzing the expression levels of the microRNAs selected for validation (Table 2), we observed that 5 of them (hsa-miR-135b *, hsa-miR-592, hsa-miR-31, hsa-mir-135b, hsa-miR-944) have similar patterns of expression, i. e., there are statistically significant differences between the UAs and the control group. [score:5]
Based on this information, we consider that overexpression of miR-135b observed in ameloblastoma could be related to tumor growth and regulation of osteogenesis. [score:4]
When analyzing the expression of each miRNA, we observed statistically significant differences in 6 microRNAs among the UAs and the control group, (p <0.05) (hsa-miR-135b *, hsa-miR-592, hsa-miR-31, hsa-mir-135b, hsa-miR-944, hsa-miR-142-5p)). [score:3]
On the SA group, we observed differences in the expression between SAs and the control group in seven out of the 13 microRNAs selected for biological validation (p <0.05), (hsa-miR-135b *, hsa-miR- 489, hsa-miR-592, hsa-miR-369-5p, hsa-miR-31, hsa-mir-135b, hsa-miR-944). [score:3]
MicroRNA-135b acts as a tumor promoter by targeting the hypoxia-inducible factor pathway in genetically defined mouse mo del of head and neck squamous cell carcinoma. [score:2]
MicroRNAs with a differential expression in both SA and UA when compared to the control group are the microRNA miR-135b, miR-135b *, miR-31, miR-592 and miR-944. [score:2]
There are also several studies [26, 27] that linked deregulation of miR-135b with the progression of some malignant neoplasms, such as squamous cell carcinoma of the head and neck. [score:2]
After applying the inclusion criteria (|FC| <0.2 or> 5 and p adjusted <0.05), as previously mentioned, biological validation was performed by RT-qPCR of the 13 differently regulated miRNAs (hsa-miR-9, hsa-miR-135b*, hsa-miR-194*, hsa-miR-489, hsa-miR-592, hsa-miR-369-5p, hsa-miR-876-5p, hsa-miR-31, hsa-miR-135b, hsa-miR-211, hsa-miR-944, hsa-miR-142-5p, hsa-miR-455-3p), in an independent set of 46 samples corresponding to 19 SA, 8 UA and 19 controls. [score:2]
It has been previously described [24] that miR-135b is a regulator of mineralization in the process of osteoblastic stem cell differentiation. [score:2]
In addition, a serum increase of miR-135b was recognized in patients with multiple myeloma who present bone lesions, a finding that could help to identify these patients [25]. [score:1]
Furthermore, Jin et al. [28] linked miR-135b with the stimulation of osteosarcoma recurrence and lung metastasis via Notch and Wnt/β-Catenin signaling. [score:1]
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[+] score: 32
One hundred seven human placenta samples were analyzed for the expression of candidate miRNA previously shown to be expressed in the placenta and involved in regulating cell growth and developmental processes by targeting genes in a variety of cell growth and cell functioning pathways, specifically, miR-16, miR-21, miR-93, miR-135b, miR-146a, and miR-182. [score:9]
We analyzed 107 primary, term, human placentas for expression of 6 miRNA reported to be expressed in the placenta and to regulate cell growth and development pathways: miR-16, miR-21, miR-93, miR-135b, miR-146a, and miR-182. [score:7]
Since miRNA have been described as playing important roles in development and are susceptible to the environment, we sought to further characterize the expression of six candidate miRNA previously shown to be expressed in the placenta and previously reported to target genes in pathways crucial for regulating key cell processes – miR-16 [9], [14], miR-2 1 [9], [15], miR-93 [12], [13], miR-135b [11], miR-146a [9], [16], and miR-182 [10] – in a large series of human placentas for associations with fetal growth. [score:7]
Median (amol) Range (amol) miR-16 18.64 3.53–399.50 miR-21 54.86 5.25–434.74 miR-93 4.26 0.14–118.39 miR-135b 4.72 0.13–216.92 miR-146a 0.1 0.002–3.95 miR-182 0.23 0.001–3.63 Observing that expression in the lowest quartiles of miR-16 and miR-21 was associated with reduced birthweight percentile, we more specifically examined the association between low expression (≤median vs. [score:5]
Expression of miR-16, miR-21, miR-93, miR-135b, miR-146a, and miR-182 determined through qRT-PCR in 107 primary human term placenta samples. [score:3]
0021210.g001 Figure 1(A) miR-16 (p = 0.04), (B) miR-21 (p = 0.02), (C) miR-93 (p = 0.88), (D) miR-135b (p = 0.84), (E) miR-146a (p = 0.46), and (F) miR-182 (p = 0.55). [score:1]
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Recently, expression profiling studies in both colon cancer and prostate cancer have shown consistent overexpression of miR-135b in affected tissues [19, 20]. [score:5]
Furthermore, 3 of these candidates (miR-135b, miR-542-5p, and miR-652) had no expression in tumor samples and osteosarcoma cell lines, which minimizes the likelihood that expression differences are a result of differences between immortalized cell lines and heterogeneous tumor samples. [score:5]
In our samples, miR-135b was significantly overexpressed, and it has already been shown to have a role in normal osteoblastic differentiation; high levels of miR-135b result in abnormal mineralization. [score:3]
Overexpression of miR-135b resulted in abnormal mineralization, and differentiation of unrestricted somatic stem cells [21]. [score:3]
However, further analyses exploring the targets of miR-135b are warranted. [score:3]
Using this strategy, we were able to identify twenty-two differentially expressed microRNAs, and 4 (miR-135b, miR-150, miR-542-5p and miR-652) were selected for individual confirmations. [score:3]
We hypothesize that high levels of miR-135b may inhibit normal differentiation of stem cells into osteoblasts and this might explain the abnormal growth of osteosarcoma cells. [score:3]
Of the 22 miRNAs initially identified, 4 were selected for individual confirmation (miR-135b, miR-150, miR-542-5p and miR-652) based upon the fact that they were differentially expressed in both comparisons of human tumor and osteosarcoma cell lines when compared to osteoblasts. [score:2]
In the tumor samples used in our study, miR-135b was one of the miRs found to be significantly overexpressed in human osteosarcoma when compared to normal osteoblasts. [score:2]
Additionally, a recent study has demonstrated that low levels of miR-135b are important for the normal development and mineralization of osteoblasts. [score:2]
Individual miRNA assays were performed on total RNA from the initial tumor samples to determine the expression levels of miR-135b, miR-150, miR-452-5p and miR-652 when compared to normal human osteoblasts. [score:1]
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[+] score: 31
We have revealed common small non-coding RNA molecules (miR-26a, miR-195, miR- miR-126, miR-122, miR-21, miR-155, miR-9, miR-135b, miR-29b, miR-142-3p, miR-210, miR-181, miR- 224) in HCC and CRC, which suppress the expression of multiple genes involved in tumor- stromal interactions, immune invasion and tumor angiogenesis. [score:5]
Tumorigenesis in CRC E-cadherin[41, 42] miR-135b HCC cell metastasis; CRC proliferation HSF1, MSH2[44, 45] miR-29b Apoptosis promotion Bcl-2 and Mcl-1, MMP-2[47, 48] miR-142-3p HCC and CRC proliferation RAC1, CD 133, Lgr 5, ABCG2[60, 62, 107] miR-210 HCC metastasis; overexpressed in CRC VMP1, CPEB2[51, 52] miR- 181a Oncogenic role in HCC; poor survival in patients with CRC CDX2, GATA6, NLK, EGFR[64, 65] miR- 224 Oncogenic role in HCC; prognostic marker in CRC SMAD4, API-5[49, 63]Previous studies indicated that miR-34a inhibits tumor growth, miR-21 promotes apoptosis resistance of tumor cells proliferation while the miR-200 family is strongly associated with the epithelial- mesenchymal transition (EMT) [18, 19]. [score:5]
Tumorigenesis in CRC E-cadherin[41, 42] miR-135b HCC cell metastasis; CRC proliferation HSF1, MSH2[44, 45] miR-29b Apoptosis promotion Bcl-2 and Mcl-1, MMP-2[47, 48] miR-142-3p HCC and CRC proliferation RAC1, CD 133, Lgr 5, ABCG2[60, 62, 107] miR-210 HCC metastasis; overexpressed in CRC VMP1, CPEB2[51, 52] miR- 181a Oncogenic role in HCC; poor survival in patients with CRC CDX2, GATA6, NLK, EGFR[64, 65] miR- 224 Oncogenic role in HCC; prognostic marker in CRC SMAD4, API-5[49, 63] Previous studies indicated that miR-34a inhibits tumor growth, miR-21 promotes apoptosis resistance of tumor cells proliferation while the miR-200 family is strongly associated with the epithelial- mesenchymal transition (EMT) [18, 19]. [score:5]
heat shock transcription factor 1 (HSF1) directly activates the miR-135b expression, consequently enhancing HCC invasiveness [44]. [score:4]
Additionally, the reversion-inducing-cysteine-rich protein with kazal motifs (RECK) and ecotropic viral integration site 5 (EVI5) were identified as the functional and direct targets of miR-135b in HCC. [score:4]
Recent research identified miR-135b as a key effector of oncogenic pathways and a promising target for CRC therapy [45]. [score:3]
The miR-135b blockage in CRC experimental mouse mo dels diminishes tumor evolution by suppressing the genes involved in proliferation, apoptosis and invasion. [score:3]
The development of new therapeutics against HCC could be thus facilitated by the recently identified HSF1/miR-135b/RECK&EVI5 axis in the mechanisms of HCC metastasis [17; 44]. [score:2]
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[+] score: 29
We observed a significant overexpression of miR-21, miR-96, miR-135, miR-141, miR-182, miR-205, miR-429, miR-520b (all p<0.001) in UUTUC; the microRNAs miR-10a (p = 0.012) and miR-200b (p = 0.006) showed a distinct trend towards upregulation, whereas miR-1244 (p = 0.600) was similar in normal and malignant tissue. [score:6]
The expression of eleven microRNAs (miR-10a, miR-21, miR-96, miR-135, miR-141, miR-182, miR-200b, miR-205, miR-429, miR-520b, miR-1244) formerly shown to be upregulated in urothelial bladder cancer were studied in corresponding normal and cancerous tissue samples of patients undergoing nephroureterectomy for UUTUC. [score:6]
MicroRNA expression allowed differentiation of normal and cancerous tissue: miR-21, miR-96, miR-135, miR-141, miR-182, miR-205, miR-429 and miR-520b were significantly overexpressed. [score:5]
In order to investigate the role of microRNAs as non-invasive biomarkers in patients with UUTUC, the expression of eleven microRNAs (miR-10a, miR-21, miR-96, miR-135, miR-141, miR-182, miR-200b, miR-205, miR-429, miR-520b, miR-1244) earlier shown to be upregulated in urothelial cancer of the bladder [13– 20], was analyzed [11] in corresponding normal ureter and UUTUC tissue. [score:4]
Especially miR-21, miR-96, miR-135, miR-141, miR-182, miR-205, miR-429 and miR-520b were distinctly overexpressed in UUTUC. [score:3]
Tumor grade and stage are usually correlated in urothelial cancer, and thus one would expect significant correlations with stage (miR-205) or grade (miR-10a, miR-135), respectively. [score:1]
miR-182 (p = 0.083), miR-21 (p = 0.532) and miR-135 (p = 0.261) were similar in UUTUC patients and controls. [score:1]
Furthermore, we observed lower levels of miR-10a and miR-135 in UUTUC patients. [score:1]
miR-135 also showed a trend towards lower levels in cancer patients with muscle-invasive tumors (2.18 vs. [score:1]
The miR-205 tissue levels were also correlated with undifferentiated UUTUC, and miR-10a and miR-135 were decreased in serum of patients with muscle-invasive UUTUC. [score:1]
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[+] score: 29
P-values for chosen candidates were as follows: miR-17(1.92E [−09]), miR-18a(2.62E [−09]), miR-29c(4.71E [−09]), miR-106a(1.84E [−08]), miR-135a(8.26E [−09]), miR-135b(1.99E [−08]), miR-221(9.19E [−05]), miR-222(2.04E [−05]) (see Supporting Table S2) Expression profiles of these candidates can be found in Figure 2. Three out of eight miRNAs exhibited decreasing expression during brain development (miR-17, miR-18a (belonging to the same cluster), miR-106a) [24]. [score:6]
Therefore, miRNAs up-regulated in F50 cerebellum (e. g. miR-135a, miR-135b and miR-7, see Figure 2) and F100 cerebellum (e. g. miR-216a and miR-216) make promising candidates for developmental switches in the cerebellum. [score:5]
Interestingly, miR-135b is predicted to target a leucin zipper putative tumor suppressor 1 gene (LZTS1). [score:5]
Interestingly miR-135a and miR-135b have previously been described in prostate cancer [33], breast cancer [34], as well as involved in osteoblastic differentiation (by regulating expression of bone-related genes) [35]. [score:4]
Moreover, we have revealed an interesting and novel expression pattern of the miR-135a and miR-135b cluster in the brain. [score:3]
In addition, miR-135b was highly expressed in the adult cerebellum. [score:3]
A third group is represented by two miRNAs belonging to the same cluster, namely, miR-135a and miR-135b. [score:1]
The correlation coefficient values (R [2]) for particular miRNAs include: miR-17 (R [2] = 0.84), miR-18a (R [2] = 0.94), miR-29c (R [2] = 0.92), miR-106a (R [2] = 0.81) and miR-135a (R [2] = 0.89) miR-135b (R [2] = 0.95), miR-221 (R [2] = 0.91) and miR-222 (R [2] = 0.88). [score:1]
Eight different candidate miRNAs: hsa-miR-17, hsa-miR-18a, hsa-miR-29c, hsa-miR-106a, hsa-miR-135a hsa-miR-135b, hsa-miR-221 hsa-miR-222 and two reference miRNAs: hsa-miR-103 and hsa-miR-191 were profiled by. [score:1]
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In more detail, the expression level of miR-199b in BSMC exosomes was 3.75±0.81 folds increase at day 4 of osteogenic differentiation compared to that of day 0. miR-218 has a 2.81±1.01 over expression on day 3 osteogenic differentiation relative to that of day 0. There was a 3.11±0.94 increase of expression levels of miR-148a on day 1 compared to that of day 0. miR-135b has 2.99±o. [score:5]
TaqMan real-time RT-PCR to validate the expression levels of nine up regulated miRNAs, including let-7a, miR-199b, miR-218, miR-148a, miR-135b, miR-203, miR-219, miR-299-5p, and miR-302b (A) and three down regulated miRNAs, including miR-885-5p, miR-181a, and miR-320c (B) from miRNA array were selected for further validation using individual exosomal samples from BMSCs when cultured at 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 7 days. [score:5]
0114627.g002 Figure 2. TaqMan real-time RT-PCR to validate the expression levels of nine up regulated miRNAs, including let-7a, miR-199b, miR-218, miR-148a, miR-135b, miR-203, miR-219, miR-299-5p, and miR-302b (A) and three down regulated miRNAs, including miR-885-5p, miR-181a, and miR-320c (B) from miRNA array were selected for further validation using individual exosomal samples from BMSCs when cultured at 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 7 days. [score:5]
Upregulation of miR-135b was known to involve in the impaired osteogenic differentiation of mesenchymal stem cells derived from multiple myeloma patients [42]. [score:4]
Nine up regulated miRNAs (let-7a, miR-199b, miR-218, miR-148a, miR-135b, miR-203, miR-219, miR-299-5p, and miR-302b) and five down regulated miRNAs (miR-221, miR-155, miR-885-5p, miR-181a, and miR-320c) from miRNA array were selected for further validation using individual exosomal samples from BMSCs when cultured at 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 7 days. [score:3]
MicroRNA hsa-miR-135b could regulate the mineralization in osteogenic differentiation of human unrestricted somatic stem cells [41]. [score:2]
nine up regulated miRNAs (let-7a, miR-199b, miR-218, miR-148a, miR-135b, miR-203, miR-219, miR-299-5p, and miR-302b) and five down regulated miRNAs (miR-221, miR-155, miR-885-5p, miR-181a, and miR-320c) from miRNA array were further quantitated by TaqMan miRNA assays (Applied Biosystems). [score:2]
Two-dimensional grid matrix displaying 5 differential miRNAs (miR-199b, miR-218, miR-148a, miR-135b, and miR-221) was obtained by the functional heat-map in R. Columns refer to time course comparison: human BMSC culture at 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 7 days. [score:1]
Furthermore, we found that let-7a, miR-199b, miR-218, miR-148a, miR-135b, miR-203, miR-219, miR-299-5p, and miR-302b were significantly increased in individual exosomal samples from human BMSCs. [score:1]
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[+] score: 27
Table 1 MicroRNAs involved in regulating HIFs and HIF regulatory gene levels in ECs miRNA Cell type Impact of hypoxia on miRNA expression miRNA target (s) (direct or indirect*) Investigated processes miR-18a Choroidal endothelial cells Upregulated HIF1A Proliferation migration[116] miR-107 Endothelial progenitor cells—EPCs Upregulated ARNT Differentiation[121] miR-135b HUVECs Upregulated HIF1AN Angiogenesis[124] HIF1A* miR-155 Mouse skin endothelial SENDs cells and HUVECs Upregulated HIF1A Angiogenesis hypoxia[108] miR-199a Endometrial stromal cells; endothelial EA. [score:19]
An exosomal miR-135b formed during hypoxia in multiple myeloma cells directly suppresses HIF1AN in HUVECs and leads to increased HIF-1 activity and angiogenesis [124]. [score:4]
Furthermore, by suppressing HIF1AN, miR-135b may allow for a sustained hypoxic response, in spite of the fact that the oxygen levels were partially restored. [score:3]
This exosomal miR-135 provides an interesting example of potentiation of HIF-1 activity in cell-to-cell transfer. [score:1]
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[21] Out of the nine miRNAs that were screened, four were upregulated (miR-135b, miR-155, miR-205 and miR-206: Figure 1a) and five were downregulated (miR-31, miR-148a, miR-181c, miR-200b and miR-210: Figure 1b). [score:7]
[21]Out of the nine miRNAs that were screened, four were upregulated (miR-135b, miR-155, miR-205 and miR-206: Figure 1a) and five were downregulated (miR-31, miR-148a, miR-181c, miR-200b and miR-210: Figure 1b). [score:7]
Overexpression of miR-155, miR-205 and miR-206 resulted in a complete loss of HC11 dome formation, whereas, overexpression of miR-135b resulted in an increase in HC11 dome formation (Supplementary Figures 1a and b). [score:5]
For example, it is possible that repression of Brca1 in the epithelial compartment of the mammary gland causes upregulation of miR-135b, miR-155 and miR-205 in nonepithelial cells of the mammary gland. [score:4]
In contrast to the analysis of Brca1 -deficient mammary glands (Figure 1a), upregulation of miR-135b, miR-155 and miR-205 was not observed in HC11 cells in which Brca1 levels have been repressed using siRNA (Figure 1c). [score:4]
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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-18a, hsa-mir-21, hsa-mir-27a, hsa-mir-96, hsa-mir-99a, mmu-let-7g, mmu-let-7i, mmu-mir-27b, mmu-mir-30b, mmu-mir-99a, mmu-mir-124-3, mmu-mir-125b-2, mmu-mir-9-2, mmu-mir-135a-1, mmu-mir-181a-2, mmu-mir-182, mmu-mir-183, mmu-mir-199a-1, hsa-mir-199a-1, mmu-mir-200b, hsa-mir-181a-2, hsa-mir-182, hsa-mir-183, hsa-mir-199a-2, hsa-mir-181a-1, hsa-mir-200b, mmu-let-7d, hsa-let-7g, hsa-let-7i, hsa-mir-27b, hsa-mir-30b, hsa-mir-124-1, hsa-mir-124-2, hsa-mir-124-3, hsa-mir-125b-1, hsa-mir-135a-1, hsa-mir-135a-2, hsa-mir-9-1, hsa-mir-9-2, hsa-mir-9-3, hsa-mir-125b-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-15a, mmu-mir-18a, mmu-mir-21a, mmu-mir-27a, mmu-mir-96, mmu-mir-135b, mmu-mir-181a-1, mmu-mir-199a-2, mmu-mir-135a-2, mmu-mir-124-1, mmu-mir-124-2, mmu-mir-9-1, mmu-mir-9-3, mmu-mir-125b-1, hsa-mir-200a, dre-mir-182, dre-mir-183, dre-mir-181a-1, 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-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-15a-1, dre-mir-15a-2, dre-mir-18a, dre-mir-21-1, dre-mir-21-2, dre-mir-27a, dre-mir-27b, dre-mir-27c, dre-mir-27d, dre-mir-27e, dre-mir-30b, dre-mir-96, 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-125b-1, dre-mir-125b-2, dre-mir-125b-3, dre-mir-135c-1, dre-mir-135c-2, dre-mir-200a, dre-mir-200b, dre-let-7j, dre-mir-135b, dre-mir-181a-2, dre-mir-135a, mmu-mir-21b, mmu-let-7j, mmu-mir-21c, mmu-let-7k, dre-mir-181a-4, dre-mir-181a-3, dre-mir-181a-5, mmu-mir-9b-2, mmu-mir-124b, mmu-mir-9b-1, mmu-mir-9b-3
In this study, miR-135b was found in LNA arrays to be up-regulated in the vestibule, while its targets were enriched in a protein dataset and down-regulated in the vestibule. [score:9]
An example of such a miR-target pair is miR-135 and Psip, PC4- and SF-2 interacting protein/Ledgf (Elkan-Miller et al, 2011), which has been implicated in transcriptional regulation of stress-related genes, having an anti-apoptotic effect, involved in mRNA splicing, cell survival and is part of a fusion gene in leukaemia. [score:4]
The analysis predicted PSIP1-P75 as one of potential targets of miR-135b. [score:3]
miR-135 is reduced in the cochlear hair cells, while its expression is high in vestibular hair cells. [score:3]
This mo del suggests that miR-135b regulation of Psip1 plays a role in hair cell development and survival. [score:3]
In situ hybridization confirmed the differential expression of miR-135b in vestibular hair cells as compared to cochlear hair cells at P0. [score:2]
The pathways shown demonstrate potential inner ear functional pathways implicated in the miR135b-Psip regulatory network. [score:2]
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25
[+] score: 26
Although the expression of miR-124-3p and -125b-5p decreased gradually with an increase in HG-exposure time and concomitant with the early development of DR, miR-135b-5p, -145-5p, -146a-5p, and -199a-5p were upregulated on the first day and then downregulated on the following days (Figure 2(a)). [score:10]
Although miR-124-3p and -125b-5p remained downregulated during the different periods of DR examined, miR-135b-5p, -145-5p, -146a-5p, and -199a-5p exhibited increases in expression along with DR development. [score:7]
Moreover, miR-135b was identified as a biomarker for colorectal cancer [31] and reported to modulate apoptosis by targeting large tumor-suppressor kinase 2 [32]. [score:5]
These results and those presented in the preceding subsection together showed that both in vitro and in vivo, the expression of miR-124 and -125b decreased in correspondence with DR progression, but that of miR-135b and -199a decreased in retinal cells under hyperglycemia exposure and increased in the DM retina. [score:3]
By contrast, miR-135b-5p, -145-5p, -146a-5p, and -199a-5p levels were lower at 4 and 6 weeks post-STZ injection before increasing after 8 weeks to levels exceeding even those of the controls (Figure 3(c)). [score:1]
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26
[+] score: 25
Other miRNAs from this paper: hsa-mir-145, hsa-mir-195
Conversely miR-135b, which was downregulated after RA-treatment, targeted Midline 1 Ring Finger Protein (MID1), upregulated in RA -treated hMB-SLCs (Table 1). [score:9]
Interestingly our results showed a significant reduction of both miR-135b and NPM expression after RA -induced differentiation associated with a strong upregulation of MID1, highlighting their negative correlation compared to this gene and suggesting that also in this case the pharmacological regulation of these players could be very useful in order to control MB growth. [score:6]
In a recent high throughput study conducted on 6 different pediatric SLCs, not only was miR-135b significantly upregulated in the SLCs fraction compared to each non-SLCs reference fraction but also its silencing strongly inhibited their ability of self-renewal [24]. [score:5]
The second network (Figure 6(b)) comprises miR-135b, its direct target MID1, and Nucleophosmin (NPM), an important player in cell proliferation and apoptosis [17]. [score:4]
The second subnetwork (Figure 6(b)) included miR-135b, MID1, and NPM (NPM1). [score:1]
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27
[+] score: 22
Recently, we reported that type IV collagen is a target of miR135b and that miR135b suppression may improve the microenvironment and also increase the proliferative potential of epidermal basal cells [12]. [score:5]
Recently, we found that type IV collagen is a target of miR135b and that miR135b suppression improved the microenvironment and increase the proliferative potential of basal cells [12]. [score:5]
It can be concluded that PZ, which has antioxidant activity, can affect stem cell fate in the skin via inhibition of miR135b and following synthesis of type IV collagen of basement membrane. [score:3]
Results showed that levels of miR135b were decreased and expression of type IV collagen mRNA was increased. [score:3]
All these findings showed that topical application of ESE or PZ may have antiaging effects on the skin through miR135b-type IV collagen pathway. [score:1]
For qRT-PCR of has-miR135b, 10 ng of total RNA was reverse transcribed into cDNA using TaqMan MicroRNA Reverse Transcription Kit (4366596, Applied Biosystems). [score:1]
In this study, the effect of PZ was investigated in terms of miR135b and type IV collagen expression. [score:1]
Furthermore, level of miRNA135b was decreased by PZ treatment. [score:1]
It disclosed a role of miR135b in epidermal keratinocytes and may provide a way to control stem cell fate in the skin. [score:1]
RT-PCR Analysis for miR135b and mRNA of Integrins and Type IV Collagen. [score:1]
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28
[+] score: 21
Two of them, miR-133b and miR-145 were down-regulated and the remaining four, miR-31, miR-96, miR-135b and miR-183, were up-regulated, suggesting that they may potentially act as tumor suppressor genes or oncogenes, respectively. [score:9]
For the up-regulated miRNAs, miR-135b, miR-31, miR-96 and miR-183, it may be expected that gene targets belong to the class of tumor suppressor genes. [score:8]
Among the differentially expressed miRNAs, miR-31, miR-96, miR-133b, miR-135b, miR-145 and miR-183 as the most consistently deregulated in CRC. [score:4]
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29
[+] score: 19
The most significantly deregulated miRNAs were miR-31, miR-96, miR-135b, miR-183 (up-regulated in tumors and CRC cell-lines) and miR-133b, miR-145 (downregulated). [score:8]
Of note, miR-135a and miR-135b were also found to be upregulated in vivo in colorectal adenomas and carcinomas and correlated with low APC levels [13]. [score:4]
miR-135a and miR-135b decrease translation of the APC transcript in vitro. [score:3]
Expression pattern of 30 miRNAs (miR-17-3p, miR-92, miR-135b, miR-222, miR-95, etc. ) [score:3]
These observations suggest that alteration in the mir-135 family can be one of the early events in CRC's molecular pathogenesis. [score:1]
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30
[+] score: 19
We found that the three ethanol-sensitive miRNAs with the highest average expression fold changes in the hippocampus, including the well-conserved miR-135a and miR-135b, were also significantly up-regulated in serum. [score:6]
Of the remaining validated ethanol-sensitive miRNAs, miR-135a and miR-135b are well-conserved and predicted to target Complexin 1 and Complexin 2 (TargetScan, Release 6.2), which are involved in modulating neurotransmitter release [40]. [score:5]
Four out of seven miRNAs, miR-135a, miR-135b, miR-467b-5p and miR-487b, were confirmed to be significantly up-regulated in ethanol-exposed mice (Fig.   4c). [score:4]
Three miRNAs, miR-135a, miR-135b and miR-467b-5p, were significantly up-regulated (≥twofold) in the ethanol-exposed group compared to controls (Fig.   5). [score:3]
Linear regression analysis showed significant linear relationships between the hippocampus and serum for miR-135a (R [2] = 0.84, P < 0.01), miR-135b (R [2] = 0.91, P < 0.001) and miR-467b-5p (R [2] = 0.60, P < 0.05) in ethanol-exposed mice only. [score:1]
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31
[+] score: 19
Several miRNAs modulate osteogenic differentiation: miR-125b negatively regulates osteoblastic differentiation through targeting VDR, ErbB2, and Osterix [28, 29]; miR-133 (targeting RUNX2) and miR-135 (recognizing SMAD5) inhibit differentiation of mouse osteoprogenitors [30]; miR-26a and miR-29b facilitate osteogenic differentiation of human adipose tissue-derived stem cells (hADSCs), and positively modulate mouse osteoblast differentiation [31, 32]. [score:8]
In contrast, Li and coworkers reported that miR-135b (and also miR-133a/b) were downregulated during mouse osteoblast differentiation after 16 hours [30]. [score:4]
Recently miR-135b was reported to be 100-fold upregulated in USSC following DAG-induction [61]. [score:4]
In USSC, miR-133a and miR-133b as well as miR-135b are only weakly expressed even in native cells and virtually unchanged during osteogenic differentiation (see Additional file 1). [score:3]
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32
[+] score: 15
MiR-135-5p, one of the miRNAs found to be upregulated in cells treated with serum from HNSCC patients, targets the tumor suppressor APC and promotes cell growth in colorectal cancer (59). [score:8]
Both miR-31-3p and miR-135b-5p were found to be upregulated in cells treated with serum from cancer patients in this study. [score:4]
Along with miR-135b-5p, miR-31-3p has also been shown by our lab to be upregulated in tumor tissue of HNSCC patients compared with adjacent normal tissue (56). [score:3]
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33
[+] score: 15
A potential target of miR-135b is the serine protease inhibitor Kazal type 5 (Spink5), which is downregulated in CC [65]. [score:8]
miR-135b is overexpressed in colorectal cancer [66] and in CC [43] (Table 1). [score:3]
Overexpression of miR-135b and loss of SPINK5 and desmoglein 1 could decrease cellular adhesion, increase proliferation, and change the epithelial architecture of the cervix and promote a tumorigenic phenotype (Figure 1). [score:3]
These observations suggest that miR-223 may reduce cellular adhesion and promote proliferation of cancer cells as previously determined for miR-135b (Figure 1). [score:1]
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34
[+] score: 14
A few studies have described miR-135b and its relationship in NSCLC, but only Lin et al. have found upregulated miR-135b in invasive NSCLC cells [41]. [score:4]
MiR-135b expression enhances cancer cell invasive and migratory abilities in vitro and promotes cancer metastasis in vivo by targeting multiple key components on the Hippo pathway, including LATS2, BTRCP and NDR2, as well as LZTS1 [41]. [score:4]
Regarding the analyzed miRNAs, the overexpression of miR-182, miR-31, miR135b, miR-199b, miR-224 and miR-196b and miR-34a have been detected in both the training and validation set. [score:3]
Other studies in different cancer types have found an overexpression in miR-135b [42, 43]. [score:3]
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35
[+] score: 14
As indicated, lncRNA linc- MD1 “sponges” miR-133 and miR-135, antagonizing the miRNA -mediated translation suppression Another example of involvement of lncRNA in AS is sno- lncRNA, a class of nuclear-enriched intron-derived lncRNAs transcribed from a critical region of chromosome 15 (15q11-q13). [score:5]
As indicated, lncRNA linc- MD1 “sponges” miR-133 and miR-135, antagonizing the miRNA -mediated translation suppression Another example of involvement of lncRNA in AS is sno- lncRNA, a class of nuclear-enriched intron-derived lncRNAs transcribed from a critical region of chromosome 15 (15q11-q13). [score:5]
Linc- MD1 “sponges” miR-133 and miR-135 to regulate the mRNA translation of mastermind-like-1 (MAML1) and myocyte-specific enhancer factor 2C (MEF2C), respectively (Fig.   2f). [score:4]
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36
[+] score: 13
The study revealed that 10 dysregulated miRNA signature among which hsa-miR-1271-5p and hsa-miR-574-3p were down-regulated; and hsa-miR-182-5p, hsa-miR-183-5p, hsa-miR-96-5p, hsa-miR-182-3p, hsa-miR-141-5p, hsa-miR-15b-5p, hsa-miR-130b-5p, and hsa-miR-135b-3p were overexpressed in ovarian cancer tissues. [score:7]
In contrast, other miRNAs such as miR-182-5p, miR-183-5p, miR-96-5p, miR-15b-5p, miR-182-3p, miR-141-5p, miR-130b-5p, and miR-135b-3p had a significantly higher expression level in ovarian cancer tissue sample group (C group) than in the normal group (P values are presented in Table 2). [score:3]
The seven dysregulated miRNAs including hsa-miR-182-5p, hsa-miR-183-5p, hsa-miR-96-5p, hsa-miR-1271-5p, hsa-miR-182-3p, hsa-miR-1468-5p, and hsa-miR-135b-3p (Table S1 in file S1) were confirmed by the AUC of ROC curve (AUC = 0.965) with 97% sensitivity and 85% specificity (Figure S5 in file S1). [score:2]
6 out of these 7 miRNAs (hsa-miR-182-5p, hsa-miR-183-5p, hsa-miR-96-5p, hsa-miR-1271-5p, hsa-miR-182-3p, and hsa-miR-135b-3p) are in the 10-miRNAs signature. [score:1]
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37
[+] score: 13
Other APP-interacting proteins, APP -binding family B member 1 (mir-9, miR-340, and miR-135b), APP -binding family member 2 (let-7 and miR-218), and APP -binding family 2 (miR-188 and miR-206) were also predicted targets, some of which had near exact target site matches. [score:5]
PSD95 is a high-ranking target of miR-125, miR-135, miR-320, and miR-327, all of which are either exclusively expressed in brain or enriched in brain tissue (Lagos-Quintana et al. 2002; Krichevsky et al. 2003; Sempere et al. 2004). [score:5]
” Neuronal differentiation of embryonic carcinoma cells by retinoic acid in both mice and humans is coupled to induction of let-7b, miR-30, miR-98, miR-103, and miR-135 (Sempere et al. 2004), and their targets are enriched in “neurogenesis” (3.5-fold). [score:3]
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38
[+] score: 12
MiR-135b has been found to be up-regulated in mouse embryo fibroblasts and human colorectal cancer cell lines [77], and up-regulation of miR-135b resulted in a reduction in apoptosis and an increase in cell growth due to the down-regulation of transforming growth factor β receptor 2 (TGFβR2), death -associated protein kinase 1 (DAPK1),Adenomatous Polyposis Coli (APC), and FIH, and the activation of APC/β-catenin and SRC-PI3K pathways. [score:10]
An example is miR-135b in colon cancer. [score:1]
This study further reported reduced proliferation and increased apoptosis in colorectal tumors in mice treated with anti-miR-135b, suggesting a preclinical efficacy of miR-135b in vivo with low toxicity. [score:1]
[1 to 20 of 3 sentences]
39
[+] score: 12
Our results in the two cell lines agree with previously published data on the upregulation of MIR93, MIR95, MIR135B, MIR181C, MIR181D, MIR182, MIR183, MIR190, MIR196B and MIR203, and downregulation of MIR20A and MIR29C in pancreatic intraepithelial neoplasms (PanIns) or pancreatic adenocarcinomas (PDACs) as compared to normal pancreatic tissue [34- 36]. [score:6]
Differential miRNA expression levels included higher levels of MIR767, MIR135B, MIR1269, MIR182, MIR183, and MIR203 and lower levels of MIR494, MIR424, MIR381, MIR452, and MIR155 in PANC-1 cells. [score:3]
MIR135B, MIR182 and MIR183 are overexpressed in a wide range of other cancer types such as bladder, colon, prostate cancer and glioma [37- 41]. [score:3]
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40
[+] score: 12
In fact, miR-125b, miR-126, miR-10b, miR-10a and miR-191 were underexpressed whereas miR-26b, miR-607 and miR-135b were overexpressed in cancer samples examined, in comparison with the gynecomastia samples. [score:5]
miR-125b, miR-126, miR-10b, miR-10a and miR-191 were underexpressed in cancer samples, whereas miR-26b, miR-607 and miR-135b were overexpressed. [score:5]
To confirm the results of microarray analysis, we performed quantitative real-time PCR analysis on a limited number of samples (19 cancer samples, five gynecomastia samples) using probes corresponding to miR-125b, miR-126, miR-10b, miR-10a, miR-191, miR-26b, miR-607 and miR-135b (Figure 2). [score:1]
analysisTo confirm the results of microarray analysis, we performed quantitative real-time PCR analysis on a limited number of samples (19 cancer samples, five gynecomastia samples) using probes corresponding to miR-125b, miR-126, miR-10b, miR-10a, miR-191, miR-26b, miR-607 and miR-135b (Figure 2). [score:1]
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41
[+] score: 11
MiR-135 has shown high P [CT] value against GATA3 gene and has the potential to inhibit the expression of this gene and Th2 immune cell conversion. [score:4]
We also identified that miR-135 have the great potential to down regulate the expression of the STAT6 transcription factor at the post-transcriptional level in CD4 [+] T cells. [score:4]
GATA3 protein has multiple transcripts but for NM_001002295 transcript, by using all three web servers we found that miR-135 has the binding site at the 3′-UTR of GATA3 gene (position 207–213). [score:1]
MiR-135 has a putative binding site to regulate GATA3 transcription factor which control the Th2 immune cell differentiation from CD4 [+] T cells. [score:1]
STAT6 gene with 3′-UTR length of 1168 nucleotides were found to show miR-135 binding at position 1100–1107. [score:1]
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42
[+] score: 10
In the context of biomarker, findings from isomiR differential expression analysis were consistent with previous reports on upregulated miRNAs in CRC, including on hsa-miR-135b [19], − 21-5p [33], 92a-3p [33], − 7-5p [34], − 17-5p [35], − 182-5p [36, 37], − 183-5p [38], − 1246 (or U2 small nuclear RNA fragments) [39] and miR-200 family [40]. [score:6]
Among them, 58 sequences are consistently upregulated in both CRC and advanced adenoma (Additional file 9: Table S7), including isomiRs of hsa-miR-135b-5p, − 182-5p, − 183-5p, − 192-5p, −200b-3p, − 96-5p, −200a-3p, −200c-3p, and − 429. [score:4]
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43
[+] score: 10
Other miRNAs from this paper: mmu-mir-135b
Of note among the miRNAs that have recently been identified is the strong upregulation of miR-135b which has been found in invasive mammary BALB-neuT carcinomas; acting on its targets, midline 1 (MID1) and mitochondrial carrier homolog 2 (MTCH2), it regulates CSC stemness in vitro and cancer cell metastatization in vivo [49]. [score:7]
This newly unveiled role for miR-135b in mammary carcinogenesis, as observed in other tumors such as colon cancer [50], osteosarcoma [51], ependymoma [52], and hepatocellular carcinoma [53], can provide the basis for the exploration of miR-135b, MID1, and MTCH2's potential as new therapeutic targets in mammary carcinogenesis. [score:3]
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44
[+] score: 10
One of the evidences was provided by Umezu et al. They observed that miR-135b, which is overexpressed in exosomes from hypoxia-resistant multiple myeloma cells, suppresses factor-inhibiting HIF1 (FIH-1) in endothelial cells, thus promoting endothelial tube formation via the HIF–FIH signaling pathway. [score:7]
Therefore, exosomal miR-135b may be a target for controlling multiple myeloma angiogenesis. [score:3]
[1 to 20 of 2 sentences]
45
[+] score: 10
BMP2 treatment downregulated the expression of miR-133 and miR-135 that inhibit osteogenic differentiation by targeting Runx2 and Smad5 [18]. [score:10]
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46
[+] score: 10
We discovered that of these five miRNAs, miR-122 and miR-192 were upregulated at least 1.5-fold in both HES1 and HES2 cells, while miR-135b and miR-33a were upregulated only in HES2 cells, and miR-224 was upregulated only in HES1 cells. [score:10]
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47
[+] score: 10
Similarly, in breast cancer cells, it has been shown that PTENP1 modulates the expression levels of HRASLS5 (HRAS-like suppressor family, member 5) mRNA through the binding of miR-135b, a microRNA that has not been yet reported as PTEN -targeting (13). [score:7]
Pseudogene Parental gene Other genes Shared microRNAs Context Reference Oncosuppressive pseudogenes PTENP1 PTEN miR-17, 19, 21, 26, and 214 families Prostate cancer(23) Melanoma(39) Endometrial cancer(44) ccRCC(15) Hepatocellular carcinoma(30) Gastric cancer(45)(40) PTENP1 HRASLS5 miR-135b Breast cancer(13) TUSC2P TUSC2 miR-17, 93, 299-3p, 520a, 608, and 661 Breast cancer(46) INTS6P1 INTS6 miR-17-5p Hepatocellular carcinoma(47) Oncogenic pseudogenes OCT4-pg4 OCT4 miR-145 Hepatocellular carcinoma(34) OCT4-pg5 OCT4 miR-145 Endometrial carcinoma(48) HMGA1P6 HMGA1 miR-15, 16, 214, and 761 Thyroid carcinoma(49) HMGA1P7 Pituitary tumors(50) CYP4Z2P CYP4Z1 miR-125a-3p, 197, 204, 211, and 1226 Breast cancer(51) BRAFP1 BRAF miR-30a, 182, 590, and 876 DLBCL(52) Braf-rs1 Braf miR-134, 543, and 653 Diffuse large B-cell lymphoma(52) Additionally, it has been shown that pseudogenes can act as ceRNAs not only for their parental genes but also for other genes (Figure 1K and Table 1). [score:3]
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48
[+] score: 9
miR-135 has recently been shown to inhibit expression of the tumor suppressor gene Adenomatous Polyposis Coli (APC) in colorectal cancer [60]. [score:7]
We also observed a significant increase in miR-135 expression in SCLC cells compared to NSCLC cells. [score:2]
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49
[+] score: 9
Taipaleenmäki H Browne G Akech J Zustin J van Wijnen AJ Stein JL Hesse E Stein GS Lian JB Targeting of Runx2 by miRNA-135 and miRNA-203 impairs progression of breast cancer and metastatic bone diseaseCancer Res. [score:5]
Recently, Taipaleenmäki et al. showed that malignant phenotypes of breast cancer cells are significantly suppressed by miR-135/miR-203-caused direct reduction of RUNX2. [score:4]
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50
[+] score: 9
Among the differentially expressed miRNAs, only miR-135b and miR-221 are significantly up-regulated (4.3 and 1.7 fold, respectively) in the colon cancer tissue samples. [score:6]
For example, miRNA-135a and miR-135b are reported to be involved in the initiation of human colon cancer by targeting the adenomatous polyposis coli gene (APC) [18]. [score:3]
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51
[+] score: 9
Both oncogenic miRNAs and tumor suppressive miRNAs have been demonstrated and described in colon carcinogenesis and progression, such as upregulated miR-135, miR-21, miR-17-92, and miR-196a, and downregulated miR-34, miR-195, and miR-365 [9]– [13]. [score:9]
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52
[+] score: 9
MiR-135b was found to inhibit the osteogenic differentiation of human MSCs by suppressing the expression of Smad5 [21]. [score:6]
For example, Li et al. showed that Smad5 was mechanistically implicated in miR-135′s inhibition of multiple components that were deemed necessary for the osteogenesis of C2C12 mesenchymal cells [28]. [score:3]
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53
[+] score: 9
REST directly down-regulates a large number of genes at the transcriptional level, but also probably indirectly activates the expression of other genes at the post-transcriptional level via the repression of many noncoding targets (Conaco et al., 2006; Mortazavi et al., 2006; Wu and Xie, 2006; Visvanathan et al., 2007; Singh et al., 2008; Johnson et al., 2009), including several micro RNAs (miRNAs) considered to be brain-specific (such as miR9, miR124, miR132, miR135, miR139, and miR153; Figure 1). [score:9]
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54
[+] score: 9
Interestingly, Chinese mistletoe lectin-I (CMI) has been firstly reported to induce apoptotic cell death in colorectal cancer cells, by down -regulating miR-135a and miR-135b expression and up -regulating expression of their target gene adenomatous polyposis coli (APC), thereby, reducing activity of its downstream Wnt signaling [10]. [score:9]
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55
[+] score: 9
This analysis led to a restricted list of 14 miRs potentially regulated by STAT3 and targeting genes annotated in the STAT3 signaling pathway (Biocarta) that is shown in Table  2. Detailed information on this analysis is provided in additional file 2. Interestingly, some of the miRs reported in Table  2 (i. e., miR-21, miR-125b, miR-135b, miR-181b and miR-155) were already predicted to be regulated by STAT3 and also experimentally validated [16, 18– 21]. [score:5]
As shown in Fig.   1, miR-21 (A) and miR-181b (B) were down- and up-regulated, respectively, in cells treated with R5 gp120 at 18 h. Conversely, no significant difference was observed at 6 h. Likewise, gp120 treatment did not result in any significant modulation of miR-125b, whereas miR-135b did not amplify (data not shown). [score:4]
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56
[+] score: 9
LncRNAs functioning as ceRNAs can be also observed in: mouse and human myoblasts, where the large intergenic non-coding RNA (lincRNA) called linc-MD1 controls muscle differentiation by targeting miR-133 and miR-135 to regulate the expression of MAML1 and MEF2C [74]; human embryonic stem cells, where linc-RoR competes with the transcription factors NANOG, OCT4, SOX2 for binding to miR-145 regulating cell pluripotency and self-renewing [75]; human thyroid cancer, where the thyroid-specific lncRNA PTCSC3 targets miR-574-5p [76]; human embryonic kidney 293 (HEK293) cells, where the lncRNA H19 modulates the let-7 miRNAs family availability causing precocious muscle differentiation [77]. [score:9]
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57
[+] score: 8
This included the upregulation of a number of miRNAs (e. g., miR-21, miR-31, miR-96 and miR-135b, miR-182, miR-183) (14– 19, 29– 34) and downregulation of miRNAs (e. g., 133a and mir-1) (31) which were previously noted. [score:7]
Other miRNAs (i. e., miR-135b and miR-204) exhibited significant difference between tumor and normal tissues only. [score:1]
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58
[+] score: 8
Of note, miR-135a and miR-135b were also found to be upregulated in vivo in colorectal adenomas and carcinomas and correlated with low APC levels [22]. [score:4]
miR-135a and miR-135b decrease translation of the APC transcript in vitro. [score:3]
These observations indicate that alteration in the mir-135 family can be one of the early events in CRC’s molecular pathogenesis. [score:1]
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59
[+] score: 8
Hsa-miR-135b is abnormally up-regulated in MSCs from multiple myeloma patients, and it negatively regulates MSCs osteogenesis [30] and the over -expression of hsa-miR-135b results in decreased mineralization [31]. [score:7]
Interestingly, microRNAs with the highest changes were related to the osteogenesis of BMSC, including has-miR-146a, has-miR-135b, miR-378, miR-335-5p and miR-210. [score:1]
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60
[+] score: 8
Of the 9 upregulated miRNAs, miR-135b had the highest fold change (17.7-fold), but only 3 miRNAs (miR-200a, -429, and miR-135b) reached a change greater than 5-fold (Table S5). [score:4]
In the upregulated miRNAs, the fold changes of miR-96, miR-135b, and miR-141 were 6, 4.4, and 4.8, respectively. [score:4]
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61
[+] score: 8
Twelve miRNAs (hsa-miR-130b, hsa-miR-203, hsa-miR-1974, hsa-miR-592, hsa-miR-200a, hsa-miR-429, hsa-miR-183, hsa-miR-182, hsa-miR-1290, hsa-miR-141, hsa-miR-135b, and hsa-miR-96) were overexpressed, whereas 84 miRNAs (hsa-miR-1, hsa-miR-145, hsa-miR-145*, and so on) were downexpressed in tumor tissues compared with those in normal tissues. [score:4]
For example, E Bandrés et al. reported that miR-31, miR-96, miR-133b, miR-135b, miR-145, and miR-183 are the most significantly deregulated miRNAs and the expression level of miR-31 was correlated with the stage of CRC tumor [2]. [score:4]
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62
[+] score: 8
From the 20 most differentially regulated microRNAs (10 most up-regulated and 10 most down-regulated, see Table 2) 7 are shared with female breast cancer (miR-21, miR-127, miR-122a, miR-135b, miR-140, miR-497, miR-145). [score:8]
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63
[+] score: 7
Other miRNAs from this paper: hsa-let-7a-1, hsa-let-7a-2, hsa-let-7a-3, hsa-mir-16-1, hsa-mir-17, hsa-mir-19a, hsa-mir-21, hsa-mir-24-1, hsa-mir-24-2, hsa-mir-25, hsa-mir-26a-1, hsa-mir-29a, hsa-mir-30a, hsa-mir-31, hsa-mir-92a-1, hsa-mir-92a-2, hsa-mir-96, hsa-mir-100, hsa-mir-106a, hsa-mir-107, hsa-mir-192, hsa-mir-198, hsa-mir-129-1, hsa-mir-148a, hsa-mir-139, hsa-mir-10b, hsa-mir-34a, hsa-mir-182, hsa-mir-203a, hsa-mir-205, hsa-mir-210, hsa-mir-212, hsa-mir-214, hsa-mir-215, hsa-mir-216a, hsa-mir-217, hsa-mir-221, hsa-mir-223, hsa-mir-200b, hsa-let-7g, hsa-mir-122, hsa-mir-124-1, hsa-mir-124-2, hsa-mir-124-3, hsa-mir-125b-1, hsa-mir-128-1, hsa-mir-130a, hsa-mir-135a-1, hsa-mir-135a-2, hsa-mir-141, hsa-mir-142, hsa-mir-143, hsa-mir-144, hsa-mir-191, hsa-mir-9-1, hsa-mir-9-2, hsa-mir-9-3, hsa-mir-125a, hsa-mir-125b-2, hsa-mir-126, hsa-mir-129-2, hsa-mir-134, hsa-mir-146a, hsa-mir-149, hsa-mir-150, hsa-mir-154, hsa-mir-320a, hsa-mir-155, hsa-mir-128-2, hsa-mir-200a, hsa-mir-302a, hsa-mir-34b, hsa-mir-34c, hsa-mir-99b, hsa-mir-26a-2, hsa-mir-302c, hsa-mir-367, hsa-mir-370, hsa-mir-375, hsa-mir-376a-1, hsa-mir-378a, hsa-mir-379, hsa-mir-328, hsa-mir-151a, hsa-mir-335, hsa-mir-133b, hsa-mir-449a, hsa-mir-451a, hsa-mir-410, hsa-mir-486-1, hsa-mir-146b, hsa-mir-520f, hsa-mir-518d, hsa-mir-517c, hsa-mir-376a-2, hsa-mir-92b, hsa-mir-584, hsa-mir-602, hsa-mir-629, hsa-mir-638, hsa-mir-449b, hsa-mir-449c, hsa-mir-378d-2, hsa-mir-298, hsa-mir-1246, hsa-mir-1908, hsa-mir-718, hsa-mir-2861, hsa-mir-378b, hsa-mir-378c, hsa-mir-4306, hsa-mir-378d-1, hsa-mir-378e, hsa-mir-378f, hsa-mir-378g, hsa-mir-378h, hsa-mir-378i, hsa-mir-3976, hsa-mir-4644, hsa-mir-203b, hsa-mir-451b, hsa-mir-4728, hsa-mir-4734, hsa-mir-378j, hsa-mir-6165, hsa-mir-486-2
Qu et al. (2016a) MiR-34a, MiR-141, MiR-134, MiR-135a, MiR-135b, and MiR-370The adenocarcinomic human alveolar basal epithelial cell line A549 cells The collection of non-small cell lung cancer (NSCLC) patient tissue samples qRT-PCR analysis, Electron microscopy assay, and Western blotting YKT6 downregulation is associated with a remarkable reduction in exosome release in an NSCLC cell line and that low YKT6 expression is associated with better clinical outcome in NSCLC patients. [score:4]
Thus, YKT6 is a SNARE protein in the regulation of exosome release in lung cancer cells and is in turn accurately regulated by miR-134 and miR-135b. [score:3]
[1 to 20 of 2 sentences]
64
[+] score: 7
For the chronic stage, 9 mature miRNA sequences were identified: 8 were up-regulated (miR-146a-5p, miR-23a-3p, miR-135b-5p, miR-21-5p, miR-132-5p, miR-132-3p, miR-210-3p, and miR-212-5p) and one was down-regulated (miR-551b-3p) (Table  2). [score:7]
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65
[+] score: 7
Other miRNAs from this paper: hsa-mir-22, hsa-mir-647, hsa-mir-1229
The results exhibited miR-647 was significantly up-regulated in ox-LDL treated VSMCs, whereas no obvious change in miR-135b and miR-1229 (n = 3, P < 0.05) (Fig. 5A). [score:4]
Three miRNAs, miR-135b, miR-647 and miR-1229 were selected as candidate targets of APPAT (Table S5). [score:3]
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66
[+] score: 7
Three miRNAs associated with human basal-type tumors (miR-135b, miR-505 and miR-155), and seven miRNAs associated with human luminal type tumors (let-7a, let-7f, miR-100, miR-130a, miR-152, miR-214 and miR-29b) are similarly expressed in mouse basal-like and luminal-type tumors, respectively. [score:3]
Comparison of expression levels between the data and the PCR results demonstrated a strong correlation between the two platforms for miR-107, -10b, -193, -200b, -494, -505, -7a, and let7f; a modest association for miR-30b, -412; and weak or no association with miR-135b, -155, and -301 (Additional file 4). [score:3]
miR-135b, miR-505 and miR-155 are expressed in both basal human and mouse mammary tumors and many basal -associated miRNAs have not been previously characterized. [score:1]
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67
[+] score: 7
The top 20 miRNAs significantly up- or down-regulated in Exo [Hypoxic] compared to Exo [Normoxic] are listed in Table 1. Nine miRNAs were expressed at a significantly lower level in Exo [Hypoxic] compared to Exo [Normoxic]: miR-521 (Fold change = 0.0005), miR-27a (Fold change = 0.24), miR-324 (Fold change = 0.446), miR-579 (Fold change = 0.448), miR-502 (Fold change = 0.396), miR-222 (Fold change = 0.232), miR-135b (Fold change = 0.325), miR-146a (Fold change = 0.456) and miR-491(Fold change = 0.482). [score:4]
Among these, 15 miRNAs (miR-143, miR-146a, miR-181a, miR-204, miR-222, miR-27a, miR-335, miR-433, miR-491, miR-502, miR-521, miR-92a, miR-127, miR-135b and miR-451) target 211 mRNAs when the confidence limit was set as “Experimentally Observed” only. [score:3]
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68
[+] score: 7
MiR-143 and miR-135 inhibitors treatment induces skeletal myogenic differentiation of human adult dental pulp stem cells. [score:3]
Cell type microRNA mRNA target Differentiation DPSCs miR-135 Nd MyogenicLi et al., 2015 miR-143 DPSCs miR-720 DNMT3a, NANOG OsteogenicHara et al., 2013 PDLSCs miR-21 PLAP-1 OsteogenicLi et al., 2012 miR-101 DPCs miR-424 VEGF, KDR Angiogenic (endothelial cells)Liu et al., 2014 DPSCs miR-196 HOX C8 OsteogenicGardin et al., 2016 DPSCs miR-218 RUNX2 OsteogenicGay et al., 2014 GMSCs PDLSCs DPSCs miR-816-3a WNT5A, EGRF Control of cell fateVasanthan et al., 2015 miR-7-5p DPSCs miR-32 DSPP OdontoblasticWang et al., 2011 miR-586 miR-885-5 WNT5A, WNT FAMILY MEMBER 5A; EGRF, EPIDERMAL GROWTH FACTOR RECEPTOR; DSPP, DENTIN-SIALOPHOSPHOPROTEIN; DNMT3A, DNA METHYLTRANSFERASE 3A; NANOG, NANOG HOMEOBOX; PLAP-1, PERIODONTAL LIGAMENT-ASSOCIATED PROTEIN 1; VEGF, VASCULAR ENDOTHELIAL GROWTH FACTOR; KDR, VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR-2/KINASE INSERT DOMAIN RECEPTOR; and RUNX2, RUNT-RELATED TRANSCRIPTION FACTOR2. [score:3]
It was found that the application of 5-aza-dC impaired the function of both miR-135 and miR-143 and arrested cell proliferation to sustain myogenic differentiation, indicating that miRNAs could perform a decisive function in DPSC fate. [score:1]
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69
[+] score: 7
In the example of pure sponge module (Figure  5A), PTENP1 appears to regulate the expression of HRASLS5, a member of the HRAS-like suppressor family, via antagonizing mir-135b in normal breast tissue. [score:6]
Plots are shown for, from left to right: PTENP1 versus HRASL5, mir-135b versus HRASL5, mir-135b versus PTENP1. [score:1]
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70
[+] score: 7
Other miRNAs from this paper: hsa-mir-93
The CXCL12 gene plays a role in placentation [30] and is linked to the development of pre-eclampsia [31], whereas miR-135b is expressed in trophoblast cells [29]. [score:4]
Tamaru et al. demonstrated that overexpression of miR-135b significantly reduced the invasive capacity of HTR-8/SV. [score:3]
[1 to 20 of 2 sentences]
71
[+] score: 7
Other miRNAs from this paper: hsa-mir-135a-1, hsa-mir-135a-2
It has been shown experimentally that in in vitro miRNA system – miR135a and miR135b interact with 3’UTR transcript of the APC gene and affect the level of mRNA and, in this way, regulate APC expression and consequently the Wnt proliferation control pathway. [score:4]
miRNA precursors are made up of 93, 102 and 99 nucleotide sequences and can be found on chromosome 3 - miR135a-1, on chromosome 12 miR-135a-2 and chromosome 1 miR-135b, respectively. [score:1]
The miR-135b coding gene is located on chromosome 1q32.1 in intron 1 of the LEMD1 gene. [score:1]
Furthermore, it was observed that increased quantities of miR-135a and miR-135b lead to the reduction in the amount of mRNA of the APC gene in neoplastic tumours of the intestine [63]. [score:1]
[1 to 20 of 4 sentences]
72
[+] score: 7
In addition, ectopic expressions of miR-138 and miR-135 targeting the FAK 3′UTR reportedly suppress FAK -mediated tumor growth and invasion as well as drug sensitivity [150]. [score:7]
[1 to 20 of 1 sentences]
73
[+] score: 7
They found that miR-199b-5p and miR-100-3p were downregulated and miR-155-5p, miR-135-5p, and miR-146-5p upregulated in more aggressive osteosarcoma cell lines. [score:7]
[1 to 20 of 1 sentences]
74
[+] score: 7
Several such miRNAs have been identified in colorectal cancer, including the upregulated miR-31, miR-96, miR-135b, and miR-183 and the downregulated miR-133b and miR-145 [19]. [score:7]
[1 to 20 of 1 sentences]
75
[+] score: 7
Similarly, our very recent study has demonstrated that microRNA-135b-5p (“miR-135b-5p”) inhibited LPS -induced TNFα production via activating AMPK [11]. [score:3]
Our previous studies have shown that GSK621 [10] or miR-135b-5p [11] inhibited LPS -induced ROS production, thus blocking the downstream NFκB activation. [score:3]
miR-135b-5p activated AMPK signaling via silencing its phosphatase Ppm1e [11]. [score:1]
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76
[+] score: 7
Other miRNAs from this paper: hsa-mir-21, hsa-mir-143, hsa-mir-126
For instance, in human CRC, the upregulation of miRNA-135b is common, while in cervical cancer, miR-21, miR-126, and miR-143 are commonly upregulated[99]. [score:7]
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77
[+] score: 7
In cSCC most of the altered miRNAs are downregulated (miR-125b, miR-34a, miR-214, miR-124, miR-361, miR-193b, miR-365a, miR-20a, miR-199a) [19– 25] whereas only a small number of miRNAs have been found to be upregulated and act as onco-miRNAs, being involved in angiogenesis, colony formation, migration and invasion, and metastatic spread (miR-365, miR-9, miR-184, miR-21, miR-31, miR-135b, miR-205, let-7a) [25– 34]. [score:7]
[1 to 20 of 1 sentences]
78
[+] score: 6
Notably, linc-MD1 detaches miR-135 away from MEF2C mRNA, and thus, depresses the expression of MEF2C in skeletal muscle development and disease [86]. [score:6]
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79
[+] score: 6
Expression of mastermind-like-1 (MAML1) is controlled by miR-133, and myocyte-specific enhancer factor 2C (MEF2C) is the target of miR-135 [64]. [score:5]
linc-MD1 acts as a natural decoy for two muscle-specific miRNAs, miR-133 and miR-135 (Figure1 C) [64]. [score:1]
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80
[+] score: 6
Umezu et al. demonstrated that exosomes derived from multiple myeloma cells can transfer miR135b to endothelial cells to directly suppress factor-inhibiting hypoxia-inducible factor 1 (FIH-1), and activate HIF-1α via the HIF-FIH signaling pathway, leading to the overproduction of angiogenic cytokines such as VEGF, angiopoietin-1, and osteopontin, therefore resulted in endothelial cell migration, proliferation, and angiogenesis [50]. [score:6]
[1 to 20 of 1 sentences]
81
[+] score: 6
When comparing the two types of immortalized keratinocyte clones against primary cells, in order to identify the miRNAs characteristic for immortalized cells regardless of the mode of immortalization, miR-135b-3p and miR-146b-5p were downregulated while miR-205-5p was upregulated in both types of immortalized keratinocyte clones. [score:5]
MiRNAs miR-135b-3p, miR-146b-5p, miR-205-5p, miR-425-3p, miR-625-3p, and miR-485-3p which are involved in signaling and cell migration connected with epithelial to mesenchymal transition, tumor invasion, and metastasis, were detected in both the comparison of HPV immortalized keratinocytes with primary keratinocytes and the comparison of telomerase immortalized clones with primary keratinocytes. [score:1]
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82
[+] score: 6
In our in vivo study, the expression of miRNAs targeting Ras (let-7f, miR-135b, miR-143, miR-466h, miR-470, and miR-487b) was regulated in the lung of metformin -treated mice, along with another miRNA (miR-376c) playing an antioxidant role. [score:6]
[1 to 20 of 1 sentences]
83
[+] score: 6
Bourdon J. A. Saber A. T. Halappanavar S. Jackson P. A. Wu D. Hougaard K. S. Jacobsen N. R. Williams A. Vogel U. Wallin H. Carbon black nanoparticle intratracheal installation results in large and sustained changes in the expression of miR-135b in mouse lung Environ. [score:3]
Carbon black NP also induced pulmonary expression of miR-21, as well as miR-135b and miR-146b, all of which were increased following exposure [103]. [score:3]
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84
[+] score: 6
The dysregulation of miRNAs in CRC has been reported using miRNA expression profiling studies with different miRNAs identified either as enhancers (miR-21, miR-31, miR-103, miR-107) or suppressors (miR-135, miR-145, miR-200c) in the initiation and evolution of tumor metastasis [8- 13]. [score:6]
[1 to 20 of 1 sentences]
85
[+] score: 5
Several genes including oncogene MYC, tumor suppressor gene APC and negative regulator of WNT pathway AXIN2 were regulated by miR-34a, miR-135a and miR-135b. [score:5]
[1 to 20 of 1 sentences]
86
[+] score: 5
Conversely, neuronal differentiation can be brought about by miR-125a/b and miR-135b blocking BMP signalling [223], miR-124, and miR-9 via the targeting of several components of the Notch signalling pathway, which in turn regulates neuronal development and expansion of neural progenitors [195, 224, 225], or the activation of PAX6 by miR-135b, promoting neural lineage entry [226]. [score:5]
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87
[+] score: 5
MiR-133 and miR-135 also negatively regulate the osteogenic differentiation of hBMSCs induced by BMP2 by directly targeting RUNX2 and Smad5, respectively 24. [score:5]
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88
[+] score: 5
MiR-135b is a direct PAX6 target and specifies human neuroectoderm by inhibiting TGF-beta/BMP signaling. [score:5]
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89
[+] score: 5
The miRNA signatures generated for ER status (miR-342, miR-299, miR-217, miR-190, miR-135b, miR-218), for PR status (miR-520g, miR-377, miR-527-518a, miR-520f-520c) and for HER2/ neu status (miR-520d, miR-181c, miR-302c, miR-376b, miR-30e) include miRNAs that have previously been identified as dysregulated in breast cancer and other cancers [7, 9, 37- 43] and involved in the regulation of cell functions such as growth, apoptosis, migration and invasion [38, 42, 43]. [score:3]
Stepwise ANN analysis identified predictive miRNA signatures corresponding with oestrogen (miR-342, miR-299, miR-217, miR-190, miR-135b, miR-218), progesterone (miR-520g, miR-377, miR-527-518a, miR-520f-520c) and HER2/ neu (miR-520d, miR-181c, miR-302c, miR-376b, miR-30e) receptor status. [score:1]
The ER signature consisted of six miRNA transcripts (miR-342, miR-299, miR-217, miR-190, miR-135b, miR-218), and discriminated cases correctly with a median accuracy of 100% when classifying between ER -positive and ER -negative phenotypes. [score:1]
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90
[+] score: 5
Targeting of Runx2 by miR-135 and miR-203 impairs progression of breast cancer and metastatic bone disease. [score:5]
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91
[+] score: 5
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-26b, hsa-mir-27a, hsa-mir-29a, hsa-mir-30a, hsa-mir-33a, hsa-mir-98, hsa-mir-29b-1, hsa-mir-29b-2, mmu-let-7g, mmu-let-7i, mmu-mir-27b, mmu-mir-29b-1, mmu-mir-30a, mmu-mir-30b, mmu-mir-126a, mmu-mir-133a-1, mmu-mir-135a-1, mmu-mir-141, mmu-mir-194-1, mmu-mir-200b, hsa-mir-30c-2, hsa-mir-30d, mmu-mir-30e, hsa-mir-203a, hsa-mir-211, hsa-mir-218-1, hsa-mir-218-2, hsa-mir-200b, mmu-mir-300, mmu-let-7d, hsa-let-7g, hsa-let-7i, hsa-mir-27b, hsa-mir-30b, hsa-mir-133a-1, hsa-mir-133a-2, hsa-mir-135a-1, hsa-mir-135a-2, hsa-mir-141, hsa-mir-194-1, mmu-mir-30c-1, mmu-mir-30c-2, mmu-mir-30d, 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-26b, mmu-mir-29a, mmu-mir-29c, mmu-mir-27a, mmu-mir-98, mmu-mir-326, rno-mir-326, rno-let-7d, rno-mir-343, rno-mir-135b, mmu-mir-135b, hsa-mir-200c, mmu-mir-200c, mmu-mir-218-1, mmu-mir-218-2, mmu-mir-33, mmu-mir-211, mmu-mir-29b-2, mmu-mir-135a-2, hsa-mir-194-2, mmu-mir-194-2, hsa-mir-29c, hsa-mir-30c-1, hsa-mir-200a, hsa-mir-30e, hsa-mir-326, 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-21, rno-mir-26b, rno-mir-27b, rno-mir-27a, rno-mir-29b-2, rno-mir-29a, rno-mir-29b-1, rno-mir-29c-1, rno-mir-30c-1, rno-mir-30e, rno-mir-30b, rno-mir-30d, rno-mir-30a, rno-mir-30c-2, rno-mir-33, rno-mir-98, rno-mir-126a, rno-mir-133a, rno-mir-135a, rno-mir-141, rno-mir-194-1, rno-mir-194-2, rno-mir-200c, rno-mir-200a, rno-mir-200b, rno-mir-203a, rno-mir-211, rno-mir-218a-2, rno-mir-218a-1, rno-mir-300, hsa-mir-429, mmu-mir-429, rno-mir-429, hsa-mir-485, hsa-mir-511, hsa-mir-532, mmu-mir-532, rno-mir-133b, mmu-mir-485, rno-mir-485, hsa-mir-33b, mmu-mir-702, mmu-mir-343, mmu-mir-466b-1, mmu-mir-466b-2, mmu-mir-466b-3, hsa-mir-300, mmu-mir-511, rno-mir-466b-1, rno-mir-466b-2, rno-mir-532, rno-mir-511, mmu-mir-466b-4, mmu-mir-466b-5, mmu-mir-466b-6, mmu-mir-466b-7, mmu-mir-466b-8, hsa-mir-3120, rno-mir-203b, rno-mir-3557, rno-mir-218b, rno-mir-3569, rno-mir-133c, rno-mir-702, rno-mir-3120, hsa-mir-203b, mmu-mir-344i, rno-mir-344i, rno-mir-6316, mmu-mir-133c, mmu-mir-21b, mmu-let-7j, mmu-mir-21c, mmu-mir-30f, mmu-let-7k, mmu-mir-3569, rno-let-7g, rno-mir-29c-2, rno-mir-29b-3, rno-mir-466b-3, rno-mir-466b-4, mmu-mir-203b
Cesana et al. showed that a long-intergenic ncRNA (lincRNA), linc-MD1, regulates muscle differentiation by interacting with two miRNAs, miR-135 and miR-133, which can bind to MAML1 and MEF2C to regulate their expression levels. [score:5]
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92
[+] score: 5
This occurs via the transfer of miR-135b that targets factor-inhibiting hypoxia-inducible factor 1 (HIF-1). [score:5]
[1 to 20 of 1 sentences]
93
[+] score: 5
Moreover, osteogenic differentiation of MSC can be inhibited by miR-125b, miR-133, miR-135 and miR-206 which attenuate the expression of ERBB2 as one of the epidermal growth factor receptors, RUNX2 (Runt-related transcription factor 2) essential for osteoblast differentiation and skeletal morphogenesis, Smad5 as a signaling modulator of bone morphogenic proteins, and connexin-43 as a transmembrane protein and part of gap junctions, respectively. [score:5]
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94
[+] score: 5
For example, hsa-mir-135b shows dramatically decreasing expression during early childhood, while at prenatal time points hsa-mir-135b showed much higher but somewhat consistent expression. [score:5]
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95
[+] score: 5
miR-135b- and miR-146b -dependent silencing of calcium-sensing receptor expression in colorectal tumors. [score:3]
A further cause of silencing of the CaSR in colorectal tumors has been proposed to be increased expression of miR-135b and miR-146b that are considered to be oncogenic (Fetahu et al., 2016). [score:2]
[1 to 20 of 2 sentences]
96
[+] score: 5
MiR-135b is a direct PAX6 target and specifies human neuroectoderm by inhibiting TGF-beta/BMP signaling. [score:5]
[1 to 20 of 1 sentences]
97
[+] score: 5
Its lower expression is instead significantly correlated with larger tumor size and poor prognosis in colorectal cancer patients (74) Linc-MD1 MusclesGoverns the timing of muscle differentiation by acting as a competing endogenous RNA (ceRNA) with respect to miR-133 and miR-135 in mouse and human myoblasts (75) Xist Somatic cellsExpressed by the future inactive X chromosome, triggers gene silencing in cis by coating the chromosome. [score:5]
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98
[+] score: 5
For instance, microRNA-135b promotes lung cancer metastasis by targeting tumour suppressor LZTS1 and multiple key components in the Hippo pathway such as LATS2, β-TrCP and NDR2 23. [score:5]
[1 to 20 of 1 sentences]
99
[+] score: 5
For instance, linc-MD1 is a muscle-specific intergenic lncRNA that acts as a sponge for miR-133 and miR-135, preventing their suppression of MAML1 and MEF2C and activating muscle-specific gene expression [6]. [score:5]
[1 to 20 of 1 sentences]
100
[+] score: 5
For example, miRNAs, such as miR-135, miR-27, mir-155, miR-129, miR-106b, let-7, miR-125, miR-663, and miR-142, target APC and activate canonical Wnt signaling [100, 138, 139, 140, 141, 142, 143, 144, 145, 146]. [score:3]
Nagel R. le Sage C. Diosdado B. van der Waal M. Oude Vrielink J. A. Bolijn A. Meijer G. A. Agami R. Regulation of the adenomatous polyposis coli gene by the miR-135 family in colorectal cancer Cancer Res. [score:2]
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