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177 publications mentioning hsa-mir-218-1 (showing top 100)

Open access articles that are associated with the species Homo sapiens and mention the gene name mir-218-1. Click the [+] symbols to view sentences that include the gene name, or the word cloud on the right for a summary.

1
[+] score: 432
Other miRNAs from this paper: hsa-mir-29a, hsa-mir-34a, hsa-mir-218-2, hsa-mir-375, hsa-mir-424
The results showed that inhibition of HPV16 E6 downregulated SFMBT1 and DCUN1D1 and that downregulation of miR-218 rescued the inhibitory effect of the knockdown of HPV16 E6 on the expression of SFMBT1 and DCUN1D1(Figure 7H). [score:14]
The results showed that the ectopic expression of SFMBT1 nearly completely rescued the miR-218 -mediated suppression of invasion in miR-218 -overexpressing cells (P<0.001, Figures 5A), while re -expression of DCUN1D1 partially rescued the miR-218 -mediated suppression of invasion (P<0.001, Figures 5B). [score:11]
These results suggest that miR-218 can downregulate SFMBT1 and DCUN1D1 expression by directly targeting their 3′UTRs. [score:9]
B. Most specimens with high DCUN1D1 expression have low miR-218 expression, while more specimens with low DCUN1D1 expression have high miR-218 expression ([***], P<0.001). [score:9]
At the protein level, cervical cancer cells transfected with miR-218 mimics led to a significant increase in the expression of E-cadherin, which is a typical protein expressed by epithelial cells (Figure 2B), and led to a decrease in the expression of N-cadherin, which is a typical protein expressed by mesenchymal cells (Figure 2B). [score:9]
To determine whether the inhibition of EMT and invasion after the knockdown of HPV16 E6 in cervical cancer cells depends on miR-218 upregulation, we transfected both a synthetic siRNA against HPV16 E6 and a miR-218 inhibitor into SiHa cells. [score:9]
At the protein level, cervical cancer cells transfected with miR-218 inhibitor showed a decrease in the expression of E-cadherin and an increase in the expression of N-cadherin (Figure 2B). [score:7]
SFMBT1 overexpression rescues the inhibitory effect of miR-218 on EMT with more pindle-like mesenchymal phenotype in miR-218 -overexpressing SiHa cells. [score:7]
Therefore, we knocked down HPV16 E6, HPV16 E7, HPV18 E6 and HPV18 E7 using synthetic siRNA in SiHa or HeLa cells to identify the most important oncogenic component in HPV that downregulate miR-218 expression (Figure 7B and Supplementary Figure S3). [score:7]
We found that the expression of miR-218 was significantly upregulated only in the cervical cancer cells transfected with synthetic siRNA against HPV16 E6 (P<0.05). [score:6]
The inhibition of miR-218 on EMT, migration and invasion of cervical cancer cells downregulated by HPV16 E6. [score:6]
On the basis of the representation of miR-218 sites in their 3′untranslated regions (UTRs), over 100 mRNAs were predicted to be downregulated by miR-218. [score:6]
We found that miR-218 is downregulated in cervical cancer tissue and inhibits EMT, migration and invasiveness of cervical cancer cells, while HPV16 E6 induces EMT, and promotes invasiveness by repressing miR-218. [score:6]
The results showed that knockdown of SFMBT1 or DCUN1D1 inhibited invasion of cervical cancer cell similarly as those that were observed in miR-218 overexpression treatment (Figure 5A and 5B). [score:6]
Figure 5MiR-218 overexpression and SFMBT1 inhibition produce similar changes, which are restored by SFMBT1 ectopic expression in vitro A. Transwell invasion assays of SiHa cells were performed after transfection with NC, siRNA against SFMBT1, and/or miR-218 as indicated (up); SFMBT1 protein were detected by Western blot analysis (down). [score:6]
To determine whether miR-218 targets these genes directly, we constructed vectors that contained the 3′UTR of each of the eleven putative miR-218 targets and a luciferase construct. [score:6]
Some studies also demonstrated that the expression of miR-218 was strongly downregulated by HPV E6 [14, 20], but the mechanisms of the function of HPV on miR-218 and the role of miR-218 on the metastasis of cervical cancer are not well understood. [score:6]
Collectively, our findings indicate that HPV16 E6 decreases miR-218 and upregulates its targets, which plays an important role in the metastasis of cervical cancer. [score:6]
MiR-218 overexpression and SFMBT1 inhibition produce similar changes, which are restored by SFMBT1 ectopic expression in vitro. [score:6]
As reported, miR-218 sensitizes cancer cells to apoptosis and inhibits tumorigenicity and migration in some cancers through different targets, such as IKK-beta and Robo1 receptor [27, 28]. [score:5]
Figure 6 A. Immunostaining shown that DCUN1D1 expression is negatively correlated with miR-218 expression (scale bar, 100μm). [score:5]
To study the relationship between miR-218 and its target genes, we detected the expression of DCUN1D1 in another cervical cancer tissue microarray. [score:5]
In addition, transfection with miR-218 inhibitor significantly increased the expression of SFMBT1 and DCUN1D1 protein in SiHa cells (Figure 4E). [score:5]
These results indicate that HPV16 E6 promotes EMT and invasion in cervical cancer via the repression of miR-218, while miR-218 inhibits EMT and invasion in cervical cancer by targeting SFMBT1 and DCUN1D1. [score:5]
Figure 2MiR-218 inhibits cervical cancer cell EMT in vitro A. Phase contrast microscopy (up, scale bar, 50μm), F-actin staining (down, scale bar, 20μm) of SiHa cells transfected with the negative control (NC), miR-218 mimics, anti-NC, or miR-218 inhibitor for 48 hours. [score:5]
In accordance with these results, we found a clear decrease in endogenous SFMBT1 and DCUN1D1 protein expression in cervical cancer cells when miR-218 was overexpressed (Figure 4E). [score:5]
The results showed that DCUN1D1 expression by immunostaining is negatively correlated with miR-218 expression in cervical cancer tissues (P<0.001, Figure 6A and 6B, Table 3). [score:5]
To determine the molecular basis of the effect of miR-218 on the progression and metastasis of cancer, we used PicTar [21] and TargetScan [22] software to identify putative target genes of miR-218. [score:5]
Recent studies revealed that miR-218, as a tumor suppressor, was strongly downexpressed and related to proliferation, apoptosis and invasion in cervical cancer and some other cancers [16– 19]. [score:5]
A. Immunostaining shown that DCUN1D1 expression is negatively correlated with miR-218 expression (scale bar, 100μm). [score:5]
Considering our own findings as well as those that have been previously published, we speculate that miR-218 might inhibit the invasion and metastasis of cervical cancer by targeting SFMBT1. [score:5]
These results indicate that the ability of miR-218 to inhibit EMT is attributable to it's capacity of inhibiting SFMBT1. [score:5]
We found that miR-218 overexpression inhibited EMT in SiHa cells as shown by the changes in cell morphology and F-actin distribution (Figure 2A). [score:5]
Correlation between the expression of miR-218 and target genes. [score:5]
In total, we suggest that HPV16 E6 may promote the metastasis of cervical cancer by repressing miR-218 expression, and then promote the expression of SFMBT1 and DCUN1D1. [score:5]
miR-218 inhibits cancer cell EMT via the inhibition of SFMBT1. [score:5]
This suggests that the decrease in SFMBT1 and DCUN1D1 expression is required for the decrease in the invasiveness of miR-218 -overexpressing cervical cancer cells. [score:5]
In order to identify the effect of HPV on miR-218 expression, we detected the expression of miR-218 in cervical cancer cells that are infected with different types of HPV. [score:5]
Moreover, we identified SFMBT1 and DCUN1D1, which are responsible for the metastasis of cervical cancer, as the direct functional targets of miR-218. [score:4]
miR-218 directly targets the 3′UTRs of SFMBT1 and DCUN1D1. [score:4]
Recently, miR-218 has been shown to be downregulated in cancers and this is associated with poor prognosis [16, 18]. [score:4]
Our study shows that miR-218, as a tumor suppressor miRNA, also is a negative regulator of the pro-metastasizing genes SFMBT1 and DCUN1D1. [score:4]
Interestingly, we found that DCUN1D1 was targeted by miR-218 and knockdown of DCUN1D1 significantly decreased the invasiveness of cervical cancer cells. [score:4]
Our results showed that SFMBT1, as the direct and functional target of miR-218, promotes EMT and invasion in cervical cancer, which establishes SFMBT1 as a critical promoter of metastasis. [score:4]
Our findings identify a new mechanism of HPV16 E6 promoting EMT and metastasis by repressing miR-218, and then upregulating SFMBT1 and DCUN1D1. [score:4]
In total, the results demonstrate that miR-218 is downregulated in cervical cancer tissues, especially in advanced cervical cancer, and may be involved in the progression and metastasis of cervical cancer. [score:4]
Figure 3MiR-218 inhibits cervical cancer cell migration and invasiveness in vitro A. SiHa cells were transfected with NC, miR-218 mimics, anti-NC, or miR-218 inhibitor subjected to transwell migration and invasion assays (scale bar, 100μm). [score:4]
In contrast, SiHa cells transfected with miR-218 inhibitor changed from a round shape to a spindle-like mesenchymal phenotype (Figure 2A). [score:3]
Recent reports have suggested that oncogenic HPV E6 may interrupt the expression of various miRNAs, such as miR-34a [13] and miR-218 [14]. [score:3]
Correlation between the clinicopathologic features and expression of miR-218 in cervical cancer. [score:3]
B. The percentage of specimens showing low or high miR-218 expression in relation to clinicopathologic parameters by Fisher's Exact Test. [score:3]
A. Three representative cases of miR-218 expression are shown (scale bar, 100μm). [score:3]
Our results imply that DCUN1D1 may play a vital role in the inhibitory effects of miR-218 on cervical cancer metastasis. [score:3]
In this study, we identified that it is HPV16 E6 responsible for the decrease of miR-218 expression in cervical cancer cells. [score:3]
Figure 1 In situ hybridization was used to detect miR-218 expression in a cervical cancer tissue microarray. [score:3]
B. qRT-PCR analysis of miR-218 expression in SiHa or HeLa cells transfected with NC or siRNAs as indicated. [score:3]
MiR-218 directly targets the SFMBT1 and DCUN1D1 3′UTR. [score:3]
The association between miR-218 and protein expression was analyzed by the χ [2] test or Fisher's Exact Test. [score:3]
Wt, wild-type; mut, mutation at 49–52 nt of the SFMBT1 3′UTR; C. Mutation in the putative binding sites of miR-218 in DCUN1D1 3′UTRs abrogated the responsiveness to miR-218. [score:3]
HPV16 E6 induces EMT and promotes invasiveness of cervical cancer via the repression of miR-218 expression. [score:3]
These results indicate that miR-218 can inhibit EMT in cervical cancer. [score:3]
Because distant metastasis is responsible for patient mortality in the vast majority of cases of human carcinoma, miR-218 might become a key and potential prognostic factor and a candidate target for therapy in patients with cervical cancer. [score:3]
The results showed that lower miR-218 expression was significantly associated with advanced clinical stage (P= 0.006), poor tumor differentiation (P<0.001) and nodal metastasis (P= 0.003) (Figure 1B, Table 2). [score:3]
Figure 7 A. qRT-PCR analysis of miR-218 expression in SiHa (HPV16 [+]), HeLa (HPV18 [+]) and C33A (HPV [−]) cells. [score:3]
To identify the role of miR-218 in cervical cancer metastasis, we transfected the cervical cancer cell lines SiHa and HeLa with synthesized miR-218 mimics or inhibitors. [score:3]
Accordingly, cervical cancer cells transfected with miR-218 inhibitors showed a significant increase in cell migration and invasion. [score:3]
Despite the tumor suppressive role of miR-218 has been implicated in previous studies, the role of miR-218 in tumor metastasis and its molecular mechanism is not fully understood. [score:3]
In situ hybridization was used to detect miR-218 expression in a cervical cancer tissue microarray. [score:3]
miR-218 is encoded within intronic sequences of SLIT2 and SLIT3, which act as a tumor suppressor gene in many cancers [26]. [score:3]
C. SiHa and HeLa cells transfected with miR-218 inhibitors showed a significant increase in cell migration and invasion. [score:3]
The results showed that miR-218 overexpression inhibited the migration and invasion of SiHa (Figure 3A and 3C) and HeLa (Figure 3B and 3C) cells as measured by crystal violet staining. [score:3]
Moreover, we found that HPV16 E6 increases the expression of SFMBT1 and DCUN1D1 and miR-218 rescues the function of HPV16 E6. [score:3]
However, miR-218 expression was not significantly different between the various age groups and between patients with different tumor histologies. [score:3]
In order to identify the role of miR-218 in cervical cancer, we detected the expression of miR-218 in a cervical cancer tissue microarray that contained 94 cervical cancer tissues and 10 adjacent normal cervical tissues (Table 1). [score:3]
However, in HeLa cells with HPV18 infection, it appears that neither HPV18E6 nor HPV18E7 affects miR-218 expression. [score:3]
Clinical associations of miR-218 with DCUN1D1 expression. [score:3]
In the present study, we demonstrated the role of miR-218 and its mechanism of inhibiting cervical cancer metastasis. [score:3]
B. Immunoblotting of E-cadherin and N-cadherin in SiHa and HeLa cells transfected with NC, miR-218 mimics, anti-NC, or miR-218 inhibitor. [score:3]
A. Phase contrast microscopy (up, scale bar, 50μm), F-actin staining (down, scale bar, 20μm) of SiHa cells transfected with the negative control (NC), miR-218 mimics, anti-NC, or miR-218 inhibitor for 48 hours. [score:3]
A decrease of SFMBT1 and DCUN1D1 is required for miR-218 -mediated inhibition of motility and invasiveness of cervical cancer cells. [score:3]
miR-218 inhibits EMT, migration and invasive ability of cervical cancer cells. [score:3]
Clinical associations of miR-218 and DCUN1D1 expression. [score:3]
These in vitro results suggest that miR-218 inhibits EMT, migration and invasiveness of cervical cancer cells. [score:3]
A. qRT-PCR analysis of miR-218 expression in SiHa (HPV16 [+]), HeLa (HPV18 [+]) and C33A (HPV [−]) cells. [score:3]
MiR-218 inhibits cervical cancer cell migration and invasiveness in vitro. [score:2]
Furthermore, mutations in the putative binding sites of miR-218 in these two 3′UTRs abrogated their responsiveness to miR-218 (Figures 4B, 4C and 4D). [score:2]
The results showed that the expression of miR-218 was significantly decreased in SiHa (HPV16 [+]) (P<0.001) and HeLa (HPV18 [+]) (P<0.001) cells compared with C33A (HPV [−]) cells (Figure 7A). [score:2]
B. Mutation in the putative binding sites of miR-218 in SFMBT1 3′UTRs abrogated the responsiveness to miR-218. [score:2]
We found that the expression of miR-218 was significantly lower in cervical cancer tissues compared with adjacent normal cervical tissues (P<0.001) (Figure 1A). [score:2]
A. SiHa cells were transfected with NC, miR-218 mimics, anti-NC, or miR-218 inhibitor subjected to transwell migration and invasion assays (scale bar, 100μm). [score:2]
MiR-218 expression is lower in cervical cancer tissues. [score:2]
Moreover, the expression of miR-218 was lower in malignant tumors compared with benign tumors and were negatively correlated with the clinical stage and metastasis of cervical cancer. [score:2]
Reporter assays revealed that miR-218 significantly repressed two of the UTRs: SFMBT1 and DCUN1D1 (Figure 4A) in miR-218 -overexpressing SiHa cells. [score:2]
B. HeLa cells were transfected with NC, miR-218 mimics, anti-NC, or miR-218 inhibitor subjected to transwell migration and invasion assays. [score:2]
Downregulation of miR-218 is correlated with the progression of cervical cancer and is associated with clinicopathologic characteristics. [score:2]
MiR-218 inhibits cervical cancer cell EMT in vitro. [score:2]
To determine whether SFMBT1 and DCUN1D1 serve as critical mediators in the role of miR-218 on cervical cancer, we knocked down SFMBT1 and DCUN1D1 by the application of synthetic siRNA in SiHa and HeLa cells. [score:2]
These results further implicate the important role of miR-218 in the development and metastasis of cervical cancer through DCUN1D1. [score:2]
Then, we analyzed the association of miR-218 expression with clinicopathologic characteristics, including age, histology, clinical stage, differentiation and lymph node metastasis in 94 cervical cancer specimens. [score:1]
For normalization, U6 and β-actin were used as the endogenous controls for miR-218 and HPV E6/E7, respectively. [score:1]
cDNA was synthesized with the M-MLV reverse transcriptase (Invitrogen, Grand Island, NY, USA) for miR-218 or with the PrimeScript™ RT reagent Kit with gDNA Eraser (TaKaRa Otsu, Shiga, Japan) for HPV E6/E7. [score:1]
The intensity of the miR-218 and protein staining in epithelial cells of the 104 cervical cancer samples was scored according to a semiquantitative scale as previously described [41, 42]. [score:1]
In the present study, we attempted to further explore the role of miR-218 on the metastasis of cervical cancer. [score:1]
Next, we asked whether SFMBT1 or DCUN1D1 is involved in the relationship between miR-218 and EMT. [score:1]
E. The protein levels of SFMBT1 and DCUN1D1 were determined by Western blot analyses after transfection with NC, miR-218 mimics, anti-NC, or anti-miR-218 in SiHa cells. [score:1]
Figure 4 A. Luciferase activity in SiHa cells transfected with miR-218 mimics or NC after transfection of the indicated 3′UTR -driven reporter constructs. [score:1]
The sequence of the probes (Exiqon, Vedbaek, Denmark) for the hsa-miR-218 containing the locked nucleic acid/digoxigenin–modified bases was as follows: ACATGGTTAGATCAAGCACAA. [score:1]
Here, we found that HPV16 E6 promotes EMT and enhances the invasiveness of cervical cancer cells, which is consistent with the effects of SFMBT1 and DCUN1D1 and is contrary to the effect of miR-218 on cervical cancer metastasis. [score:1]
Real-time PCR was performed in a Real-Time Thermocycler 7500 (Applied Biosystems, Foster City, CA, USA) with a SYBR Green I Real-Time PCR Kit (GenePharma, Shanghai, China) for miR-218 or with a SYBR Premix Ex TaqTM (Tli RNaseH Plus) (TaKaRa Otsu, Shiga, Japan) for HPV E6/E7. [score:1]
D. The putative miR-218 -binding site in the SFMBT1 and DCUN1D1 3′UTR. [score:1]
A. Luciferase activity in SiHa cells transfected with miR-218 mimics or NC after transfection of the indicated 3′UTR -driven reporter constructs. [score:1]
We show a graphical representation illustrating the role of the miR-218 -mediated pathway in cervical cancer metastasis (Figure 7C). [score:1]
Next, we explored the interaction between HPV16 E6 and miR-218 in EMT and invasiveness of cervical cancer. [score:1]
In this study, we show that miR-218 was decreased in cervical cancer. [score:1]
Surprisingly, we found that SiHa cells showed less spindle-like mesenchymal phenotype when SFMBT1 was repressed (Figure 5C), which mimics the effect of miR-218 on EMT. [score:1]
C. A graphical representation illustrates the role of the miR-218 -mediated pathway in cervical cancer metastasis. [score:1]
The results showed that HPV16 E6 is the most important HPV oncoprotein that is involved in the repression of miR-218 in cervical cancer cells (Figure 7B). [score:1]
Thus, we think that miR-218 may be repressed by some other genes instead of HPV18E6 or HPV18E7 in HeLa cells, which is an interesting issue to be explored in the future. [score:1]
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2
[+] score: 338
TargetScan 4.1 [41], [42], [43] and miRBase Targets V5 [30], [31], [32] reported 570 and 946 miR-218 target sites respectively, where multiple target sites could be present in the one gene. [score:9]
Predicted mRNA targets of miR-218 were identified by using four online miRNA target prediction programs: PicTar (5 species conservation) [40], TargetScan 4.1 [41],, miRBase Targets Version 5 [30], [31], [32] and miRNAMap 2.0 [44], [45]. [score:9]
Concordant Downregulation of miR-218, SLIT2 and SLIT3 mRNA ExpressionTo confirm predicted host gene down-regulation, we measured SLIT2 and SLIT3 expression in 37 of the 39 NSCLC samples and compared it with their paired normal lung tissue (19 ACs and 18 SCCs). [score:8]
With this approach we identified putative tumour suppressor miR-218, experimentally confirmed its downregulation in NSCLC, and provided additional support for an association between reduced expression and cigarette smoke exposure. [score:8]
Reduced miR-218 Expression is Associated With SLIT2 and SLIT3 Copy Number LossCorrelation of miR-218 expression with host gene (SLIT2 and SLIT3) arrayCGH probe copy number found the majority of samples (31/39, 79.5%) demonstrated miR-218 down-regulation with a decrease in SLIT2 and/or SLIT3 copy number however the correlation was not significant (p>0.05; Pearson) (Figure S1a). [score:8]
For instance, in the ‘gene expression, cancer and cell morphology’ network, miR-218 may target genes directly and indirectly linked to two oncogenes, MYC and SRC (Figure S4). [score:7]
MiR-218, SLIT2 and SLIT3 Downregulation is Associated with SLIT2 and SLIT3 Gene DosageNext, we compared SLIT2 and SLIT3 copy number with miR-218, SLIT2 and SLIT3 expression to determine if their expression was due to gene dosage. [score:7]
In addition, we identified relevant cancer-related target genes and pathways targeted by miR-218, supporting a potential role as a tumour suppressor gene for NSCLC, especially SCCs. [score:7]
Statistically significant downregulation of miR-218 expression was observed in current and former smokers of both NSCLC subtypes. [score:6]
Nonetheless, further evidence including structural mutations and demonstrable tumour suppressor functions should be gathered before miR-218 can be appropriately designated as a tumour-suppressor gene for lung cancer. [score:6]
Correlation of miR-218 expression with host gene (SLIT2 and SLIT3) arrayCGH probe copy number found the majority of samples (31/39, 79.5%) demonstrated miR-218 down-regulation with a decrease in SLIT2 and/or SLIT3 copy number however the correlation was not significant (p>0.05; Pearson) (Figure S1a). [score:6]
Further, Schembri et al has also demonstrated a link between miR-218 downregulation and smoking; exposing human bronchial epithelial cells to cigarette smoke extract decreased miR-218 expression levels [58]. [score:6]
To determine whether this intragenic miRNA is co-regulated with host gene expression, we examined miR-218 and SLIT2/ SLIT3 expression levels. [score:6]
Concordant Downregulation of miR-218, SLIT2 and SLIT3 mRNA Expression. [score:6]
Despite noting a reduction in both miR-218 and host gene expression in the majority of NSCLCs, only a moderate correlation between miR-218 and SLIT2 expression was detected, with no significant relationship with SLIT3. [score:5]
No significant associations were observed between miR-218 expression and HPV, asbestos, disease recurrence or survival. [score:5]
Complete concordance (loss of both host genes plus a decrease in miR-218 expression) between SLIT2 and SLIT3 copy number and miR-218, SLIT2 and SLIT3 expression, was observed in 9/19 (47.4%) ACs and 10/18 (55.6%) SCCs. [score:5]
For 18 SCCs with miR-218 expression data, 9% (2/18) tested positive for HPV (subtypes 18 and 31) (Table 2) and HPV status not found to be associated with a reduction in miR-218 expression (Figure 3b). [score:5]
Table S8 Summary of miR-218 expression and SLIT2/SLIT3 expression and copy number changes. [score:5]
For one AC and two SCCs, miR-218 expression was increased despite reduced host gene copy numbers and expression. [score:5]
For clarity, additional miRNAs and their targets involved in this network were removed therefore only 9 of the 11 miR-218 targets are shown. [score:5]
MiR-218 was recently identified as a tumour suppressor in cervical cancer [25] where its downregulation was linked with human papilloma virus (HPV) [25]. [score:5]
Recent studies have begun to authenticate miR-218 target genes, including LAMB3 (laminin-5 β3) [25], ECOP (Epidermal growth factor receptor-coamplified and overexpressed protein) [58], [62] and transcription factor MAGF (v-maf musculoaponeurotic fibrosarcoma oncogene homolog G) [58]. [score:5]
Figure S1 Relationship between host gene copy number, host gene expression and miR-218 expression in lung adenocarcinomas and squamous cell carcinomas. [score:5]
We identified predicted target genes of miR-218 using four online miRNA target prediction algorithms. [score:5]
No significant correlation was observed between miR-218 expression and SLIT3 expression (SCC: 0.459, p = 0.055; AC: 0.297, p = 0.216). [score:5]
com) was performed on both the entire miR-218 target gene list and a prioritised list of miR-218 targets found to be enriched ≥2.0 by DAVID gene functional classification. [score:5]
No association was observed between miR-218 expression levels and disease recurrence or NSCLC survival post-resection (Figure 3d–e). [score:5]
Figure S4 Network of enriched miR-218 target genes linked to the biological functions of gene expression, cancer and cell morphology identified from Ingenuity Pathway Analysis. [score:5]
Over-represented gene ontologies (GO) and functional classes for putative target genes of miR-218 predicted by two or more of the algorithms were identified using the Database for Annotation, Visualization and Integrated Discovery (DAVID, April 2008 release) gene-GO enrichment analysis (ranked by the Expression Analysis Systematic Explorer (EASE) score threshold) and gene functional classification (performed with the highest stringency setting) [46], [47]. [score:5]
As such, miR-218 emerged as a strong candidate tumour suppressor, within a region of copy number loss in greater than two NSCLC studies and with demonstrated loss of expression in a third independent cohort. [score:5]
Target prediction found miR-218 can target numerous oncogenes, such as KIT, RET, BCL9, DCUN1D1 and PDGFRA. [score:5]
Similarly, no significant associations between miR-218 or host gene expression with host gene copy number were identified, but we found that complete concordance (copy number loss of both host genes with reduced miRNA and host gene expression) observed in 51% of lung cancers studied. [score:5]
Complete concordance (loss of both host genes plus a decrease in miR-218 expression) between SLIT2 and SLIT3 copy number and miR-218, SLIT2 and SLIT3 expression, was observed in 9/19 (47.4%) ACs and 10/18 (55.6%) SCCs (Figure S2 and Table S8). [score:5]
These findings would suggests that genetic loss may contribute to the observed reduction in miR-218, SLIT2 and SLIT3 expression, however it is likely that aberrations in multiple regulatory mechanisms are involved, including alterations to miRNA biogenesis and epigenetic controls. [score:4]
Concordant down-regulation of miR-218, SLIT2 and SLIT3 was observed in 15/18 (83.3%) SCCs and 15/19 (79%) ACs. [score:4]
Next, we compared SLIT2 and SLIT3 copy number with miR-218, SLIT2 and SLIT3 expression to determine if their expression was due to gene dosage. [score:4]
MiR-218 expression was down-regulated in 85% (33/39) of NSCLC tumours compared with paired normal lung. [score:4]
Additional support for a role for miR-218 in NSCLC comes from the potential association between miR-218 downregulation and cigarette smoke exposure. [score:4]
MiR-218 may target genes (coloured orange) directly and indirectly linked to two well known oncogenes, MYC and SRC (coloured red). [score:4]
GO enrichment analysis revealed that biological processes such as cell adhesion, protein modifications and transport, development and cell signalling were over-represented amongst miR-218 targets (p<0.001). [score:4]
Two miRNAs, miR-218 and miR-216, were common to training and all test sets, however, only miR-218 demonstrated concordant loss of copy number and expression (Figure 1). [score:3]
MiR-218 has also been shown to be downregulated in cervical carcinoma through the action of the HPV 16 E6 oncogene and may be important in early cervical tumourigenesis [25]. [score:3]
No significant associations were demonstrated between miR-218 expression and total number of pack years smoked (in current and former smokers) or time since quitting smoking (former smokers) in SCCs or ACs (data not shown). [score:3]
Produced from two separate precursors, miR-218 is found within host genes SLIT2 and SLIT3, with both the miRNA and its host genes demonstrating reduced expression in the majority (80%) of NSCLCs. [score:3]
Using this strategy we report for the first time, identification of miR-218 (hsa-miR-218; MIMAT0000275) located within a region of genomic loss (4p15.31 and 5q35.1) as a putative tumour suppressor in non-small cell lung cancer (NSCLC). [score:3]
RELN is also a predicted target of miR-218 but was not included in the enriched gene list. [score:3]
Core analysis for 578 predicted miR-218 target genes. [score:3]
Line illustrates the ratio of miR-218 target genes in the pathway divided by the total number of genes in the pathway. [score:3]
Altered miR-218 expression in NSCLC was also examined in relation to asbestos exposure. [score:3]
Identification of miR-218 from concordant copy number variation and gene expression from independent data sets. [score:3]
Table S9 Enriched miR-218 target gene groups identified by gene functional classification in DAVID. [score:3]
Relationship of miR-218 expression to smoking (a), HPV (b), asbestos (c), recurrence (d) and survival (e). [score:3]
Notably, one AC had concordant increases in miR-218, SLIT2 and SLIT3 expression with CN loss of only SLIT3. [score:3]
Putative Targets of miR-218 Support its Role in Carcinogenesis. [score:3]
Altered miR-218 expression was not found to be associated with asbestos exposure (Figure 3c) nor asbestos fibre burden (number of AB/gww lung tissue - data not shown). [score:3]
We did not find any link between HPV status and miR-218 expression but one reason may be that neither of our HPV positive samples were HPV type 16, and reduced miR-218 has only been reported with the HPV 16 – E6 oncogene. [score:3]
In lung cancer, we found no relationship between miR-218 expression levels and NSCLC recurrence or patient survival. [score:3]
Thus, epigenetic silencing is an alternative or additional ‘hit’, and strengthens the case for miR-218 and its host genes as potential tumour suppressor genes. [score:3]
Only one of the 89 miRNAs, miR-218, demonstrated concordant changes in copy number and expression. [score:3]
Table S10 Top 10 networks for predicted miR-218 target genes from ingenuity pathway analysis. [score:3]
Presence of HPV DNA was assessed in a cohort of 72 lung SCCs accessed from TPCH Tumour Bank, including the 18 cases with miR-218 expression data. [score:3]
The 15 ACs and 15 SCCs found to have concomitant reduced miR-218 and host gene expression also demonstrated copy number loss in SLIT2 and/or SLIT3. [score:3]
Complete concordance, that is, a reported loss of both host genes plus a decrease in miR-218 expression, was observed in 55.6% (10/18) SCCs and 38.1% (8/21) of ACs. [score:3]
We also examined whether the decrease in miR-218 expression was associated with asbestos, a well known lung carcinogen, but found no significant correlation. [score:3]
To confirm decreased miR-218 dosage and expression in lung cancer, we measured mature miR-218 expression in 21 ACs and 18 SCCs from our arrayCGH training set and their paired normal lung. [score:3]
Expression of miR-218 and its host genes in primary NSCLCs and their paired normal lung. [score:3]
MiR-218, SLIT2 and SLIT3 Downregulation is Associated with SLIT2 and SLIT3 Gene Dosage. [score:3]
Our observation that in both subtypes of NSCLC, miR-218 expression is significantly reduced in subjects with a history of cigarette smoking, provides additional support the notion that miR-218 may be involved in tobacco-related carcinogenesis [58]. [score:3]
Reduced miR-218 Expression is Associated With SLIT2 and SLIT3 Copy Number Loss. [score:3]
These findings were reflected in the Ingenuity Pathway Analysis, with miR-218 potentially regulating genes involved in cancer-related biological functions and three recognised cancer signalling pathways. [score:2]
MiR-218 has also been reported to be reduced in gastric cancer, with reduced expression linked to Helicobacter pylori infection and carcinogenesis [62]. [score:2]
Compared to normal lung tissue, miR-218 expression was significantly decreased in tumours of current (SCC: FC-4.4; AC: FC-4.1; p<0.05) and former (SCC: FC-5.1; AC: FC-1.9; p<0.05) smokers for both subtypes of NSCLC (Figure 3a) but no decrease was observed in never smokers (albeit small sample: SCC n = 3, ACs n = 3). [score:2]
Figure S2 MiR-218, SLIT2 and SLIT3 expression and SLIT2 and SLIT3 copy number in lung squamous cell carcinomas (a) and adenocarcinomas (b). [score:2]
Focused pathway analysis also revealed that miR-218 may regulate genes directly and indirectly related to MYC and SRC, two well characterised oncogenes [20], [21], [63], [64], [65]. [score:2]
As miR-218 may play a role in metastasis, with Leite et al reporting high levels of miR-218 in high grade prostate cancer compared to significantly reduced levels in metastatic prostate cancers [59], we examined the survival of our cases with miR-218 dysregulation. [score:1]
Association of miR-218 with Clinicopathological Phenotypes. [score:1]
This may be a reflection of disproportionate production of miR-218 from each genomic site, alterations in miRNA biogenesis or miR-218 may have a promoter separate from its host gene. [score:1]
MiR-218 Expression is Reduced in NSCLCs Compared with Paired Normal Lung. [score:1]
Both precursors are intragenic, with mir-218-1 situated within intron 15–16 or 14–15 of SLIT2 (Slit Homolog 2) and mir-218-2 residing within intron 14–15 of SLIT3 (Slit Homolog 3) (Figure 1). [score:1]
Zhang et al reported copy number losses of mir-218-1 and SLIT2 in ovarian (16%), breast (36%) and melanoma (33%), however, the alternative precursor and host gene were not mentioned [48]. [score:1]
Table S7 Summary of arrayCGH analysis for mir-218-1 and mir-218-2. (0.07 MB DOC) Click here for additional data file. [score:1]
Figure S3 Ingenuity Pathway Analysis miR-218. [score:1]
MiR-218 is produced from two unique miRNA precursors (hsa-mir-218-1; MI0000294 and hsa-mir-218-2; MI0000295), encoded in separate genomic locations, 4p15.31 and 5q35.1 respectively. [score:1]
In SCCs, miR-218 was moderately correlated with SLIT2 (R = 0.496, p = 0.036) and SLIT3 (R = 0.459, p = 0.055), however, only SLIT2 was statistically significant. [score:1]
The genomic location of miR-218 within its two host genes, SLIT2 and SLIT3, is also illustrated. [score:1]
However, mir-218-1 was located in a region of loss unique to SCCs, with an average fold loss of SLIT2 flanking probes −1.13 (range −1.95 to +1.29) (Table S7). [score:1]
Although we observed a significant reduction in miR-218 in subjects with a history of cigarette smoking we found no relationship between HPV and miR-218 in lung SCCs. [score:1]
To attempt to define a more specific network or pathway associated with miR-218, we performed a focused analysis using 121 enriched genes (≥2.00) identified with functional annotation clustering in DAVID. [score:1]
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Also, MiR-218 was significantly downregulated in PCa clinical specimens and loss of tumor-suppressive miR-218 enhanced cancer cell migration and invasion in PCa through direct regulation of LASP1 [27]. [score:8]
In the present study, we find that miR-218 overexpression in PCa cells inhibits HUVEC proliferation, migration and tube formation in vitro and suppresses tumor angiogenesis in the xenografts and rabbit corneas. [score:7]
miR-218 inhibits VEGFA expression by targeting RICTOR 3’-UTR. [score:7]
MiR-218 is downregulated and inhibits the invasion and metastasis of gastric cancer by targeting the Robo1 receptor [23]. [score:7]
Among the candidate target genes, we focus on RICTOR, the mTOR component 2. Indeed, we demonstrate that miR-218 negatively regulates RICTOR by binding to a specific target site within the 3’-UTR of RICTOR. [score:6]
RICTOR knockdown phenocopied miR-218 overexpression in inhibiting prostate cancer angiogenesis. [score:6]
miR-218 is down-regulated in PCa cells and inhibits HUVEC migration in vitro. [score:6]
Also, the and WB assay showed that knockdown of RICTOR inhibited mTOR/HIF1α&HIF2α/VEGFA axis (Figure 6E-6F), which was similar with the effects of miR-218 overexpression in PCa cells. [score:5]
Therefore, these results suggest that overexpression of miR-218 inhibits the process of tumor angiogenesis of PCa cells. [score:5]
Moreover, through repressing TPD52 expression, miR-218 could inhibit prostate cancer growth and promote apoptosis [28]. [score:5]
After incubation for 18 hours, the migration of HUVECs was suppressed by miR-218 overexpression in LNCaP, C4-2 and CWR22Rv1 cells (Figure 1C). [score:5]
miR-218 inhibits VEGFA expression. [score:5]
VEGFA expression is inhibited by miR-218 in PCa cells. [score:5]
In addition, the phosphorylation status of AKT at Ser-473, mTOR, HIF1α, HIF2α and VEGFA expression are decreased in miR-218 -overexpressing PCa cells at the protein level. [score:5]
Therefore, our data here show that miR-218 can inhibit angiogenesis through targeting RICTOR/VEGFA axis in PCa (Figure 7). [score:5]
Also, we find that overexpression of miR-218 in human PCa cell lines inhibits RICTOR at both mRNA and protein level. [score:5]
These results indicate that miR-218 may suppress RICTOR/mTOR/HIF1α&HIF2α/VEGFA axis, and then inhibits tumor angiogenesis of PCa cells. [score:5]
Overexpression of miR-218 suppressed luciferase activity of the wild-type reporter (50%). [score:5]
B. miR-218 overexpression suppressed tube formation of HUVECs. [score:5]
Overexpression of miR-218 significantly suppressed the luciferase activity of wild-type reporter (50%) but not mutant reporter (Figure 4B). [score:5]
Moreover, we downloaded the microRNA expression data from GEO database to compare the miR-218 expression level between human PCa samples and their normal adjacent benign prostate tissues. [score:5]
The wild-type (WT) and mutant (MUT) versions of the RICTOR 3’-UTR containing site-directed mutations in the putative miR-218 target sites, were cloned into the reporter plasmids. [score:5]
As expected, overexpression of miR-218 also inhibited the secreted VEGFA protein level (Figure 3C). [score:5]
MiR-218 suppresses nasopharyngeal cancer progression and restoring miR-218 expression in NPC might be useful for the clinical management [24]. [score:5]
D. Overexpression of miR-218 suppressed the recruitment of HUVECs in a co-cultured system. [score:5]
In addition, overexpression of miR-218 in PCa cell lines, including LNCaP, C4-2 and CWR22Rv1, resulted in the down-regulation of RICTOR both at mRNA level and protein level compared with the negative control (Figure 4C and 4D). [score:5]
These data indicate that miR-218 may inhibit tumor angiogenesis via suppressing RICTOR/mTOR/HIF1α&HIF2α/VEGFA axis in PCa cells. [score:5]
Firstly, we search the potential targets of miR-218 using TargetScan. [score:5]
RICTOR, the mTOR component 2, was a direct target of miR-218 and miR218/RICTOR axis was the potential mechanism. [score:4]
However, the regulation of angiogenesis-related cytokines in human cancer cells is very complex, so we could not rule out the possibility that other signaling pathways modulating VEGF expression may also be affected by miR-218. [score:4]
Asterisks indicate a significant difference compared with controls at *p < 0.05, **p < 0.01. miR-218 inhibits tumor angiogenesis of PCa cells in vitroTo reveal the impact of miR-218 on tumor angiogenesis in PCa, three different PCa cell lines with ectopic miR-218 overexpression were constructed (Figure 1B). [score:4]
The formation of tube-like structures in Matrigel was also suppressed by miR-218 overexpression in LNCaP, C4-2 and CWR22Rv1 cells compared with the control groups (Figure 2B). [score:4]
miR-218 is down-regulated in PCa cell lines and tissues. [score:4]
Mechanistically, miR-218 exerts these functions by down -regulating expression of VEGFA, which is the most prominent factor among the angiogenic cytokines [30– 32]. [score:4]
In addition, miR-218 also suppresses prostate cancer development as well. [score:4]
Overall, these results indicate that miR-218 is down-regulated in both PCa cell lines and tissues. [score:4]
To further demonstrate that miR-218 in PCa cells affects the angiogenesis of HUVECs through the regulation of RICTOR, RICTOR knockdown PCa cell lines were constructed. [score:3]
Therefore, our findings provide new insights into the potential mechanisms of PCa oncogenesis, revealing the potential of miR-218 as a useful biomarker or therapeutic target for PCa. [score:3]
Published data shows that miR-218 is a tumor suppressive miRNA in human cancers including prostate cancer. [score:3]
C. Real-time PCR was used to analyze the expression level of RICTOR in LNCaP, C4-2 and CWR22Rv1 cells transfected with LV3-NC or LV3-miR-218. [score:3]
To determine whether miR-218 is mis-regulated in PCa cell lines, we performed miRNA RT–PCR experiments, and the result showed that several PCa cell lines, including LNCaP, C4-2 and CWR22Rv1, had undetectable or very low level of miR-218 expression compared to normal prostate epithelial cell line BPH-1 (Figure 1A). [score:3]
The result showed that the expression level of miR-218 in human PCa tissues was much lower than that in the adjacent normal tissues (Supplementary Figure 1A), especially in metastatic PCA tissues (Supplementary Figure 1B). [score:3]
Also, these findings indicate that miR-218 can be used as a biomarker for diagnosis and treatment of prostate cancer in the future, and miR-218 -based molecular targeting therapy may be another useful therapeutic strategy for prostate cancer. [score:3]
B. Stable miR-218 overexpression PCa cell lines were constructed. [score:3]
Also, the phosphorylation status of AKT at Ser-473, p-mTOR, HIF1α and HIF2α decreased in the miR-218 -overexpressed PCa cells at the protein level (Figure 4E). [score:3]
Figure 3 A. Real-time PCR was used to analyze the expression level of VEGFA in LNCaP, C4-2 and CWR22Rv1 cells transfected with LV3-NC or LV3-miR-218. [score:3]
To reveal the impact of miR-218 on tumor angiogenesis in PCa, three different PCa cell lines with ectopic miR-218 overexpression were constructed (Figure 1B). [score:3]
MiR-218 was significantly overexpressed in all localized high GS and pT3 PCa as well as metastatic carcinoma, suggesting that miR-218 may be involved in the process of metastases of PCa [26]. [score:3]
Many researches have reported that miR-218 acts as a tumor suppressor in kinds of human cancers. [score:3]
miR-218 inhibits HUVEC proliferation and tube formation in vitro. [score:3]
miR-218 inhibits tumor angiogenesis of PCa cells in vitro. [score:3]
In a co-cultured system, the migration of HUVECs was abolished by miR-218 overexpression in LNCaP, C4-2 and CWR22Rv1 cells as well (Figure 1D). [score:3]
miR-218 inhibits tumor growth and angiogenesis in vivo. [score:3]
A. The expression level of miR-218 was analyzed by miRNA Real-time PCR in a normal prostate epithelial cell line BPH-1 and different PCa cell lines (i. e., LNCaP, C4-2 and CWR22Rv1). [score:3]
In order to confirm the direct targeting and binding between miR-218 and the 3’-UTR of RICTOR, a dual-luciferase reporter assay was performed. [score:3]
The stable miR-218 overexpression subclones were maintained by using 2–3 μg/ml puromycin-resistant culturing (puromycin, Sigma, USA). [score:3]
org/) was used to predict genes which were targeted by miR-218, and we identified a putative miR-218 binding site within the 3’-UTR of RICTOR (Figure 4A). [score:3]
This suggests that the 3’-UTR of RICTOR is specifically targeted by miR-218. [score:3]
A. miR-218 overexpression reduced the proliferation of HUVECs. [score:3]
miR-218 inhibits tumor growth and angiogenesis of PCa cells in vivo. [score:3]
A. Real-time PCR was used to analyze the expression level of VEGFA in LNCaP, C4-2 and CWR22Rv1 cells transfected with LV3-NC or LV3-miR-218. [score:3]
Figure 7 In conclusion, we demonstrate that miR-218 suppresses PCa progression by modulating angiogenesis through the RICTOR/VEGFA axis. [score:3]
Figure 4 by targeting RICTOR 3’-UTR A. RICTOR 3’-UTR regions containing the wild-type or mutant binding site and the sequence complementarity between miR-218 and the RICTOR 3’-UTR (WT and MUT) were shown. [score:3]
Figure 2 A. miR-218 overexpression reduced the proliferation of HUVECs. [score:3]
miR-218 targets RICTOR by binding to its 3’-UTR. [score:3]
miR-218 suppresses RICTOR/mTOR/HIF1α&HIF2α/VEGFA axis. [score:3]
miR-218 inhibits tumor growth and angiogenesis of PCa cells in vivoTo confirm the effects of miR-218 on tumorigenicity in vivo, transfected CWR22Rv1 cells were injected into the flanks of nude mice to form xenograft tumors. [score:3]
Taken together, it is found that miR-218 can inhibit tumor growth and angiogenesis in vivo. [score:3]
C. Overexpression of miR-218 decreased the recruitment of HUVECs by conditioned medium (CM), which was collected from the LNCaP, C4-2 and CWR22Rv1/LV3-NC or LV3-miR-218 cells. [score:3]
MiR-218/survivin axis inhibits cervical cancer progression by regulating clonogenicity, migration, and invasion [25]. [score:3]
C- F. The expression of CD31, PCNA, RICTOR and VEGFA were analyzed in paraffin fixed tumor sections from CWR22Rv1/LV3-NC and CWR22Rv1/LV3-miR-218 xenografts by immunohistochemistry; representative photographs were shown at magnification × 200 (CD31) or × 400 (PCNA, RICTOR, VEGFA). [score:3]
Figure 5miR-218 inhibits tumor growth and angiogenesis in vivo A. Subcutaneous xenografts of CWR22Rv1/LV3-NC and CWR22Rv1/LV3-miR-218 subclones were harvested 2 weeks after inoculation. [score:3]
Figure 1 A. The expression level of miR-218 was analyzed by miRNA Real-time PCR in a normal prostate epithelial cell line BPH-1 and different PCa cell lines (i. e., LNCaP, C4-2 and CWR22Rv1). [score:3]
Therefore, we suppose that miR-218 may also inhibit tumor angiogenesis in PCa. [score:3]
MiR-218 can inhibit cell growth, migration, invasion and cancer stem-like cell self-renewal, and induce apoptosis in cancers [13– 15]. [score:2]
After that, cells were analyzed for miR-218 expression using the miRNA real-time quantitive PCR (qPCR) assay described as above. [score:2]
Compared with the control groups, VEGFA mRNA level in all PCa cell lines with miR-218 overexpression decreased (Figure 3A). [score:2]
The commercial LV3-miR-218 lentivirus vector (pre-miR-218) (containing green fluorescent protein GFP and the puromycin sequence) were constructed by GenePharma (Shanghai, China). [score:1]
In the present study, we found that miR-218 repressed tumor angiogenesis of PCa cells in vitro and in vivo. [score:1]
However, the underlying role of miR-218 in tumor angiogenesis of PCa remains unclear. [score:1]
Three weeks after miR-218 -transfected CWR22Rv1 cells transplanted into rabbit cornea, CWR22Rv1/NC cells induced a neovascular response and formed visible tumors, but CWR22Rv1/LV3-miR-218 cells lost these abilities (Figure 5G). [score:1]
Also, further experiments reveal the mechanisms how miR-218 affects VEGFA. [score:1]
A. Subcutaneous xenografts of CWR22Rv1/LV3-NC and CWR22Rv1/LV3-miR-218 subclones were harvested 2 weeks after inoculation. [score:1]
The 3’UTR of the RICTOR mRNA containing either the putative or mutated miR-218 binding site was synthesized by GENECHEM (Shanghai, China). [score:1]
However, the role of miR-218 in PCa angiogenesis remains unknown. [score:1]
1.5 × 10 [5] CWR22Rv1/pre-miR-218 or miR-NC cells were implanted into the micropockets (four rabbits per group). [score:1]
G. CWR22Rv1/LV3-NC cells but not CWR22Rv1/LV3-miR-218 cells could induce angiogenesis in rabbit cornea (n = 3). [score:1]
To confirm the effects of miR-218 on tumorigenicity in vivo, transfected CWR22Rv1 cells were injected into the flanks of nude mice to form xenograft tumors. [score:1]
B. Relative luciferase activity was analyzed after transfection with the wild-type or mutant 3’-UTR reporter plasmids in LV3-NC or LV3-miR-218 293T cells. [score:1]
A slower tumor growth in the CWR22Rv1/LV3-miR-218 group was observed (Figure 5A). [score:1]
A. RICTOR 3’-UTR regions containing the wild-type or mutant binding site and the sequence complementarity between miR-218 and the RICTOR 3’-UTR (WT and MUT) were shown. [score:1]
Schematic representation of the roles of miR-218-RICTOR/pAKT/pmTOR-HIF1α&HIF2α-VEGFA signaling on the angiogenic properties of PCa cells. [score:1]
The average tumor weight from the CWR22Rv1/LV3-miR-218 group was lower than that from the control group (Figure 5B). [score:1]
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We further found that miR-218 negatively regulated IL-6 receptor and JAK3 gene expression by directly targeting the 3′-UTR of their mRNAs. [score:7]
Our findings that miR-218 was downregulated in ALDH positive lung cells aid to clarify the mechanism of upregulation of STAT3 signaling in these cells. [score:7]
Overall, our findings of the anti-proliferative effects of miR-218 in lung adenocarcinima cells, through the direct targeting of IL-6R and JAK3, further corroborate a tumor suppressive role for miR-218 in NSCLC. [score:6]
This suppressive effect was abolished by the mutations in the miR-218 targeted 3′ UTR regions (Fig. 3b). [score:6]
Compared with the tumors from the control group, tumor tissues with miR-218 overexpression showed lower levels of phosphorylated STAT3(Fig. 6c) and Ki67 (Fig. 6d), suggesting that overexpressing miR-218 inhibited the STAT3 signaling and reduced tumor growth in vivo. [score:6]
a IL-6R and JAK3 gene was predicted as a direct target of miR-218 (TargetScan). [score:6]
We observed that the expression of miR-218 was significantly down-regulated in lung cancer tissues compared to normal lung tissues. [score:5]
Overexpression of miR-218 in lung cancer cells reduced cell proliferation and invasiveness, suggesting miR-218 is acting as tumor suppressor consistent with its function in other reported human cancer types [16, 18– 20]. [score:5]
Finally, we report the correlation between the levels of miR-218 host genes, as well as its targeted genes, and the prognosis of lung cancer disease. [score:5]
Additionally, overexpression of miR-218 inhibited ALDH1A1 positive to survive in anchorage-independent conditions and their ability to form tumor-spheres (Fig. 5e). [score:5]
Twenty-four hours after seeding, the ALDH1A1 positive cells were infected with lentivirus expressing miR-218 or miR-control To investigate whether overexpression of miR-218 would reduce tumor growth in vivo, we infected A549 cells with lentivirus expressing miR-218. [score:5]
Overexpression of miR-218 reduces tumor growth in vivo by targeting STAT3 signaling. [score:5]
MiR-218 is a vertebrate-specific intronic miRNA co-expressed with its host genes, tumor suppressor gene SLIT2/3. [score:5]
To determine whether the IL-6R and JAK3 mRNA expression is regulated by miR-218 through direct binding to their 3′-UTR regions, we used a dual-luciferase reporter system containing either the wild-type or the mutated 3′-UTR of IL-6R and JAK3. [score:5]
In summary, miR-218 is capable to inhibit lung cancer cell proliferation and invasion, at least partially through repressing IL-6R and JAK3 genes expression. [score:5]
The results of cell proliferation showed that re -expression of miR-218 reduced cell proliferation (Fig. 2a), whereas overexpression of anti-miR-218 promoted cell proliferation (Fig. 2b). [score:5]
Overexpression of miR-218 significantly reduced the expression of JAK3, IL-6R and phosphorylated STAT3 (Fig. 3c, d). [score:5]
To further investigate lung tumorigenesis, we also analyzed the expression of SLIT2 and SLIT3 since miR-218 co-expresses with these host tumor suppressor genes. [score:5]
We overexpressed miR-218 in ALDH1A1 positive cells by lentivirus expressing miR-218 (Fig. 5c) and found that the levels of IL-6R, JAK3 and phosphorylated STAT3 were reduced (Fig. 5d). [score:5]
To further gain evidence, we examined the mRNA and protein expression of IL-6/JAK/STAT3 pathway after overexpressing miR-218 by qRT-PCR and western blotting. [score:5]
Our study using lung cancer samples included in TCGA database reaffirmed the results of the previous study in lung squamous cell carcinoma and also found that the levels of miR-218 and its host genes SLIT2/3 are downregulated in the tissues of lung adenocarcinoma. [score:4]
In addition, in EGFR mutated lung cancer cells, miR-218 can also negatively regulate pSTAT3 signaling through targeting EGFR [31]. [score:4]
We further observed that ALDH1A1 positive cells had higher levels of IL-6R, JAK3 and phosphorylated STAT3 (Fig. 5b), suggesting that the lower levels of miR-218 may be responsible for the upregulation of STAT3 signaling in ALDH positive lung cancer cells. [score:4]
A previous study highlighted that the levels of miR-218 is downregulated in the tissues of lung squamous cell carcinoma, in association with cigarette smoking [17]. [score:4]
The data were the means ± SD of three individual experiments To further gain insights by which miR-218 could potentially regulate the cell growth and differentiation of lung cancer cells, we performed predictions using programs TargetScan, miRDB, PicTar and PITA. [score:4]
These data suggest that both miR-218 and the related host genes were downregulated in both of lung cancer NSCLC subtypes. [score:4]
In a previous study, miR-218 was reported to positively regulate STAT3 in the spinal cord and microglia through targeting SOCS3 [51]. [score:4]
Lentivirus vector expressing miR-218 was purchased from Applied Biological Materials (Richmond, BC). [score:3]
f Cell proliferation was determined by cell counting using H1975 and A549 cells 48 h after transfection of miR-218 or miR-control with or without IL-6 treatment Fig. 4Inhibition of IL-6/JAK3/STAT3 signaling reduces cell proliferation and colony formation in vitro. [score:3]
MiR-218 was downregulated in NSCLC, which then caused constitutive activation of STAT3 signaling. [score:3]
Finally, utilizing TCGA data we studied the association of target genes of miR-218 with the prognosis of lung cancer. [score:3]
c and d Tissue levels of phosphorylated STAT3 and Ki67 in an A549 xenograft were visualized by immunofluorescence co-staining with DAPI In order to correlate our findings with lung cancer prognosis in clinical settings, we analyzed the data from 1405 lung cancer patients and the gene expression of miR-218 host genes (SLIT2/SLIT3), IL-6, IL-6R, JAK3 and STAT3 in their tumor tissues [32]. [score:3]
a The expression levels of miR-218 in 430 lung adenocarcinoma tumor tissues and 46 normal tissues were obtained from TCGA. [score:3]
Overexpressing miR-218 in lung cancer reduced STAT3 signaling when tested both in vitro and in vivo. [score:3]
Bioinformatics analysis of miR-218 target genes. [score:3]
Furthermore, immunofluorescence staining revealed that overexpression of miR-218 decreased phosphorylation of STAT3 (Fig. 3e). [score:3]
Therefore, it could be asserted that miR-218 could portray its inhibitory effects by at least partially modifying IL-6/JAK/STAT3 signaling mediator molecules. [score:3]
Our data also demonstrated that overexpression of miR-218 decreased cell invasion (Fig. 2c) and colony formation ability (Fig. 2d). [score:3]
H1975 and A549 cells were transiently transfected with miR-218 mimic or miR-218 inhibitor or small interfering RNA (siRNA) (Ambion/Life Technologies, Grand Island, NY; Sigma-Aldrich, St. [score:3]
c ALDH1A1 positive cells were infected by lentivirus expressing miR-218 or miR-control. [score:3]
It was predicted that miR-218 could target components of IL-6/JAK/STAT3 pathway. [score:3]
Expression levels of miR-218 and its host gene SLIT2/3 in normal and lung tumor tissues. [score:3]
Here, we evaluated the expression and function of miR-218 in human lung cancer and ALDH positive lung cancer cells to understand the potential mechanisms responsible for disease pathology. [score:3]
b 5 × 10 [6] A549 cells infected with lentivirus expressing miR-218 or miR-control were injected subcutaneously into two groups of nude mice (five mice per group). [score:3]
Our data suggest that overexpressing miR-218 in ALDH positive lung cancer cells could also exhibit similar responses in reducing self-renewal capability of these cells. [score:3]
Twenty-four hours after seeding, the ALDH1A1 positive cells were infected with lentivirus expressing miR-218 or miR-control. [score:3]
MiR-218 is downregulated in ALDH positive lung cancer cells. [score:3]
Human lung cells A549 were infected with lentivirus expressing miR-218 or miR-control. [score:3]
MiR-218 acts as a tumor suppressor in diverse human cancer types impacting regulation of multiple genes in oncogenic pathways. [score:3]
Overexpression of miR-218 affects lung cancer cell proliferation and invasiveness. [score:3]
Overexpression of miR-218 in ALDH positive cells was carried to test the survival by tumorsphere culture. [score:3]
Overexpression of miR-218 decreased cell proliferation, invasion, colony formation, and tumor sphere formation in vitro and repressed tumor growth in vivo. [score:3]
a A549 cells were infected with lentivirus expressing miR-218 or miR-control. [score:3]
c The mRNA expression of IL-6R and JAK3 was analyzed by quantitative real-time PCR 24 h after transfection of miR-218 or miR-control. [score:3]
In this present study, we attempted to determine the publicly-available data from The Cancer Genome Atlas (TCGA) for comparison of miR-218 and its host gene SLIT2/3 expression levels between lung cancer tissues and normal lung tissues. [score:3]
We found that miR-218 also targeted two molecules of IL-6/JAK/STAT3 signaling pathway, which is constitutively activated in NSCLC [45]. [score:3]
MiR-218 acts as a tumor suppressor in lung cancer via IL-6/STAT3 signaling pathway regulation. [score:3]
Fig. 6Overexpression of miR-218 represses tumor growth in vivo. [score:3]
Expression levels of miR-218 and its host gene SLIT2/3 in normal and lung tumor tissuesThe levels of miR-218 were found to be significantly lower in lung adenocarcinoma tissues and were compared to normal lung tissues (fold change of cancer vs. [score:2]
Compared to the control group, the mean volume of the tumors in the miR-218 overexpressing group was significantly smaller (Fig. 6b). [score:2]
Similar low expression levels of miR-218, SLIT2and SLIT3 were obtained in lung cancer tissues when compared to normal lung tissues (the fold change of miR-218 in cancer vs. [score:2]
To study whether re -expression of miR-218 would affect cell behavior, we transfected miR-218 or anti-miR-218 into A549 and H1975 cells and then performed cell proliferation, trans-well invasion, and colony formation assays. [score:2]
Cells infected with miR-218 expressing virus showed reduced cell proliferation compared to cells infected with control virus (Fig. 6a). [score:2]
e- f The expression levels of SLIT2 and SLIT3 in 483 lung squamous cell carcinoma tumor tissues and 50 normal tissues were obtained from TCGA Additionally, we also compared the levels of miR-218, SLIT2 and SLIT3 in lung squamous cell carcinoma subtype and normal tissues. [score:2]
Overall, our data indicated that miR-218 negatively regulated STAT3 signaling through IL-6R and JAK3 in EGFR wild type cells and through IL-6R, JAK3, and EGFR in EGFR mutated cells. [score:2]
e- f The expression levels of SLIT2 and SLIT3 in 483 lung squamous cell carcinoma tumor tissues and 50 normal tissues were obtained from TCGA Additionally, we also compared the levels of miR-218, SLIT2 and SLIT3 in lung squamous cell carcinoma subtype and normal tissues. [score:2]
Therefore, miR-218 is not able to positively regulate STAT3 in NSCLC, whose SOCS3 is silenced. [score:2]
MiR-218 has been reported to target EGFR [31], an important kinase implicated in signaling in lung cancer cells. [score:2]
Taken together, these data suggest that miR-218 modulated lung cancer cell phenotype through negatively regulating the STAT3 signaling pathway. [score:2]
To explore whether miR-218 would be dysregulated in these small populations of cells marked by ALDH1A1, we isolated ALDH1A1 positive cells from both H1975 and A549 cells by flow cytometry. [score:2]
In addition to IL-6R and JAK3, miR-218 was also reported to negatively regulate EGFR, leading to reduced levels of pSTAT3 [31]. [score:2]
We also analyzed the correlation between levels of IL6-R and miR-218, as well as the correlation between levels of JAK3 and miR-218 in patients with lung adenocarcinima TCGA cohort, which showed significant negative correlation (Additional file 1: Figure S2). [score:1]
The mature form of miR-218 is generated from two separate loci, miR-218-1 and miR-218-2, which are located at the introns of SLIT2 and SLIT3, respectively [15– 17]. [score:1]
Transfection of miR-218 to investigate its function in lung cancer cells was done and in vivo effects were determined using miR-218 expressing lentiviruses. [score:1]
Especially considering the significant decrease of miR-218 in ALDH positive cells with cancer stem cell characterics, further investigation of IL-6/STAT3 as a potentially therapeutic target in NSCLC is warranted. [score:1]
More importantly, we found that ALDH positive lung cancer cells, marked by ALDH1A1, had lower levels of miR-218 and higher levels of STAT3 signaling than in ALDH negative cells. [score:1]
H1975 and A549 cells were transfected with miR-218 or miR-control. [score:1]
Forty-eight hours after miR-218 mimic transfection, cells were fixed with 50% methanol and 50% acetone at 4 °C for 30 min and blocked with 1% BSA for 1 h. After incubation with pSTAT3 or Ki67 primary antibody(Cell Signaling Technology, Danvers, MA), the cells were incubated with FITC or Alexa Fluor(R) 555-coupled secondary antibody(Cell Signaling Technology, Danvers, MA) for 1 h and then stained with the nuclear marker DAPI(Cell Signaling Technology, Danvers, MA) for 10 min. [score:1]
The newly-identified miR-218–mediated IL-6R and JAK3 genes silencing may facilitate a better understanding of the molecular mechanisms of lung cancer progression and present a new strategy to treat patients with lung cancer. [score:1]
Fig. 2Functional studies of miR-218 in lung cancer cells. [score:1]
Twenty-four hours after transfection or treatment with miR-218 or miR-control,H1975 and A549 cells were treated with 0.25% trypsin plus 0.5 mM EDTA solution and re-plated in six-well plates at a density of 500 cells per well and were cultured with RPMI 1640 supplemented with 10% FBS for 10 days. [score:1]
We also investigated the downstream targets of miR-218 in lung cancer cells for its underlying mechanism of action. [score:1]
microRNA-218 Lung cancer STAT3 Interleukin-6 receptor Cancer stem cell In China, lung cancer is the most common incident cancer with high mortality rate [1]. [score:1]
d Protein levels of JAK3, IL-6R, pSTAT3 and STAT3 in A549 and H1795 cells were examined by western blotting 36 h after transfection of miR-218 or miR-control. [score:1]
The wild-type or mutant luciferase reporter constructs, together with the pRL-TK Vector (Promega, Madison, WI), were co -transfected into cells with miR-218 mimic or mimic-control by lipofectamine 2000 (Life Technologies, Grand Island, NY). [score:1]
However, the molecular mechanism of miR-218 in NSCLC remains unclear. [score:1]
Correlation of IL-6R/JAK3 and miR-218 in patients with lung adenocarcinoma in TCGA cohort. [score:1]
d Colony formation capability in H1975 and A549 cells was examined after transfection of miR-218 or miR-control. [score:1]
The levels of miR-218 in these infected cells were examined by real time PCR. [score:1]
Several lines of evidence suggests that the miR-218 is depleted in some human solid cancers, such as cervical cancer [16], lung squamous cell carcinoma [17], bladder cancer [18], glioma [19], and gastric cancer [20], where tumor cell invasion and proliferation are relatively enhanced. [score:1]
Twenty-four hours after miR-218 mimic transfection, total RNA was isolated from H1975 and A549 cells using the miRNeasy Mini Kit (Qiagen, Valencia, CA) according to the manufacturer’s protocol. [score:1]
MiR-218 negatively regulates IL-6/JAK/STAT3 pathway. [score:1]
e The phosphorylated STAT3 in H1975 and A549 cells was determined by immunofluorescence 36 h after transfection of miR-218 or miR-control. [score:1]
Publicly-available data from The Cancer Genome Atlas (TCGA) was mined to compare the levels of miR-218 and its host gene SLIT2/3 between lung cancer tissues and normal lung tissues. [score:1]
To validate these findings we examined whether activating STAT3 signal with IL-6 treatment can rescue cells upon miR-218 transfection, we treated miR-218 transfected cells with IL-6. Our data showed that IL-6 treatment partially rescued cells transfected by miR-218 (Fig. 3f). [score:1]
In addition, the levels of both miR-218 host genes and the components of IL-6/STAT3 pathway correlated with prognosis of lung cancer patients. [score:1]
b Cell proliferation was determined in H1975 and A549 cells 48 h after transfection of anti-miR-218 or anti-miR-control. [score:1]
Both miR-218 and host genes, SLIT2 and SLIT3 were negatively correlated with poor prognosis (Fig. 7a, b), whereas IL-6, IL-6R, JAK3 and STAT3 were positively correlated with poor prognosis (Fig. 7c-f). [score:1]
a Cell proliferation effects in H1975 and A549 cells were determined 48 h after transfection of miR-218 or miR-control. [score:1]
Double-stranded oligonucleotides corresponding to the wild-type (WT 3′-UTR) or mutant (Mut 3′-UTR) miR-218 binding site in the 3′-UTR of IL-6R and JAK3 genes were synthesized and inserted into the PmeI and XbaI sites of the pmirGLO Vector (Promega, Madison, WI), respectively. [score:1]
Fig. 7The components of the IL-6/JAK/STAT3 pathway and miR-218 host genes correlate with prognosis in lung cancer patients. [score:1]
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5
[+] score: 235
[8] In the first place, we examined whether CCAT1 has any effect on miRNA-218-5p target genes and found that CCAT1 knockdown inhibited the expression of Bmi1 (Tu et al. [27]) and caveolin-2 (Yamasaki et al. [26]), whereas co-transfection of miRNA-218-5p inhibitor attenuated this inhibition (Figure 4a). [score:12]
Knockdown of CCAT1 increased the expression of miRNA-218-5p, while ectopic expression of CCAT1 induced the downregulation of miRNA-218-5p and the miRNA-218-5p -binding site is indispensable for the CCAT1 -mediated repression. [score:9]
NOZ cells (1 × 10 [6]) stably expressing control shRNA or CCAT1 shRNA, or miRNA-218-5p inhibitor or CCAT1 shRNA+miRNA-218-5p inhibitor were subcutaneously injected into either side of flank area of 4-week-old female athymic nude mice (n=3 mice per group). [score:7]
Both CCAT1 overexpression and silencing had no significant effect on the expression level of pre-miRNA-218-5p with Dicer overexpression (Figure 3d). [score:7]
Our results demonstrated that although Dicer overexpression increased the level of mature miRNA-218-5p (Figure 3c) and in the meantime decreased the level of pre-miRNA-218-5p (Figure 3d), CCAT1 overexpression inhibited the increase of mature miRNA-218-5p induced by Dicer, and CCAT1 silencing had an opposite effect (Figure 3c). [score:7]
11, 14 CCAT1 negatively regulates Bmi1, a miRNA-218-5p target geneHaving demonstrated that CCAT1 could negatively regulate miRNA-218-5p expression, we then examined the functional aspect. [score:7]
In GBC-SD cells, although ectopic expression of CCAT1 upregulated Bmi1 at both transcript and protein levels, miRNA-218-5p mimic relieved the increase (Figures 4f and g). [score:6]
As illustrated in Figure 3a, although CCAT1 siRNA significantly upregulated mature miRNA-218-5p, it had almost no effect on the expression levels of pri-miRNA-218-5p and pre-miRNA-218-5p. [score:6]
miRNA-218-5p was shown to be downregulated in a variety of carcinomas, including mesenchymal glioblastoma, [24] pancreatic cancer [25] and renal cell carcinoma, [26] and exhibits tumor-suppressive activities, 24, 25, 26, 27 while CCAT1 was shown to promote tumor progression. [score:6]
Furthermore, our data demonstrated that the expression level of Bmi1 of the tumor from the shRNA-CCAT1 group was lower compared with the control group with immunochemistry analysis and miRNA-218-5p inhibitor abrogated the decrease (Figures 8c and d) Recent evidence has shown that ncRNAs have an important role in cancer pathogenesis and could provide new insights into the biology of this disease. [score:6]
CCAT1 siRNAs significantly decreased the endogenous CCAT1 transcript level in NOZ cells (Figure 2c); meanwhile, CCAT1 siRNAs upregulated the expression level of miRNA-218-5p in NOZ cells (Figure 2d). [score:6]
The present study revealed that although knockdown of CCAT1 inhibited the proliferation and migration of GBC cells, miRNA-218-5p inhibitor reversed the effects that CCAT1-specific siRNA exerted partially through modulating Bmi1, both in vivo and in vitro. [score:6]
Hsa-miRNA-218-5p mimic/negative control mimic and hsa-miRNA-218-5p inhibitor/negative control inhibitor were purchased from Genechem, Shanghai, China. [score:5]
CCAT1 overexpression and silencing had no significant effect on the expression level of pre-miRNA-218-5p. [score:5]
To explore the underlying mechanism of such a negative regulation of miR-218 by CCAT1, we examined the expression level of pri-miRNA-218-5p, pre-miRNA-218-5p and mature miRNA-218-5p in response to CCAT1 knockdown. [score:5]
The expression levels of miRNA-218-5p were also determined in GBC tissues from Figure 1. The miRNA-218-5p was markedly downregulated in GBC tissues compared with adjacent normal tissues (Figure 1e, P<0.001). [score:5]
In contrast, ectopic expression of CCAT1 increased the transcript level of CCAT1 in GBC-SD cells (Figure 2e), while it decreased the expression level of miRNA-218-5p (Figure 2f). [score:5]
Previous studies suggest that miRNA-218-5p inhibits tumor invasion, migration and proliferation by targeting the polycomb group gene Bmi1 (Tu et al. [27]). [score:5]
The final concentrations of miRNAs/plasmids employed in this study were as the followings: Bmi1 siRNA/negative control siRNA 20 nM/ml, CCAT1 siRNA/negative control siRNA 20 nM/ml, CCAT1-wt/CCAT1-mut 50 nM/ml, miRNA-218-5p mimic/negative control mimic 100 nM/ml and miRNA-218-5p inhibitor/negative control inhibitor 200 nM/ml. [score:5]
CCAT1 inhibited the increase of mature miRNA-218-5p induced by Dicer overexpression and CCAT1 silencing had an opposite effect. [score:5]
The incomplete rescue of caveolin-2 by miRNA-218-5p inhibitor suggests that other mechanisms might also be involved in its regulation. [score:4]
However, miRNA-218-5p mimics abolished this upregulation (Figure 5b). [score:4]
CCAT1 negatively regulated the expression of miRNA-218-5p. [score:4]
CCAT1 negatively regulates Bmi1, a miRNA-218-5p target gene. [score:4]
As illustrated in Figure 5a, CCAT1 knockdown decreased the luciferase activity in the Luc–Bmi1-3′-UTR -transfected NOZ cells, which was rescued by miRNA-218-5p inhibitor. [score:4]
With respect to the regulation of miRNA-218-5p by CCAT1, we hypothesize that CCAT1 promotes the degradation of miRNA-218-5p via binding to the RISC complex, in which case CCAT1 functions as an ‘miRNA,' while miRNA-218-5p acts as the ‘miRNA targeting mRNA'. [score:4]
11, 14 Having demonstrated that CCAT1 could negatively regulate miRNA-218-5p expression, we then examined the functional aspect. [score:4]
However, there was no obvious difference in CCAT1 level after ectopic expression or knockdown of miRNA-218-5p (Figure 2g). [score:4]
Furthermore, our data demonstrated that the expression level of Bmi1 of the tumor from the shRNA-CCAT1 group was lower compared with the control group with immunochemistry analysis and miRNA-218-5p inhibitor abrogated the decrease (Figures 8c and d) The relative expression level of CCAT1 was evaluated by using real-time PCR in 40 patients with GBC and paired normal tissues. [score:4]
CCAT1's oncogenic activity is in part through negative regulation of miRNA-218-5p in vivoTo provide additional evidence to the idea that CCAT1's oncogenic activity is in part through the negative regulation of miRNA-218-5p, we stably transfected NOZ cells with a lentivirus construct containing desired vector. [score:3]
[20] To further explore whether the downregulation of mature miRNA-218-5p by CCAT1 was through the interference of the processing of Dicer, we applied Dicer to assay the levels of pre-miRNA-218-5p and mature miRNA-218-5p. [score:3]
miRNA-218-5p was demonstrated to suppress tumor growth, 24, 25, 26, 27 while CCAT1 was shown to promote tumor progression. [score:3]
We observed that although si-CCAT1 decreased Bmi1 transcript and protein levels, miRNA-218-5p inhibitor abrogated this decrease in NOZ cells (Figures 4c and d). [score:3]
The pcDNA3.1-CCAT1 with point mutations in the miRNA-218-5p response elements (seed sequence binding fragment 5′-TCAAATCCAAAGCACA-3′ changed to 5′-ACGAGATCAGGATGTT-3′) was synthesized using a QuikChange Site-Directed Mutagenesis kit (Stratagene) and named pcDNA3.1-CCAT1-mut (miRNA-218-5p). [score:3]
A decrease in the percentage of S-phase cells was observed in GBC cell NOZ after transfection of CCAT1 siRNA but was reversed by cotransfection of miRNA-218-5p inhibitor (Figures 7a and b). [score:3]
Our data demonstrated that CCAT1 had no effect on the expression level of pri-miRNA-218-5p and pre-miRNA-218-5p. [score:3]
Furthermore, we detected miRNA-218-5p in the same pellet, supporting that miRNA-218-5p is bona fide CCAT1 -targeting miRNA (Figure 3f). [score:3]
The underlying mechanism of the negative regulation of miRNA-218-5p by CCAT1. [score:2]
This mutant CCAT1 clone revealed no significant suppression of miRNA-218-5p compared with WT of CCAT1 (Figure 2f). [score:2]
To confirm the direct binding between CCAT1 and miRNA-218-5p, luciferase reporter constructs were generated. [score:2]
These data confirmed the direct binding between CCAT1 and miRNA-218-5p. [score:2]
After 4 weeks, we observed a decrease in tumor growth in the NOZ-shRNA-CCAT1 group compared with the NOZ-vector group and miRNA-218-5p inhibitor abrogated this decrease in tumor growth (Figures 8a and b). [score:2]
Our data suggest that the regulation between miRNA-218-5p and CCAT1 might be in a way similar to the miRNA -mediated silencing of protein-coding genes. [score:2]
To provide additional evidence to the idea that CCAT1's oncogenic activity is in part through the negative regulation of miRNA-218-5p, we stably transfected NOZ cells with a lentivirus construct containing desired vector. [score:2]
The 815-nt region at the 3′-end of either CCAT1 or CCAT1-mut (miRNA-218-5p) was amplified using PCR and subcloned into the pmirGLO vector (Promega, Madison, WI, USA) for using the one-step directed cloning kit (Novoprotein, Shanghai, China). [score:2]
Our study suggests that CCAT1 may promote tumor development through ‘spongeing' miRNA-218-5p. [score:2]
As CCAT1 shares regulatory miRNA-218-5p with Bmi1 (Figure 4b), we would like to explore whether CCAT1 could modulate miRNA-218-5p and then Bmi1. [score:2]
To demonstrate the specificity of the association between CCAT1 and miRNA-218-5p, we detected miRNA-211, which was shown to be negatively regulated by loc285194 (Liu et al. [11]) and did not form complementary base pairing with CCAT1 according to our prediction results. [score:2]
CCAT1's oncogenic activity is in part through negative regulation of miRNA-218-5p in vivo. [score:2]
All these data imply that the oncogenic activity of CCAT1 is partly associated with the regulation of miRNA-218-5p and then Bmi1. [score:2]
Furthermore, we explored the underlying mechanism of the negative regulation of miRNA-218-5p by CCAT1. [score:2]
Taken together, it suggests that the regulation of miRNA-218-5p by CCAT1 is through another mechanism. [score:2]
Our results revealed that CCAT1 and Bmi1 shared the same miRNA-responsive element in their sequences and displayed the same miRNA-218-5p -dependent regulation pattern. [score:2]
CCAT1's oncogenic activity is in part through negative regulation of miRNA-218-5p and then modulating Bmi1 in vitro. [score:2]
To determine whether CCAT1 is associated with the RISC complex, we performed using synthesized biotin-labeled CCAT1 as a probe and then detected Ago2 from the pellet by western blotting or detected miRNA-218-5p by qRT-PCR. [score:1]
However, the alignment between the CCAT1 and miRNA-218-5p is not very specific, as 22 miRNAs were predicted to form complementary base pairing with CCAT1. [score:1]
In this study, we provide evidence that CCAT1 exhibits oncogenic activities partly through modulation of miRNA-218-5p and then Bmi1. [score:1]
We focused on miRNA-218-5p, as it is of the greatest fold change. [score:1]
Forty-eight hours after transfection, CCAT1 and miRNA-218-5p expression levels were measured. [score:1]
[23] We performed RNA pull-down experiments by using CCAT1 probe and then examined Ago2 and miRNA-218-5p simultaneously as described previously, 11, 12 to determine whether CCAT1 and miRNA-218-5p are in the same RISC complex. [score:1]
We then focused on miRNA-218-5p, which is of the greatest fold-change in response to CCAT1-specific siRNA. [score:1]
Furthermore, CCAT1 transcript level was significantly correlated with miRNA-218-5p mRNA level in GBC tissues (Figure 5c). [score:1]
[23]We performed RNA pull-down experiments by using CCAT1 probe and then examined Ago2 and miRNA-218-5p simultaneously as described previously, 11, 12 to determine whether CCAT1 and miRNA-218-5p are in the same RISC complex. [score:1]
What's more, miRNA-218-5p may also act independently of lncRNA-CCAT1, as it shares homology with a number of protein-coding genes such as caveolin-2 (Yamasai et al. [26]) and Bmi1 (Tu et al. [27]). [score:1]
pmirGLO, pmirGLO-CCAT1 wt or pmirGLO-CCAT1-mut (miRNA-218-5p) was cotransfected with miRNA-218-5p mimics or pmiRNA NC into NOZ cells by Lipofectamine -mediated gene transfer. [score:1]
[8] We studied the biological aspect of CCAT1 and miRNA-218-5p in GBC cells. [score:1]
We observed that miRNA-218-5p mimics reduced the luciferase activities of wild-type (WT) CCAT1 reporter vector. [score:1]
However, luciferase activities in cells transfected with CCAT1 mutant and the miRNA-218-5p mimics were almost comparable to that of control cells (Figure 2b). [score:1]
We found that CCAT1 and miRNA-218-5p bound to the same RISC complex. [score:1]
The 3′-UTR of Bmi1 mRNA containing the intact miRNA-218-5p family recognition sequences were PCR-amplified and subcloned into the SacI and SalI sites of pmirGLO vector. [score:1]
[1 to 20 of 70 sentences]
6
[+] score: 225
Other miRNAs from this paper: hsa-mir-218-2
Firstly, miR-218 inhibits the expression of the target gene inhibitor of nuclear factor κB (NF-κB) kinase β, and in a dose -dependent manner, inhibits the expression of NF-κB, whilst reducing the expression of matrix metalloproteinase (MMP) 9 and inhibiting the invasion and migration ability of glioma cells (12). [score:17]
Studies have identified that the ectopic expression of miR-218 contributes to the inhibition of proliferation, invasion and migration in glioma cells, as well as the induction of apoptosis by downregulating the gene that was directly targeted by miR-218 (12– 15). [score:11]
Previous studies identified that miR-218 inhibited invasion and metastasis of gastric cancer by targeting the Robo1 receptor and suppressed nasopharyngeal cancer progression through the downregulation of survivin and the Slit2-Robo1 pathway (16, 17). [score:10]
Accumulated evidence has revealed that upregulation of miR-218 can inhibit tumor cell invasion and proliferation in glioma cells by altering the expression of multiple target genes (12– 15). [score:10]
Previous studies have found that miR-218 inhibited the invasion and metastasis of gastric cancer by targeting the roundabout, axon guidance receptor, homolog 1 (Robo1) receptor and suppressing nasopharyngeal cancer progression through the downregulation of survivin and the Slit homolog 2 (Slit2)-Robo1 pathway (16, 17). [score:10]
Furthermore, it was found that miR-218 was involved in modulation of the Slit2-Robo1 signaling pathway and downregulation of Robo1 expression by directly targeting the Robo1 3′-UTR. [score:9]
Previous studies have revealed that miR-218 expression is often downregulated in several human cancers, including gastric cancer, lung squamous cell carcinoma, malignant astrocytomas and medulloblastomas, which indicates that miR-218 may function as a tumor suppressor (21– 23). [score:8]
Thirdly, the expression of lymphoid enhancer -binding factor 1 (LEF1) and MMP-9 in the high grade glioma group is extremely high, while the expression in the low-grade glioma group is extremely low, and is negatively correlated with the expression of miR-218. [score:7]
Overexpression of miR-218 inhibits the Wnt/LEF1 signaling pathways that lead to a reduction in MMP-9 synthesis, inhibiting tumor invasion (14). [score:7]
Overexpression of miR-218 in the glioma cell lines can inhibit CDK6 expression and glioma cell proliferation and promote its apoptosis (15). [score:7]
Finally, the abnormal expression of miR-218 in glioma cells decreased, but there was an abnormal increase in cyclin -dependent kinase (CDK) 6 expression, with the expression level of the two being negatively correlated. [score:7]
Upregulation of miR-218 inhibited cell invasion in U87 cells. [score:6]
This finding indicates that the upregulation of miR-218 inhibits the invasive ability of glioma cells in vitro. [score:6]
The present study also observed, using qPCR and western blot analysis, that treatment with the miR-218 mimic for 24 h significantly upregulated the expression of Slit2, which was followed by a decrease in Robo1 (Fig. 3). [score:6]
Upregulation of miR-218 reduces Robo1 expression via the inactivation of Slit2-Robo1 signaling. [score:6]
Secondly, epidermal growth factor receptor-coamplified and overexpressed protein (ECOP) has been identified as a functional downstream target gene of miR-218 that can regulate NF-κB transcription activity and is associated with the apoptotic response. [score:6]
To assess the role of Robo1 in the miR-218 -dependent inhibition of cell migration and invasion, miR-218 inhibitor was transfected into U87 cells treated with Robo1 siRNA. [score:5]
Overexpression of miR-218 can restrain the activity of NF-κB through ECOP, thus inducing glioma cell apoptosis and inhibiting the activity, proliferation and tumorigenicity of glioma cells (13). [score:5]
In the present study, Robo1 was identified as a notable novel target of miR-218 using the conventional prediction tool TargetScan (www. [score:5]
In addition, Robo1 siRNA can reduce the invasive ability of the cells subsequent to its enhancement by the exogenous expression of the miR-218 inhibitor. [score:5]
To analyze the expression levels of miR-218, a qPCR analysis of miR-218 expression was conducted in the U251, U87, SNB19 and LN229 glioma cell lines. [score:5]
Robo1 was identified as a notable novel target of miR-218 using the conventional prediction tool, TargetScan (www. [score:5]
The enhanced invasive ability of miR-218 inhibitor -transfected U87 cells declined when Robo1 siRNA was co -transfected with the miR-218 inhibitor (Fig. 6). [score:5]
The present study demonstrated that Robo1 is a direct target of miR-218. [score:4]
miR-218 is downregulated in glioma tissues. [score:4]
Overall, the present results indicate that miR-218 is downregulated in glioma cell lines and glioma tissues. [score:4]
In the present study we examined how miR-218 affects the migration and invasion of glioma cells and the mechanism for miRNA -mediated direct suppression of the Slit2-Robo1 pathway in gliomas. [score:4]
The present results revealed that miR-218 is downregulated in all glioma cell lines compared with the NHA cells (P<0.05). [score:3]
This result demonstrates that miR-218 expression decreases markedly between normal brain tissue and low grade to GBM tissue. [score:3]
These results indicate that miR-218 reduced the expression of Robo1 via the inactivation of Slit2-Robo1 signaling. [score:3]
Among these miRNAs, miRNA 218 (miR-218) has been demonstrated to be downregulated in human GBM specimens compared with the adjacent tumor-free brain tissue (9– 12). [score:3]
Overall, the present results indicate that miR-218 inhibits the migration and invasion of glioma cells through the Slit2-Robo1 signaling pathway. [score:3]
It was found that the expression of miR-218 and Slit2 was always inverse to that of Robo1. [score:3]
Robo1 is a functional downstream target of miR-218. [score:3]
The 3′-UTR sequence of Robo1 predicted to interact with miR-218 or a mutated sequence with the predicted target sites was synthesized and inserted into the XbaI and FseI sites of a pGL3 control vector (Promega Corporation, Madison, WI, USA). [score:3]
The expression levels of miR-218, Robo1 and Slit2 were detected in 70 tissue samples, consisting of normal brain tissue and low- and high-grade glioma tissues, using RT-qPCR and western blot analysis. [score:3]
In addition, when miR-218 expression was measured in 10 normal brain tissue and 60 glioma tissue samples, it was observed that the expression level of miR-218 was significantly decreased in the glioma tissues, particularly in grade III/IV glioma tissues, compared with the normal brain tissues (Fig. 1). [score:2]
The expression level of miR-218 was quantified using an miRNA-specific TaqMan miRNA Assay kit (Applied Biosystems, Foster City, CA, USA). [score:2]
Therefore, the development miR-218 as a biomarker for glioma or as a potential therapeutic candidate for miRNA replacement therapy is extremely promising (26, 27). [score:2]
The luciferase activity for the wild-type 3′-UTR of Robo1 was significantly inhibited by co-transfection with miR-218 mimics compared with constructs containing mutated 3′-UTRs. [score:2]
Notably, the mRNA and protein levels of Robo1 were significantly decreased and the mRNA and protein levels of Slit2 were significantly increased subsequent to the transfection of miR-218 mimics into U87 cells. [score:1]
Transfections with miR-218 were performed in serum-free medium 24 h subsequent to plating, using Lipofectamine 2000 (Invitrogen Life Technologies). [score:1]
Robo1 siRNA can imitate the role of miR-218 in U87 glioma cells. [score:1]
An in vitro Matrigel invasion assay revealed that the invasiveness of U87 cells transfected with the miR-218 mimic was suppressed compared with control and NC groups (Fig. 2A and B). [score:1]
These results indicate that Robo1 is essential for miR-218 -dependent cell migration and invasion. [score:1]
A luciferase reporter assay further confirmed the direct interaction between miR-218 and the 3′-UTR of Robo1 mRNA (Fig. 4). [score:1]
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7
[+] score: 212
Other miRNAs from this paper: hsa-mir-218-2, hsa-mir-520a
In conclusion, the present study provided evidence that miR-218 and miR-520a are downregulated in HCC, and that these miRNAs act as tumor suppressors to inhibit cell proliferation, partly by regulating E2F2 expression. [score:11]
Based on these factors, it is hypothesized that miR-218 regulates E2F2 expression; this occurs not only by directly targeting E2F2 but additionally via the suppression of CDK4; however, further studies are required to validate this hypothesis. [score:9]
Collectively, these results indicated that miR-218 negatively regulated the expression of E2F2 via directly binding to its 3′-UTR, while miR-520a affected E2F2 expression indirectly. [score:8]
Collectively, it was concluded that miR-218 negatively regulates E2F2 expression via directly binding to its 3′-UTR, whereas miR-520a affects E2F2 expression indirectly. [score:8]
Fig. 1B demonstrates that the expression levels of miR-218 and miR-520a were significantly upregulated (P<0.01) following transfection, indicating that Huh7 and MHCC-97H cells were effective and adjustable mo dels for the functional study of miR-218 and miR-520a expression. [score:8]
The expression of miR-218 is downregulated and may serve as a potential tumor suppressor in glioblastoma, clear cell renal cell carcinoma and gastric, nasopharyngeal, cervical, breast, oral and non-small cell lung cancer (17– 24). [score:8]
The present study aimed to provide evidence that miR-218 directly targets E2F2 to regulate its expression in HCC. [score:7]
The results demonstrated that upregulation of miR-218 or miR-520a downregulated E2F2 mRNA and protein levels. [score:7]
In addition, Li et al (25) reported that miR-218 is downregulated in HCC tissues and may inhibit cell proliferation and promote cell apoptosis. [score:6]
The tumor suppressor miR-218 was reported to be frequently downregulated in various types of cancer (17– 25). [score:6]
As demonstrated in Fig. 1A, miR-218 and miR-520a expression levels were significantly downregulated in human HCC cells. [score:6]
miR-218 and miR-520a expression are downregulated in human HCC cell lines. [score:6]
miR-218 and miR-520a suppress E2F2 expression. [score:5]
Target genes of miR-218 and miR-520a were assessed using the miRNA target prediction tool miRanda (http://www. [score:5]
To further investigate the mechanism of miR-218- and miR-520a -mediated inhibition of cell proliferation, the candidate target genes were assessed using the miRNA target prediction tool miRanda (http://www. [score:5]
As presented in Fig. 3C, compared with the NC group, relative mRNA expression of E2F2 was significantly downregulated (P<0.05) in Huh7 and MHCC-97 cells trans-fected with either miR-218 or miR-520a mimics. [score:5]
miR-218 has been reported to inhibit CDK4 expression in colon cancer (34). [score:5]
Furthermore, the colony formation assay demonstrated that the colony number in cells transfected with miR-218 or miR-520a mimics was significantly lower than that in the NC (P<0.001 for miR-218 in Huh7; P=0.001 for miR-520a in Huh7; P<0.001 for miR-218 in MHCC-97; P=0.001 for miR-520a in MHCC-97), suggesting that the colony-forming abilities of Huh7 and MHCC-97H cells were suppressed by the upregulation of miR-218 or miR-520a (Fig. 2B). [score:5]
These results suggested that E2F2 is a direct target of miR-218 but not miR-520a. [score:4]
These results suggested that miR-218 and miR-520a may serve as suppressors in the development of HCC. [score:4]
miR-218 directly targets the 3′-UTR of E2F2. [score:4]
E2F2 was identified to be a direct target of miR-218 but not miR-520a in HCC. [score:4]
To detect the expression of miR-218 and miR-520a in human HCC cells, RT-qPCR was applied to determine the miRNA expression in four HCC cell lines (Huh7, MHCC-97H, HepG2 and BEL-7402), compared with a human normal hepatic cell line (L02). [score:4]
The results indicated that the levels of miR-218 and miR-520a were downregulated in cancer cells, which is consistent with the results of previous studies (17– 26). [score:4]
It was hypothesized that miR-218 and miR-520a may serve as tumor suppressors in HCC. [score:3]
In addition, Huh7 and MHCC-97H cells were observed to exhibit low levels of miR-218 and miR-520a expression amongst the four HCC cell lines examined. [score:3]
In the present study, it was hypothesized that miR-218 and miR-520a are downregulated in HCC cells compared with normal hepatic cells. [score:3]
Therefore, it was inferred that miR-218 and miR-520a function as tumor suppressors in HCC. [score:3]
First, RT-qPCR was conducted in order to examine the expression levels of miR-218 and miR-520a in four human HCC cell lines and a normal hepatic cell line. [score:3]
Among these genes, including BMI1, MDGA2 and CDK6, E2F2 was predicted as a potential target of miR-218 and miR-520a. [score:3]
miR-218 and miR-520a inhibit the proliferation of HCC cells. [score:3]
In addition, Huh7 and MHCC-97H cells appeared to express lower levels of miR-218 and miR-520a than HepG2 and BEL-7402 cells. [score:3]
In addition, the restoration of miR-218 and miR-520a was suggested to inhibit cell proliferation by inducing cell cycle arrest at the G [0]/G [1] phase checkpoint. [score:3]
MTT growth curves indicated that the cell proliferative abilities were markedly reduced when miR-218 and miR-520a were overexpressed (P=0.001 for miR-218 in Huh7; P= 0.007 for miR-520a in Huh7; P= 0.002 for miR-218 in MHCC-97; P=0.013 for miR-520a in MHCC-97). [score:3]
Furthermore, overexpression of miR-218 or miR-520a was observed to induce cell cycle arrest at the G [0]/G [1] phase checkpoint. [score:3]
These results suggested that miR-218 and miR-520a inhibited the proliferation of the HCC cell lines Huh7 and MHCC-97H. [score:3]
Consistent with the results of RT-qPCR, western blot analysis indicated that transfection of Huh7 and MHCC-97 cells with either miR-218 or miR-520a resulted in a significant reduction in E2F2 protein expression (P<0.05; Fig. 3D). [score:3]
s were conducted in Huh7 cells to investigate whether E2F2 was a direct target of miR-218 and miR-520a. [score:2]
To understand the molecular mechanisms by which miR-218 and miR-520a inhibit cell proliferation in HCC, bioinformatics -based predictions and a dual-luciferase reporter assay were utilized. [score:2]
The expression levels of miR-218, miR-520a and the endogenous control U6 were quantified using the TaqMan MicroRNA Assay kit (Applied Biosystems). [score:2]
The wild-type (WT) 3′-UTR of E2F2 containing the potential binding site of miR-218 or miR-520a and the corresponding mutational 3′-UTR of E2F2 were cloned into the psiCheck2 dual luciferase reporter vector (Promega Corporation, Madison, WI, USA). [score:2]
Previous studies have demonstrated that miRNA-218 (miR-218) and miR-520a are associated with tumor pathogenesis and the development of various types of human cancer. [score:2]
In addition, RT-qPCR and western blot analyses were conducted in order to investigate whether miR-218 and miR-520a may regulate E2F2 expression. [score:2]
Huh7 and MHCC-97H cells were plated in 60-mm dishes and transfected with NC, miR-218 or miR-520a, respectively. [score:1]
In addition, the activity in the reporter vector with the mutant 3′-UTR of E2F2 was affected by neither miR-218 nor miR-520a (Fig. 3B). [score:1]
In order to measure miR-218 and miR-520a expression levels, cDNA was synthesized using the TaqMan miRNA Reverse Transcription kit (Applied Biosystems, Life Technologies, Thermo Fisher Scientific, Waltham, MA, USA). [score:1]
However, the role of miR-218 and miR-520a in HCC and the molecular mechanisms by which the miRNAs exert their functions have remained elusive. [score:1]
miR-218 and miR-520a induce cell cycle arrest in G [0]–G [1] phase. [score:1]
In the present study, the expression of miR-218 and miR-520a in HCC cells and the molecular mechanisms by which the miRNAs exert their functions were investigated. [score:1]
The effects of miR-218 and miR-520a on E2F2 expression were next investigated. [score:1]
This suggested that miR-218 and miR-520a may be promising candidates for therapeutic intervention in HCC. [score:1]
Flow cytometric analyses demonstrated that the percentages of miR-218 -transfected Huh7 and MHCC-97H cells in G [0]-G [1] phase were 16% (Huh7) and 13% (MHCC-97H) greater than those in the NC group, which is consistent with the reductions of 18% (Huh7) and 23% (MHCC-97H) in the percentage sof cells in S phase. [score:1]
Following transfection with NC, miR-218 or miR-520a, respectively, for 48 h, Huh7 and MHCC-97H cells were plated in 96-well plates at a density of 3,000 cells/well. [score:1]
Dual-luciferase reporter assays were conducted in Huh7 cells to investigate whether E2F2 was a direct target of miR-218 and miR-520a. [score:1]
Fig. 3A presents the potential binding sites of miR-218 and miR-520a in the 3′-UTR of E2F2, with the corresponding sequences of the mutated 3′-UTRs of E2F2 also illustrated. [score:1]
To investigate whether E2F2 is a direct downstream target gene of miR-218 and miR-520a, dual-luciferase reporter assays were performed. [score:1]
Mimics of miR-218 and miR-520a and the negative control (NC) were purchased from Shanghai GenePharma, Co. [score:1]
Huh7 cells were transiently co -transfected with the reporter vector containing the respective 3′-UTR and either miR-218 mimics, miR-520a mimics or the NC. [score:1]
These data indicated that miR-218 and miR-520a reduced cell proliferation via the induction of cell cycle arrest in G [0]–G [1] phase. [score:1]
miR-218 and miR-520a induce cell cycle arrest in G [0]–G [1] phaseFlow cytometric analyses demonstrated that the percentages of miR-218 -transfected Huh7 and MHCC-97H cells in G [0]-G [1] phase were 16% (Huh7) and 13% (MHCC-97H) greater than those in the NC group, which is consistent with the reductions of 18% (Huh7) and 23% (MHCC-97H) in the percentage sof cells in S phase. [score:1]
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[+] score: 200
Other miRNAs from this paper: hsa-mir-218-2
In response to increased expression of miR-218 in glioma cells, the gene chip microarray analysis revealed a decrease in their HK2 expression, which was further identified as a target of miR-218 by Target Scan. [score:9]
Likewise, previously we have shown that restoring the expression of miR-218 regulated a broad range of genes involved in glioma cell development, with Bmi1 being defined as its direct functional target, and dramatically reduced the migration, invasion, proliferation, and self-renewal of glioma cells [22]. [score:8]
Indeed, it was observed that overexpression of miR-218 in glioma tumor cells did obviously decrease HK2 mRNA and protein expression, though luciferase activity analysis declined HK2 as a direct target of miR-218. [score:8]
We previously demonstrated the robust tumor suppressor role of miR-218 in glioma cells, the overexpression of which also showed, through gene chip analysis, a negative effect on HK2 expression, which was further analyzed here. [score:7]
pAKT and HIF-1α are involved in the PI3K pathway, and we provided evidence that these proteins were upregulated in both overexpression of miR-218 and knockdown of Bmi1 glioma cell lines. [score:7]
Previously we revealed the tumor suppressor function of miR-218, which could dramatically reduce the proliferation, migration, invasion and self-renewal of glioma cells, by targeting its functional downstream target Bmi1, a stem cell-promoting oncogene [22]. [score:7]
Both pAKT and HIF-1α showed increased expression after overexpression of miR-218 and knockdown of Bmi1. [score:6]
As shown in S1 Fig, there were increased expressions of both pAKT and HIF-1α proteins after overexpression of miR-218 and knockdown of Bmi1. [score:6]
Overexpression of miR-218 up-regulated the protein level of HIF-1α of glioma cell lines. [score:6]
Further, looking for the mediator facilitating the miR-218 induced HK2 downregulation, a positive correlation between Bmi1 and HK2 expression was established. [score:6]
Overexpression of miR-218 down-regulated the protein level of HK2. [score:6]
Our previously established fact that Bmi1 is a direct functional target of miR-218 in glioma condition validates the miR-218 induced HK2 suppression. [score:6]
Overexpression of miR-218 down-regulated the mRNA level of HK2. [score:6]
Among the affected genes, HK2 was also found downregulated, and was listed under the targets of miR-218, with bioinformatic software. [score:6]
Overexpression of miR-218 up-regulated the protein level of pAKT of glioma cell lines. [score:6]
This result was also consistent with the effect of miR-218 overexpression on HK2 expression, which further supports the hypothesis that Bmi1 may be the key factor of miR-218 mediated HK2 regulation. [score:6]
Considering our previously established miR-218/Bmi1 pathway in glioma inhibition, we hypothesized that Bmi1 may fill the gap between miR-218 induced HK2 suppression. [score:5]
HK2 levels are inversely correlated with miR-218 levels in glioma cells, but HK2 is not a direct target of miR-218; miR-218 may regulate HK2 through Bmi1. [score:5]
It has been shown that miR-218 regulates glioma cell invasion by downregulating IkB kinase-b and LEF1 [49]. [score:5]
In the present study, it was also shown that the inhibition of HK2 resulted in a reduction of proliferation, migration and invasion of glioma cells, an effect that resembled the effect of miR-218 overexpression. [score:5]
The effects of overexpression of miR-218 and knockdown of Bmi1 on AKT/pAKT and HIF-1α. [score:4]
The effect of HK2 downregulation, both shRNA and miR-218 induced, on cellular metabolism (glycolytic activity), ATP synthesis, or FDG uptake of glioma cells was not addressed. [score:4]
Compared to its negative controls, these miR-218 overexpressing U87 and U251 stable cell lines demonstrated a significant decrease in their expression of HK2 mRNA and protein levels, as confirmed by qRT-PCR and western blotting (Fig 4C and 4D). [score:4]
Although these results were contrary to our expectation, further supported that miR-218 might regulate glioma cells development by regulating many genes besides HK2. [score:4]
showed HK2 was not the direct target of miR-218. [score:4]
The result showed no difference in the luciferase activity between the pmirGLO-HK2 3’-UTR transfected, pmirGLO-HK2 3’-UTR-mut transfected and negative control cells, indicating that HK2 is not the direct target of miR-218 (Fig 4E). [score:4]
These data hopefully add to the current understanding of the miR-218’s regulatory network in glioma condition, and may provide potential targets in developing glioma therapies. [score:4]
To further assess the contribution of miR-218 and Bmi1 on glioma development, we examined the expression levels of pAKT and HIF-1α, which belong to the PI3K pathway. [score:4]
The expression of miR-218 and HK2 were confirmed by qRT-PCR and. [score:3]
The stable U87 and U251 cell lines overexpressing miR-218 were generated through lentivirus infection and puromycin mediated selection, and confirmed through qRT-PCR and western blotting (Fig 4A and 4B). [score:3]
miR-218 was one such microRNA which was drastically downregulated in human glioma compared to normal brain tissues [46– 48]. [score:3]
qRT-PCR analysis confirmed the increased miR-218 expression in glioma cell lines. [score:3]
These results showed that miR-218 might regulate the PI3K pathway to influence glioma development and uncovered a novel mechanism for constitutive PI3K/Akt activation in gliomas. [score:3]
Establishment of stable LV-infected U87 and U251 cells overexpressing miR-218. [score:3]
The luciferase reporter assay was performed to assess if miR-218 alters HK2 expression by post-transcriptional regulation on the 3’UTR of the HK2 gene. [score:3]
Thus, HK2 as a potential target of miR-218 was the focus for further functional analysis. [score:3]
The negative correlation between miR-218 and HK2 expression in glioma cells. [score:3]
Although further efforts are warranted for experimental confirmation, the findings highlight the importance of miR-218 in regulating HK2. [score:2]
This indicates that the miR-218/HK2 axis, in addition to regulating glucose metabolism, plays an important role in controlling tumorigenesis in glioma, thus adding a novel molecular link between tumor biology and tumor metabolism. [score:2]
Despite these limitations, this study supports/demonstrates the tumorigenic activity of HK2 in glioma condition, while also establishes a novel miR-218/Bmi1/HK2 axis in regulating the same. [score:2]
Bmi1 may facilitate the miR218 mediated HK2 regulation. [score:2]
Consequently, we aimed to reveal the role of HK2 in tumorigenesis and development of glioma, and further explored the association between miR-218 and HK2. [score:2]
The other pleiotropic functions of miR-218 in glioma development require further research. [score:2]
Lentivirus carrying hsa-miR-218 or hsa-miR -negative control (miR-NC) and Bmi1 shRNA or its negative control (shNC) was packaged following the manufacturer's manual. [score:1]
This indicated an association of miR-218 and HK2, which might play an important role in glioma. [score:1]
The Hsa-miR-218 vector (GenePharma Co. ) [score:1]
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[+] score: 126
BAX was up-regulated, while Bcl-2 was down-regulated, due to miR-218 overexpression in K562 cells. [score:9]
Further data revealed that ALAS2 can be down-regulated directly by overexpression of miRNA-218, miRNA-518, and miRNA-330 (Figure 3B). [score:7]
Data revealed that IRP2, transferrin and TFR1 were significantly up-regulated by miR-218 overexpression (OE) in K562 cells (Figure 5A). [score:6]
These data revealed that ALAS2 expression is down-regulated by miR-218 binding. [score:6]
ALAS2 Is a Down-Regulated Target of miR-218. [score:6]
Functional studies on miR-218 revealed that overexpression of miR-218 in K562 cells resulted in iron accumulation in mitochondria and inhibited erythroid differentiation. [score:5]
Through a series of screening and functional studies, we found that miR-218 inhibited erythroid differentiation and altered iron metabolism by targeting ALAS2 in K562 cells. [score:5]
These results indicate that overexpression of miR-218 inhibits induced erythroid differentiation in K562 cells. [score:5]
Statistical percentages of each stage are shown; (C) Relative mRNA expression of BAX and Bcl-2 in control K562 cells and K562 cells overexpressing miR-218 using quantitative real-time PCR normalized to GAPDH. [score:5]
Overexpression of miR-218 Inhibits Induced Erythroid Differentiation in K562 Cells. [score:5]
Figure 6The relative mRNA expression of ε-globin (A), γ-globin (B), β-globin (C), ζ-globin, (D) and α-globin (E) gene during hemin -induced erythroid differentiation of K562 pcDNA and K562 miR-218 cells was determined using quantitative real-time PCR; (F) The expression of GATA-1 and KLF1 in K562 pcDNA and K562 miR-218 cells were also identified by quantitative real-time PCR. [score:5]
Quantitative real-time PCR revealed that the ε-, γ-, β-, ζ-, and α-globin genes were up-regulated in both K562 pcDNA and K562 miR-218 cells (Figure 6A–E), which demonstrated that the erythroid differentiation induced was successful. [score:4]
However, rising globin genes’ expression were repressed by ectopic expression of miR-218 compared to the K562 control cells (Figure 6A–E). [score:4]
To assess the role of miR-218 in erythroid iron metabolism, the expression of several critical iron metabolism regulating genes was determined. [score:4]
In all, our study found that miR-218 regulated iron metabolism and erythroid differentiation by targeting ALAS2 in K562 cells. [score:4]
In addition, the two most critical erythroid transcription factors gene, GATA-1 and KLF1, were found significantly down-regulated in K562 miR-218 cells (Figure 6F). [score:4]
A certain expression of miR-218 in K562 cells (Figure 2C) may be the mainly cause of higher luciferase activity of mutated groups than control group (pcDNA/ALAS2). [score:3]
This expression level implied that the K562 miR-218 OE cells were in a situation of iron insufficiency. [score:3]
Further experimental studies confirmed that ALAS2 is a target for miR-218. [score:3]
Figure 4(A) The overexpression of miR-218 in K562 cells was confirmed using mature miRNA quantitative real-time PCR normalized to U6. [score:3]
Yungui Yang, Beijing Institute of Genomics, Beijing, China) was used to generate a plasmid overexpressing miRNAs (e. g., pcDNA miR-218). [score:3]
The mutated nucleic acid was shown in bold and underlines; (E) miR-218 inhibits wild-type, but not the mutated ALAS2 3′UTR. [score:3]
A cell line (K562 miR-218) that stably overexpressed miR-218 was generated to further study the function of miR-218 in K562 cells (Figure 4A). [score:3]
Indeed, our results indicated that the amount of iron in the mitochondria from the K562 cells expressing miR-218 was higher than that in the control cells (Figure 5B,C). [score:3]
Iron Metabolism Is Regulated by miR-218 in K562 Cells. [score:2]
To further confirm miR-218 binding to the 3′UTR of ALAS2, four different mutations at the binding site were generated (Figure 4D). [score:2]
Hsa-miR-218 Plays a Role in the Proliferation and Apoptosis of K562 Cells. [score:1]
The functional network of ALAS2 was further analyzed using the Ingenuity Pathways Analysis (IPA) system, which revealed that miR-218 and ALAS2 are part of the same network (Figure 3D). [score:1]
Figure 7(A) Growth curve of control and K562 miR-218 cells. [score:1]
miR-218 was listed in the network and highlighted by the red arrow. [score:1]
These results indicate that miR-218 repressed the proliferation of K562 cells probably by cell cycle arrest and the induction of apoptosis. [score:1]
Western blot quantification normalized to GAPDH by densitometry using ImageJ was provided; (D) Predicted binding site for the seed sequence of miR-218 in the 3′UTR of ALAS2 mRNA. [score:1]
The repressed relative luciferase activity indicated that miRNA-218 and miRNA-518 can bind the 3′UTR of ALAS2 (Figure 3C). [score:1]
To verify that, 5 × 10 [5] control or K562 miR-218 cells were seeded respectively and cultured in same incubator, cells were harvest and counted every two days. [score:1]
Figure 5(A) Relative mRNA expression of iron metabolism related genes in K562 pcDNA and K562 miR-218 cells using quantitative real-time PCR; (B) Standard curve of iron concentration against relative absorption values at OD [570 nm]; (C) The iron concentration in the mitochondria of the K562 pcDNA and K562 miR-218 cells was calculated from the standard curve. [score:1]
A cell cycle analysis (Figure 7B), indicated that more K562 miR-218 cells were blocked in the G1 stage than in the S stage. [score:1]
Quantitative real-time PCR and Western blot analyses of K562 control and K562 miR-218 cells was performed and indicated that ALAS2 was repressed both at the mRNA (Figure 4B) and protein level (Figure 4C) by miR-218. [score:1]
The expression of ALAS2 at the mRNA level (B) and at the protein level (C) in K562 control and K562 miR-218 cells was measured by quantitative real-time PCR and western blot, respectively. [score:1]
The seven miRNAs were hsa-miR-124, miR-206, miR-218, miR-222, miR-330, miR-342, and miR-518. [score:1]
For this reason miR-218 was chosen as a candidate for further study. [score:1]
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[+] score: 116
Other miRNAs from this paper: hsa-mir-218-2
The tumor suppressive microRNA miR-218 also targeted the mTOR component Rictor and blocked AKT phosphorylation in oral cancer [13], inhibited invasion and metastasis of gastric cancer by targeting the Robo1 receptor [29]. [score:9]
Overexpression of miR-218 Inhibited Expression of Rictor, an mTOR Component, and Its Downstream Pathway. [score:7]
In our studies, overexpression of miR-218 could inhibit the growth of human cervical cancer cell line HeLa both in vivo and in vitro. [score:5]
And recent study has shown that miR-218 targeted the mTOR component Rictor and inhibited AKT phosphorylation in oral cancer [13]. [score:5]
Overexpression of miR-218 markedly inhibited the cell growth rate of HeLa cells (Figure 1A). [score:5]
The key finding of our study is that the tumor suppressive microRNA miR-218 reduced the growth of tumor cells and inhibited AKT-mTOR signaling pathway in cervical cancer. [score:5]
Western blotting analysis revealed that protein levels of Rictor were aberrantly inhibited in the miR-218 overexpression group (Figure 3D). [score:5]
Rictor (rapamycin-insensitive companion of mTOR) is direct target of miR-218 which was validated in oral cancer cells before [13]. [score:4]
We have shown that miR-218 inhibited the proliferation of the human cervical cancer cell line HeLa and increased chemosensitivity to cisplatin in vitro by blocking the AKT-mTOR signaling pathway, which may provide an important layer of genetic regulation in tumorigenesis and ultimately become valuable therapeutic tools. [score:4]
Here in cervical cancer HeLa cells, we demonstrated that miR-218 also downregulated the protein levels of Rictor (Figure 2A). [score:4]
Tumor Suppressive Effect of miR-218 in the Proliferation of Cervical Cancer Cell Growth. [score:3]
Overexpression of miR-218 increased sensitivity of HeLa cells to CDDP, while restoration of Rictor reversed it and increased chemo-resistance to that of HeLa/miR-NC cells. [score:3]
These data indicated that miR-218 acted as a tumor suppressor in cervical cancer. [score:3]
Therefore, it suggested that miR-218 suppressed the growth of tumor originated from HeLa cells by AKT-mTOR signaling pathway. [score:3]
In addition, ectopic expression of miR-218 significantly increased protein levels of cleaved Caspase-3, a symbol of cell apoptosis. [score:3]
After 2–4 weeks selection, the remaining cells were stably overexpressed with miR-218 or miR-NC. [score:3]
MiR-218 is commonly downregulated in cervical cancers [15]. [score:3]
Consistent with tumor volumes, the xenograft weights were decreased by miR-218 expression. [score:3]
Furthermore, the activity analysis indicated that ectopic expression of miR-218 significantly activated both Caspase-3 and -8 (Figure 2B). [score:3]
Generation of HeLa Cells with Stable Expression of miR-218. [score:3]
In this study, we found that levels of phospho-AKT (Ser-473) were reduced when miR-218 was overexpressed, while the total protein levels of AKT were not obviously changed. [score:3]
The overexpression of miR-218 in HeLa/miR-218 cells was confirmed by RT-PCR (See Supplement Figure S1). [score:3]
Hence, targeting miR-218 may provide a novel strategy for the treatment of cervical cancer. [score:3]
As shown in Figure 2, miR-218 inhibited the level of both Rictor and Phospho-AKT in HeLa cells. [score:3]
To explore the biological roles of miR-218 in the cervical cells, we stably overexpressed miR-218 in HeLa cells (HeLa/miR-218) by transfecting plasimids carrying miR-218 gene and then selected by puromycin. [score:3]
An anchorage independent colony formation assay indicated that miR-218 reduced the numbers of colonies of HeLa cells (Figure 1B), which further demonstrated the inhibition activities of miR-218 in cervical cancer cell proliferation. [score:2]
The three groups of cells were treated with 10 uM of CDDP (~2 × IC50 of HeLa/miR-218 stable cells) for 72 h. WST-1 assay showed a remarkably decrease of cell proliferation (Figure 4B) and activities of Caspase-3 and -8 (Figure 4C,D) of miR-218 overexpressing cells. [score:2]
MiR-218 Increased Chemosensitivity of Cervical Cancer Cells to Cisplatin via Its Target Rictor. [score:2]
To further explore the roles of miR-218 in in vivo tumor growth, we employed ectopic transplantation mo del in nude mice. [score:1]
HeLa cells were selected and maintained in DMEM complete medium containing 1 mg/mL G418 (Invitrogen) after transfection with pCR-miR-218 or pCR-miR-NC (control). [score:1]
To investigate the role of miR-218 in CDDP treated cells, we detected the proliferation and apoptosis effect of miR-218 -overexpressing cells exposed in CDDP. [score:1]
We constructed adenovirus carrying Rictor (Ad-Rictor) to rescue the low protein levels of Rictor in HeLa/miR-218 cells. [score:1]
Furthermore, it is possible that miR-218 enhanced chemosensitivity to cisplatin by the AKT-mTOR signaling pathway. [score:1]
Furthermore, the treatment with miR-218 promoted chemosensitivity to cisplatin (CDDP) of HeLa cells in vitro. [score:1]
Furthermore, Rictor protein levels were reduced in the miR-218 transfectant and its levels were restored in the miR-218-Rictor co-transfectant (See Supplement Figure S2). [score:1]
To investigate whether miR-218 and its target, Rictor, play roles in the chemotherapy of cervical cancer, we exposed the stable cell lines, HeLa/miR-NC, HeLa/miR-218 or HeLa/miR-218 infected with Ad-Rictor, with different concentration of cisplatin (CDDP) ranging from 0 to 128 μM for 72h (Figure 4A). [score:1]
The concentration of CDDP was 2 × IC50 of HeLa/miR-218 stable cells. [score:1]
Stable cell lines, HeLa/miR-NC and HeLa/miR-218, were subcutaneously injected into both posterior flanks of nude mice, respectively. [score:1]
MiR-218 Impaired In Vivo Tumor GrowthTo further explore the roles of miR-218 in in vivo tumor growth, we employed ectopic transplantation mo del in nude mice. [score:1]
As shown in Table 1, the IC50 of the three groups were 15.85 ± 1.21, 5.96 ± 0.57 and 11.88 ± 0.94, respectively, which indicated that miR-218 significantly increased chemosensitivity to CDDP. [score:1]
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[+] score: 92
Because the prognostic signature of three miRNAs, mir-218, let-7g, and mir-125b were found to be the major miRNAs that associated with the three hub genes (SP1, MYC, and TP53) predicted to be their targets, we sought to determine whether there were concordant changes in their expression after in vitro treatment with the global transcription inhibitor tetra- O-methyl nordihydroguaiaretic acid (M [4]N) [26] To this aim, we exposed cell lines derived from OSCC patients to M [4]N and evaluated the cultured cells for proliferation, death, and the expression of the three hub genes with their potential miRNA regulators. [score:8]
These data are in accordance with our results showing that an increased expression of mir-218, let-7g, and mir-125b predicts disease-free and disease-specific survival in OSCC patients (Figure 3). [score:7]
The miRNA prognostic modulators centered on the three hub regulatory genes are depicted in Figure 2. The upstream regulatory miRNAs (miR-218, let-7g, and miR-125b) and the related downstream gene clusters were found to have a concordant prognostic value on disease-free survival and disease-specific survival. [score:7]
After variable selection in multivariable logistic regression analysis, we found that miR-218 was the only miRNA (Figure 1) that regulated SP1 and was a significant predictor for disease-free survival (odds ratio [OR]  = 3.215, p = 0.037) and disease-specific survival (OR = 3.012, p = 0.049) (Table S1). [score:6]
MiR-218 correlated with the expression of two SP1-related gene clusters related to disease-free survival and disease-specific survival. [score:6]
Effect of global transcription inhibition on OSCC cell growth and mir-218, let-7g, and mir-125b expression. [score:5]
From a translational standpoint, the results of our study reveal that the integration of the expression of the miR-218, let-7g, and miR-125b with traditional risk factors may improve current stratification strategies. [score:5]
50%); (B) the subgroup with low miR-218 expression showed a higher rate of distant metastases in patients with pN+ disease (86% vs. [score:5]
Taken together, these data suggest that miR-218, let-7g, and miR-125b may be valuable prognostic indicators of disease-free survival and disease specific survival. [score:5]
One unit decrease in the expression level of miR-218 and miR-125b increased the risk of disease recurrence and death by approximately two-fold. [score:5]
As expected, the specific upstream miRNAs (miR-218, let-7g, and miR-125b) were selected by the mo del as corresponding to the downstream target gene clusters. [score:3]
By contrast, a high expression of miR-218, let-7g, or miR-125b is associated with better clinical outcomes in patients' adverse pathological risk factors (pT3-4, pN+, and p-stage III–IV). [score:3]
As for patients with pN+, the decrease in one unit of miR-218 expression also increased the risk of distant metastasis by 2.1-fold (p = 0.009). [score:3]
Recent studies have shown that miR-218 and let-7g can inhibit cell invasion and metastasis in gastric cancer [35] and breast cancer [36], respectively. [score:3]
0102403.g004 Figure 4Effects of M [4]N on the expression of miR-218, miR- let-7g, and miR-125b in OSCC cancer cell lines. [score:3]
While after exposure to M [4]N, the expression of mir-218, let-7g, and mir-125b was significantly increased in all of the cell lines (Figure 4). [score:3]
Our findings demonstrate that OSCC patients with pN+ and lower expression of miR-218 have a dismal distant metastatic rate. [score:3]
Effects of M [4]N on the expression of miR-218, miR- let-7g, and miR-125b in OSCC cancer cell lines. [score:3]
In patients with pN+, a low miR-218 expression was associated with an increased risk of distant metastases (p = 0.043, Figure 3B). [score:3]
In patients with traditional risk factors, we were able to identify distinct prognostic subgroups based on the expression of miR-218, miR-125b, and let-7g. [score:3]
Table S7 Logistic regression analysis of clinical outcomes associated with the miR-218, let-7g, and miR-125b in validation cohort. [score:1]
Notably, we identified three miRNAs (miR-218, let-7g, and miR-125b) that play a key role as prognostic modulators in OSCC patients. [score:1]
To validate the clinical significance of the miRNA signature, we carried out qRT-PCR for miR-218, let-7g and miR-125b in an independent cohort. [score:1]
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[+] score: 72
Other miRNAs from this paper: hsa-mir-218-2, hsa-mir-200c, hsa-mir-130b
QRT-PCR indicated that miR-130b expression in tumor tissues was strongly elevated than adjacent non-tumor tissues (P < 0.001), while the level of miR-218 expression in osteosarcoma tissues was down-regulated than adjacent non-tumor tissues (P < 0.001). [score:8]
0.59 ± 0.12, P < 0.001; Fig.   2), while the level of miR-218 expression in osteosarcoma tissues was down-regulated than adjacent non-tumor tissues (0.61 ± 0.21 vs. [score:6]
They hypothesized that miR-218 can directly target LEF1, resulting in reduced synthesis of MMP-9. Moreover, they concluded that miR-218 is involved in the invasive behavior of GBM cells and by targeting LEF1 and blocking the invasive axis, miR-218-LEF1-MMPs, it may be useful for developing potential clinical strategies [36]. [score:6]
Jin et al. [31] indicated that miR-218 can act as inhibitor of osteosarcoma cell migration and invasion by down -regulating TIAM1, MMP2 and MMP9 expression [18]. [score:6]
In the present study, the level of miR-218 expression in osteosarcoma tissues was down-regulated in comparison with adjacent non-tumor tissues. [score:6]
Clinical correlation analysis showed that increased expression of miR-130b and decreased expression of miR-218 were significantly associated with advanced tumor stage (x [2] = 6.285, P < 0.007; x [2] = 7.172, P < 0.009), distant metastasis (x [2] = 5.528; P < 0.001; x [2] = 4.617, P < 0.001) and size of tumor (x [2] = 5.01, P = 0.013; x [2] = 4.271, P = 0.019), (Table  1). [score:5]
Clinical correlation analysis showed that increased expression of miR-130b and decreased expression of miR-218 were significantly associated with advanced tumor stage (x [2] = 6.285, P < 0.009; x [2] = 7.172, P < 0.007), distant metastasis (x [2] = 5.528; P < 0.001; x [2] = 4.617, P < 0.001) and size of tumor (x [2] = 5.01, P = 0.013; x [2] = 4.271, P = 0.019). [score:5]
A previous study indicated that LEF1 is a new direct target of miR-218, and miR-218 can reduce protein levels of LEF1 and MMP-9 in glioblastoma cells. [score:4]
Moreover, it has been reported that miR-218 inhibited osteosarcoma cell migration and invasion by down -regulating T-cell lymphoma invasion and metastasis 1 (TIAM1), matrix metalloproteinase2 (MMP2) and MMP9 [31]. [score:4]
Moreover, patients with low miR-218 expression had shorter survival in colon cancer [27]. [score:3]
Clinical correlation analysis showed that decreased expression of miR-218 was significantly associated with advanced tumor stage, distant metastasis and size of tumor. [score:3]
The clinical features of all enrolled patients were shown in Table  1. Fig. 1 Expression levels of miR-130b and miR-218 in osteosarcoma tissues and adjacent non-tumor tissues Briefly, total RNA was extracted from the tissues using TRIzol reagent (Invitrogen, Carlsbad, CA, USA), according to the manufacturer’s instructions. [score:3]
Moreover, decreased expression of miR-218 was related to a significant worse survival of HCC patients. [score:3]
Down regulation of miR-218 was found in osteosarcoma tissues [31]. [score:2]
Furthermore, deregulation of miR-218 was reported in many kinds of tumors [25– 30]. [score:2]
MiR-218 has been reported to be significantly deregulated in many kinds of tumors [25– 30]. [score:1]
It has been reported that the low level of miR-218 is associated with TNM stage, lymph node metastasis and histological differentiation in colon cancer. [score:1]
However, further studies are needed to clarify the role of miR-218 in osteosarcoma cell proliferation and apoptosis. [score:1]
Our findings suggested that that miR-218 may be a potential marker in osteosarcoma patients. [score:1]
Lower level of miR-218 has been found in patients with large tumor size and advanced TNM tumor stage in hepatocellular carcinoma tissues [30]. [score:1]
We utilized quantitative real-time PCR to evaluate the level of miR-130b and miR-218 expressions in OS patients and normal tissues and their relationship with clinicopathological features and survival in OS patients. [score:1]
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[+] score: 52
Several studies have shown that the expression of miR-218 is frequently reduced in CC (Table 1) [11, 17, 30, 43] and a recent study reported that downregulation of miR-218 had a strong relationship with later stages of SCC, cervical adenocarcinoma, and lymphatic node metastasis (Figure 1) [44], confirming that miR-218 can act as a tumor suppressor miRNA in CC. [score:8]
Moreover, Martinez et al. revealed that exogenous expression of the HPV16 E6 oncogene reduced miR-218 expression, and, conversely, RNA interference of E6/E7 oncogenes in an HPV16 positive cell line increased miR-218 expression. [score:7]
The miR-218 expression is downregulated in several cancers and is frequently deleted in ovarian, breast, and melanoma cancers [1]. [score:6]
These results suggest that the downregulation of miR-218 by E6 and the consequent overexpression of LAMB3 may contribute to cervical tumorigenesis [30]. [score:6]
It was demonstrated that miR-218 could inhibit tumor invasion and metastasis by targeting Robo1 [40], which is an oncogenic transmembrane receptor of the immunoglobulin family that upon binding to its ligand, Slit2, cooperates with the Abl kinase to induce cell migration [41, 42]. [score:5]
Although miR-218 is not defined as a transcriptional target of p53, this miRNA is underexpressed in the presence of the E6 oncoprotein [30]. [score:5]
Exogenous expression of miR-218 in HPV16 positive cell lines decreases LAMB3transcript and protein levels, a target of miR-218 which increases cell migration and tumorigenicity [30]. [score:5]
Previous publications reported that miR-218 was downregulated in several cancers such as bladder, lung, and oral cancer [37– 39]. [score:4]
Interestingly, it has been shown that also miR-218 is underexpressed in the cell lines containing integrated HPV16 DNA as compared to both the normal cervix and HPV -negative C-33A cell line. [score:2]
miR-218 is specifically underexpressed in cervical cell lines, cervical lesions, and cancer tissues containing integrated HPV16 DNA compared to the normal cervix. [score:2]
In contrast, low levels of miR-218 and miR-424 have also shown to have a good prognostic role in CC [44, 47]. [score:1]
So, this could suggest that miR-218 may be specifically affected by the presence of HPV16 [30]. [score:1]
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14
[+] score: 39
Nishikawa R. Goto Y. Sakamoto S. Chiyomaru T. Enokida H. Kojima S. Kinoshita T. Yamamoto N. Nakagawa M. Naya Y. Tumor-suppressive microRNA-218 inhibits cancer cell migration and invasion via targeting of LASP1 in prostate cancer Cancer Sci. [score:7]
Uesugi A. Kozaki K. Tsuruta T. Furuta M. Morita K. Imoto I. Omura K. Inazawa J. The tumor suppressive microRNA miR-218 targets the mTOR component Rictor and inhibits AKT phosphorylation in oral cancer Cancer Res. [score:7]
The down-regulation miR-21, combined with the overexpression of miR-34a, miR218, PTEN and E-cadherin (CDH1) could explain the benign nature of meningiomas (grades I and II) and represent barriers for grades I and II tumors from malignant progression. [score:6]
He X. Dong Y. Wu C. W. Zhao Z. Ng S. S. Chan F. K. Sung J. J. Yu J. MicroRNA-218 inhibits cell cycle progression and promotes apoptosis in colon cancer by downregulating BMI1 polycomb ring finger oncogene Mol. [score:5]
Han G. Fan M. Zhang X. microRNA-218 inhibits prostate cancer cell growth and promotes apoptosis by repressing TPD52 expression Biochem. [score:5]
After verification of the top 18 miRNAs by RT-qPCR with fold change values over ±5.17 in any of these comparisons, only six miRNAs (miR-21, miR-34a, miR-143, miR-193b, miR-218, and miR-451) were clearly differentially expressed (tumors vs. [score:3]
The differential expression of miR-218, miR-34a and miR-451 in meningiomas were previously reported, using microarray analysis [48]. [score:3]
miR-218 is considered a tumor suppressor [54, 55], suggesting that miR-218 also play a role in preventing or slowing meningioma grades I and II from malignant progression. [score:2]
Interestingly, a high abundance of miR-218 (+8/+4 fold, SOLiD/RT-qPCR) was observed in the studied meningiomas. [score:1]
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[+] score: 29
Other miRNAs from this paper: hsa-let-7a-1, hsa-let-7a-2, hsa-let-7a-3, hsa-let-7b, hsa-let-7c, hsa-let-7d, hsa-let-7e, hsa-let-7f-1, hsa-let-7f-2, hsa-mir-15a, hsa-mir-16-1, hsa-mir-17, hsa-mir-18a, hsa-mir-20a, hsa-mir-21, hsa-mir-22, hsa-mir-23a, hsa-mir-24-1, hsa-mir-24-2, hsa-mir-25, hsa-mir-27a, hsa-mir-29a, hsa-mir-30a, hsa-mir-92a-1, hsa-mir-92a-2, hsa-mir-93, hsa-mir-101-1, hsa-mir-106a, hsa-mir-107, hsa-mir-16-2, hsa-mir-192, hsa-mir-196a-1, hsa-mir-199a-1, hsa-mir-129-1, hsa-mir-148a, hsa-mir-10b, hsa-mir-34a, hsa-mir-181b-1, hsa-mir-181c, hsa-mir-196a-2, hsa-mir-199a-2, hsa-mir-203a, hsa-mir-210, hsa-mir-212, hsa-mir-214, hsa-mir-215, hsa-mir-217, hsa-mir-218-2, hsa-mir-221, hsa-mir-222, hsa-mir-223, hsa-mir-200b, hsa-let-7g, hsa-let-7i, hsa-mir-1-2, hsa-mir-15b, hsa-mir-27b, hsa-mir-122, hsa-mir-124-1, hsa-mir-124-2, hsa-mir-124-3, hsa-mir-125b-1, hsa-mir-130a, hsa-mir-141, hsa-mir-142, hsa-mir-143, hsa-mir-145, hsa-mir-153-1, hsa-mir-153-2, 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-146a, hsa-mir-150, hsa-mir-185, hsa-mir-195, hsa-mir-206, hsa-mir-200c, hsa-mir-1-1, hsa-mir-155, hsa-mir-181b-2, hsa-mir-106b, hsa-mir-29c, hsa-mir-200a, hsa-mir-101-2, hsa-mir-34b, hsa-mir-34c, hsa-mir-130b, hsa-mir-376c, hsa-mir-375, hsa-mir-378a, hsa-mir-148b, hsa-mir-338, hsa-mir-335, hsa-mir-423, hsa-mir-20b, hsa-mir-429, hsa-mir-449a, hsa-mir-433, hsa-mir-451a, hsa-mir-193b, hsa-mir-520d, hsa-mir-503, hsa-mir-92b, hsa-mir-610, hsa-mir-630, hsa-mir-650, hsa-mir-449b, hsa-mir-421, hsa-mir-449c, hsa-mir-378d-2, hsa-mir-744, hsa-mir-1207, hsa-mir-1266, hsa-mir-378b, hsa-mir-378c, hsa-mir-378d-1, hsa-mir-378e, hsa-mir-378f, hsa-mir-378g, hsa-mir-378h, hsa-mir-4512, hsa-mir-378i, hsa-mir-203b, hsa-mir-451b, hsa-mir-378j
Conversely, the tumor suppressor miR-218 promotes invasion and metastasis by targeting Robo1, and thereby activating the Slit/Robo1 signaling pathway [156, 157, 158, 159, 160]. [score:5]
Tie J. Pan Y. Zhao L. Wu K. Liu J. Sun S. Guo X. Wang B. Gang Y. Zhang Y. miR-218 inhibits invasion and metastasis of gastric cancer by targeting the Robo1 receptor PLoS Genet. [score:5]
Moreover, the tumor suppressor miR-218 regulates COX-2 (cyclooxygenase-2) via the anti-apoptotic NF-κB signaling pathway [155]. [score:4]
Of these, miR-17-5p, miR-18a, miR-20a, miR-200c, miR-21, miR-218, miR-221, miR-222, miR-25, miR-27a, miR-376c, and miR-744 were found to be significantly elevated in GC patients, and their expression was significantly reduced after surgery [26, 27, 54, 68, 71, 80, 81, 155, 187, 192, 193, 195, 196, 198, 199, 200, 201, 202, 203, 204, 205]. [score:3]
Of these, miR-122, miR-203, and miR-218 were found to be significantly reduced in GC patients, and their expression was significantly increased following surgery [155, 189, 198, 211]. [score:3]
In addition, oncomiR-20b, miR-150 [23], miR-214 [24, 74], miR-375 [39, 74, 86, 87, 88], tumor suppressor Let-7g [24, 109, 110], miR-125-5p [126], miR-146a [24, 134], miR-218 [154], miR-433 [24, 86, 109, 110, 174], and miR-451 [24, 94, 230] are associated with a poor survival prediction in GC. [score:3]
Xin S. Y. Feng X. S. Zhou L. Q. Sun J. J. Gao X. L. Yao G. L. Reduced expression of circulating microRNA-218 in gastric cancer and correlation with tumor invasion and prognosis World J. Gastroenterol. [score:3]
Conversely, several tumor-suppressor miRNAs circulating in the blood of GC patients can also be used as diagnostic biomarkers to distinguish GC patients from healthy individuals, including miR-122, miR-195-5p, miR-203, miR-218, and miR-375 [155, 189, 198, 209, 210, 211]. [score:3]
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[+] score: 26
Interestingly, HOTAIR silencing activates the main BMI1 downstream targets P16(Ink4a) and P14(ARF), by enhancing miR-218 and inhibiting BMI1 expression, thus resulting in the suppression of tumorigenesis in HCC [120]. [score:9]
In primary human HCC specimens, HOTAIR was shown to be concordantly upregulated with the oncogene BMI1, which is a target of miR-218. [score:6]
Indeed, miRNA sponging appears to be a general mechanism of HOTAIR, as HOTAIR also targets miR-218, resulting in increased cell viability, cell cycle upregulation, and tumorigenicity [120]. [score:6]
Fu W. M. Zhu X. Wang W. M. Lu Y. F. Hu B. G. Wang H. Liang W. C. Wang S. S. Ko C. H. Waye M. M. Hotair mediates hepatocarcinogenesis through suppressing mirna-218 expression and activating p14 and p16 signalingJ. [score:5]
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[+] score: 24
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]
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]
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]
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]
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]
In addition, miR-218/Wnt signaling circuit amplifies both the osteoblast phenotype and osteomimicry-related tumor activity [40]. [score:1]
A signal-amplification circuit between miR-218 and Wnt/β-catenin signal was reported to promote human adipose tissue-derived stem cells osteogenic differentiation [39]. [score:1]
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]
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[+] score: 23
MiR-218 can directly target lymphoid enhancer -binding factor 1 (LEF1) and downregulate the expression of its downstream proteins, e. g., MMPs, reducing ECM degradation, whereas inhibition of miR-218 expression enhances glioma cell invasiveness, suggesting a tumor-suppressive role of the miRNA. [score:15]
A group of miRNAs, including miR-218, miR-21, miR-132, miR-134, miR-155, and miR-409-5p, were reported to be overexpressed by three times as much in GBM compared with oligodendrogliomas, while miR-128 expression in oligodendrogliomas is four times higher than that in GBM. [score:4]
MiR-218 is expressed at low levels in glioma tissues, particularly in GBM, which might contribute to the acquisition of invasive potential [114]. [score:2]
Liu Y. Yan W. Zhang W. Chen L. You G. Bao Z. Wang Y. Wang H. Kang C. Jiang T. MiR-218 reverses high invasiveness of glioblastoma cells by targeting the oncogenic transcription factor LEF1 Oncol. [score:2]
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19
[+] score: 22
Here, we intended to identify suitable MREs for bladder cancer specific adenovirus -mediated TRAIL expression from the miRNAs with downregulated expression in bladder cancer, including miR-1 [18- 21], miR-99a [22], miR-100 [23], miR-101 [24, 25], miR-125b [23, 26, 27], miR-133a [18, 20, 21, 23, 28- 30], miR-143 [22, 23, 31- 33], miR-145 [21, 23, 29- 31, 34], miR-195-5p [35], miR-199a-3p [36], miR-200 [37, 38], miR-203 [39, 40], miR-205 [37], miR-218 [21, 41], miR-490-5p [42], miR-493 [43], miR-517a [44], miR-574-3p [45], miR-1826 [46] and let-7c [42]. [score:8]
Bladder cancer-specific expression of TRAIL genes was achieved by employing MREs of miR-1, miR-133 and miR-218. [score:3]
The involved MREs sequences in our study were described in detail in Table  1. Table 1 MiRNA response elements (MREs) for bladder cancer-specific downregulated miRNAs miRNA primer sequences miR-1Forward: 5′-TCGAGACAAACACC ACATTCCAACAAACACC ACATTCCAACAAACACCGC-3′Reverse: 5′-GGCCGCGGTGTTTGT TGGAATGTGGTGTTTGT TGGAATGTGGTGTTTGTC-3′ miR-99aForward: 5′-TCGAGACAAACACC TACGGGTACAAACACC TACGGGTACAAACACCGC-3′Reverse: 5′-GGCCGCGGTGTTTGT ACCCGTAGGTGTTTGT ACCCGTAGGTGTTTGTC-3′ miR-101Forward: 5′-TCGAGACAAACACC GTACTGTACAAACACC GTACTGTACAAACACCGC-3′Reverse: 5′-GGCCGCGGTGTTTGT ACAGTACGGTGTTTGT ACAGTACGGTGTTTGTC-3′ miR-133Forward: 5′-TCGAGACAAACACC GGACCAAAACAAACACC GGACCAAAACAAACACCGC-3′Reverse: 5′-GGCCGCGGTGTTTGT TTTGGTCCGGTGTTTGT TTTGGTCCGGTGTTTGTC-3′ miR-218Forward: 5′-TCGAGACAAACACC AAGCACAAACAAACACC AAGCACAAACAAACACCGC-3′Reverse: 5′-GGCCGCGGTGTTTGT TTGTGCTTGGTGTTTGT TTGTGCTTGGTGTTTGTC-3′ miR-490-5pForward: 5′-TCGAGACAAACACC ATCCATGACAAACACC ATCCATGACAAACACCGC-3′Reverse: 5′-GGCCGCGGTGTTTGT CATGGATGGTGTTTGT CATGGATGGTGTTTGTC-3′ miR-493Forward: 5′-TCGAGACAAACACC ACCTTCAACAAACACC ACCTTCAACAAACACCGC-3′Reverse: 5′-GGCCGCGGTGTTTGT TGAAGGTGGTGTTTGT TGAAGGTGGTGTTTGTC-3′ miR-517aForward: 5′-TCGAGACAAACACC TGCACGAACAAACACC TGCACGAACAAACACCGC-3′Reverse: 5′-GGCCGCGGTGTTTGT TCGTGCAGGTGTTTGT TCGTGCAGGTGTTTGTC-3′The underscored sequences indicated MREs of miR-1, miR-99a, miR-101, miR-133 and miR-218, miR-490-5p, miR-493 and miR-517a. [score:3]
Application of MREs of miR-1, miR-133 and miR-218 restrained exogenous gene expression within bladder cancer cells. [score:3]
The involved MREs sequences in our study were described in detail in Table  1. Table 1 MiRNA response elements (MREs) for bladder cancer-specific downregulated miRNAs miRNA primer sequences miR-1Forward: 5′-TCGAGACAAACACC ACATTCCAACAAACACC ACATTCCAACAAACACCGC-3′Reverse: 5′-GGCCGCGGTGTTTGT TGGAATGTGGTGTTTGT TGGAATGTGGTGTTTGTC-3′ miR-99aForward: 5′-TCGAGACAAACACC TACGGGTACAAACACC TACGGGTACAAACACCGC-3′Reverse: 5′-GGCCGCGGTGTTTGT ACCCGTAGGTGTTTGT ACCCGTAGGTGTTTGTC-3′ miR-101Forward: 5′-TCGAGACAAACACC GTACTGTACAAACACC GTACTGTACAAACACCGC-3′Reverse: 5′-GGCCGCGGTGTTTGT ACAGTACGGTGTTTGT ACAGTACGGTGTTTGTC-3′ miR-133Forward: 5′-TCGAGACAAACACC GGACCAAAACAAACACC GGACCAAAACAAACACCGC-3′Reverse: 5′-GGCCGCGGTGTTTGT TTTGGTCCGGTGTTTGT TTTGGTCCGGTGTTTGTC-3′ miR-218Forward: 5′-TCGAGACAAACACC AAGCACAAACAAACACC AAGCACAAACAAACACCGC-3′Reverse: 5′-GGCCGCGGTGTTTGT TTGTGCTTGGTGTTTGT TTGTGCTTGGTGTTTGTC-3′ miR-490-5pForward: 5′-TCGAGACAAACACC ATCCATGACAAACACC ATCCATGACAAACACCGC-3′Reverse: 5′-GGCCGCGGTGTTTGT CATGGATGGTGTTTGT CATGGATGGTGTTTGTC-3′ miR-493Forward: 5′-TCGAGACAAACACC ACCTTCAACAAACACC ACCTTCAACAAACACCGC-3′Reverse: 5′-GGCCGCGGTGTTTGT TGAAGGTGGTGTTTGT TGAAGGTGGTGTTTGTC-3′ miR-517aForward: 5′-TCGAGACAAACACC TGCACGAACAAACACC TGCACGAACAAACACCGC-3′Reverse: 5′-GGCCGCGGTGTTTGT TCGTGCAGGTGTTTGT TCGTGCAGGTGTTTGTC-3′The underscored sequences indicated MREs of miR-1, miR-99a, miR-101, miR-133 and miR-218, miR-490-5p, miR-493 and miR-517a. [score:3]
AACAAACACC GGACCAAAACAAACACC GGACCAAAACAAACACC AAGCACAAACAAACACC AAGCACAA-3′), which contained two copies of miR-1 MREs, two copies of miR-133 MREs and two copies of miR-218 MREs. [score:1]
Ad-TRAIL-MRE-1-133-218 contained MREs of miR-1, miR-133 and miR-218 that were inserted immediately following TRAIL gene. [score:1]
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20
[+] score: 22
mir-218 (miR-218-1) is down-regulated in smokers [36] and it is encoded within the intronic region of the known tumor suppressor gene SLIT2 located at 4p15.31. [score:6]
A second copy of miR-218 (miR-218-2) occurs within the SLIT3 locus located at 5q35.1, and expression of SLIT3 has also been shown to be down-regulated in lung cancer [38]. [score:6]
SLIT2, which is frequently inactivated in lung and breast tumors [37], is significantly down-regulated in smokers with expression correlating to that of mir-218 [36]. [score:6]
Alteration of mir-218 levels diminishes the induction of the predicted mir-218 target MAFG in response to cigarette smoke condensate (CSC). [score:3]
Interestingly, miR-218-1 is located within FRA4D (aphidicolin type, common) and miR-218-2 is located within FRA5G (folic acid type, rare). [score:1]
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21
[+] score: 21
For example, upregulated miRNAs targeted CDC7 (targeted by miR-30a-5p and miR-630) and CDK2 (targeted by miR-638), while downregulated miRNAs targeted CDKN1A (targeted by miR-299-5p), CDKN1B (targeted by miR-218-5p and miR-495-3p) and CCNA2 (targeted by miR-218-5p). [score:21]
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[+] score: 20
miR-218 is significantly upregulated during osteoblast differentiation and targets the inhibitors of Wnt signaling [194]. [score:8]
He X. Dong Y. Wu C. W. Zhao Z. Ng S. S. Chan F. K. Sung J. J. Yu J. MicroRNA-218 inhibits cell cycle progression and promotes apoptosis in colon cancer by downregulating BMI1 polycomb ring finger oncogene Mol. [score:5]
The expression of Bmi1 is regulated by miRNAs, such as miR-128, miR-200b/c, miR-141, miR-15, miR-16, miR-203, miR-183, miR-194, and miR-218 [24, 67, 121, 122, 123, 124, 125]. [score:4]
Hassan M. Q. Maeda Y. Taipaleenmaki H. Zhang W. Jafferji M. Gordon J. A. Li Z. Croce C. M. van Wijnen A. J. Stein J. L. miR-218 directs a Wnt signaling circuit to promote differentiation of osteoblasts and osteomimicry of metastatic cancer cells J. Biol. [score:2]
Thus, miR-218 found in metastatic breast cancer cells is a potent activator of Wnt signaling and promotes the osteomimicry to facilitate bone metastasis of breast cancer cells. [score:1]
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23
[+] score: 19
We identified five downregulated miRNAs (miR-26b, miR-125b, miR-203, miR-218, and miR-373) and one upregulated miRNA (miR-15a) when we compared miRNA expression in HNSCC cells versus primary human keratinocytes (Figure 1A). [score:8]
To assess the function of the deregulated miRNAs in HNSCC, we generated two YFP-luciferase -expressing cell lines—SCC13 (established facial SCC; Rheinwald and Beckett, 1981) and SJG15 (primary lingual SCC; Goldie et al., 2012)—in which we knocked down miR-15a or stably overexpressed miR-26b, miR-125b, miR-203, miR-218, or miR-373 using lentiviral approaches (Figure S1A). [score:7]
Overexpression of miR-26b and miR-218 enhanced metastatic dissemination, whereas the other four miRNAs had no significant effect (Figure 1D). [score:3]
Since the aim of the screen was to identify antimetastatic miRNAs, we did not analyze miR-26b and miR-218 further. [score:1]
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24
[+] score: 18
Studies in vitro have shown an anti-cancer function of miR-218, and the down -expression of miR-218 increases myocyte enhancer factor 2D (MEF2D) levels by promoting lung cancer growth [57], and by inhibiting NSCLC proliferation and metastasis via by downregulating CDCP1 [58]. [score:8]
The down-regulation of miR-218 increases epithelial-mesenchymal transition and tumor metastasis in lung cancer by targeting Slug/ZEB2 signaling [59]. [score:6]
The down-regulation of miR-451a, miR-144, miR-195, miR-218, miR-145, miR-30a, miR-126 and miR-139 has been found in both the training and validation set. [score:4]
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25
[+] score: 18
Expression of miR-124 and miR-137, respectively, increased up to 8- and 24-fold, expression of miR-129 and miR-139, respectively, decreased up to 2- and 4-fold, and expression of miR-7 and miR-218 did not change appreciably. [score:7]
Of the 35 miRNAs, we identified six HGA-miRNAs, which were down-regulated in both AA and GBM tumors at a more stringent degree of significance (P < 0.01): miR-7, miR-124, miR-129, miR-137, miR-139 and miR-218. [score:4]
We identified six miRNAs of particular interest, miR-7, miR-124, miR-129, miR-137, miR-139 and miR-218, which were down-regulated in both AAs and GBMs (Figure 1A, Additional file 8 and Table 1) at a more stringent level of significance (P ≤ 0.01). [score:4]
We observed that the majority of the HGA-miRNAs show expression changes during, or have been implicated in, differentiation of various cell lineages: miR-7 during photoreceptor differentiation [23]; miR-124 and miR-137 during erythropoiesis [24]; miR-124 and miR-218 during neuronal differentiation of embryonal carcinoma cell differentiation [25]; miR-124 during neuronal differentiation of ES cells [12]. [score:3]
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26
[+] score: 18
miRNA miR function Regulation Tissue/cell type Source miR-15a Tumor suppressor Down Primary bronchial epithelial cells Schembri et al. 2009 miR-125bTargets p53, stress response miR‑199b Oncogene activation miR-218 Tumor suppressor miR-31 Apoptosis, tumor suppressor Up Normal and cancer lung cells Xi et al. 2010 miR-21 Fatty acid synthesis, apoptosis Up Human squamous carcinoma cells Zhang et al. 2014 miR-452Targets CDK1 Down Human alveolar macrophages Graff et al. 2012 Izzotti et al. (2009) analyzed miRNA expression patterns in the lungs of mice exposed to passive cigarette smoke, and they established life-course–related miRNA expression changes by comparing miRNA expression in lungs from unexposed newborn, postweaning, and adult mice. [score:18]
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[+] score: 17
This miRNA is down-regulated in different cancers [109] and transfection with a miR-218-5p mimic inhibits migration and proliferation in non-small-cell lung cancer cells by targeting the epidermal growth factor receptor (EGFR) [110]. [score:8]
MiR-218-5p, a tumor suppressor miRNA, was the most over-expressed miRNA in response to 12 Gy. [score:5]
In colorectal cancer cells, miR-218-5p reduced migration, invasion and colony formation by targeting the Metastasis Associated with Colon Cancer 1 protein (MACC1) [111]. [score:3]
On the other hand, only 4 miRNAs were differentially incremented (miR-512-5p, miR-218-5p, miR-449a and miR-1) with no differentially decreased miRNAs in cells exposed to 12 Gy (Figure 5B and Table 2). [score:1]
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[+] score: 16
It appears that miR-218 plays a key role in regulating the expression of RUNX2, a TF crucial for osteogenic differentiation, since there is a high correlation between lower levels of miR-218 and higher levels of RUNX2 transcripts, suggesting that miR-218 regulates the osteogenic pathway in hDT-MSCs by modulating the expression of RUNX2 (Gay et al., 2014). [score:7]
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]
In addition, decreasing levels of miR-218 and the enrichment of H3K4me3 on the promoter of RUNX2 seem to promote their expression. [score:3]
However, several miRNAs, including miR-210, miR-218, and miR-99a, may be implicated in the regulation of differentiation in the dental tissues mentioned above. [score:2]
Differentiation of human dental stem cells reveals a role for microRNA-218. [score:1]
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[+] score: 15
Similarly, the miRNAs down-regulated in 10-87 HP cells and 10-87 T cells, such as miR-31, miR-200c, miR-218, and miR-183, were also found to be down-regulated in A4497 VERO cells and SF-VERO cells. [score:7]
These initial changes consisted of the down-regulation of multiple miRNAs, highlighted by the down-regulation of miR-31, miR-200c, and miR-218. [score:7]
qRT-PCR analysis confirmed that miR-376a, miR-654-3p, miR-543, miR-382, miR-31, miR-200c, miR-218, and miR-183 paralleled the microarray miRNA levels. [score:1]
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[+] score: 15
miR-155 and miR-218 backbones lead to potent knockdownpME -RNAi651, pME -RNAi661 and pME -RNAi671 constructs with green fluorescent protein (GFP) marker followed by a synthetic pre-miR directed against the 3′-UTR of mCherry were cloned downstream of the ubiquitin promoter in a mini-tol2-R4R2 multisite gateway-compatible destination plasmid (Supplementary Fig. 3). [score:3]
hsa-miR218 -based plasmids: An artificial miRNA -expressing hsa-miR218 cassette was generated in our laboratory. [score:3]
However, the backbone based on dre-miR30 achieved only weak red fluorescence inhibition compared with mmu-miR155 or hsa-miR218 backbones. [score:2]
miR-155 and miR-218 backbones lead to potent knockdown. [score:2]
According to the cell-specific observations above, miR218 and miR155 backbones led to potent global knockdown with ∼74 and 83% reduction in red fluorescence, respectively, while the miR30 backbone reduced fluorescence modestly by ∼33%. [score:2]
Pri-hsa-miR218-2 was amplified and cloned into pME -RNAi651 in two steps to allow the insertion of a 2 × BsmBI repeat at the pre-miR218 position (Fig. 1). [score:1]
The third plasmid, based on an hsa-miR218 sequence, was made in our laboratory. [score:1]
pME -RNAi651 is based on a mmu-miR155 backbone, pME -RNAi661 on a dre-miR30 backbone and pME -RNAi671 on a hsa-miR218 backbone. [score:1]
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[+] score: 14
In another study, bronchial airway epithelial cells from current and never smokers differed in the expression of 28 miRNAs (especially miR-218, miR-15a, miR-199b, miR-125a/b, miR-294) in comparison to smokers, whereas the majority of deregulated miRNAs were downregulated in smokers [97]. [score:7]
Similar observation was observed in lung squamous cell carcinoma, where downregulation of miR-218 was associated with a history of cigarette smoking [98]. [score:4]
Next, miR-218 was identified as a putative tumor suppressor in non-small cell lung cancer [98]. [score:3]
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[+] score: 14
miR-218 was upregulated in liver from NASH mo del mice and miR-218 is a well studied cancer-preventive miRNA [45]. [score:4]
miR-218 may have a role in NASH progression via AdipoR2 downregulation. [score:4]
Moreover, a recent study showed that miR-218 targets adiponectin receptor 2 (AdipoR2) in cultured hepatoma cells, HepG2, and attenuates the adiponectin signal [46]. [score:3]
Further studies will be needed to clarify the function of miR-218 and miR-342 in NAFLD pathology. [score:1]
Additionally, we are the first to suggest that miR-218 and -342 are candidate NAFLD miRNAs. [score:1]
miR-218 and miR-342 were also newly predicted candidate NAFLD miRNAs based on mouse mo dels. [score:1]
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[+] score: 13
The miRNAs with a reduced expression in lymphoma relative to normal tissue only coincided partially e. g. for miR-218 and miR-200 family. [score:3]
One of the miRNAs which showed a reduced expression in both EBV -positive NK/T-cell lymphoma as well as the EBV -negative T-cell lymphomas was miR-218. [score:3]
The repression of miR-218 was already described for gastric carcinoma and shown to function as an inhibitor of invasion and metastasis [27]. [score:3]
The paper by Ng et al (2011) did not report a change in expression for miR-218, though [23]. [score:3]
Furthermore, the reduction of miR-218 was associated with strong activation of NFkB which is also often seen in NK/T-cell lymphoma [28]. [score:1]
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[+] score: 13
For example, miR-100 and miR-199a-3p suppress mTOR expression [20- 22], and miR-152 and miR-218 suppress Rictor in some cancers [23, 24]. [score:7]
Two other miRNAs that also target Rictor, miR-218 and miR-152, has shown to be downregulated in oral squamous cell carcinoma and endometrial cancer [23, 24]. [score:6]
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[+] score: 13
[53] [,] [71] [,] [72] miR-218 knock-down in zebrafish results in a phenotype similar to robo1 overexpression, suggesting functional regulation of Slit–Robo signalling by miR-218. [score:5]
Additionally, cross-talk was found between Robo1, Vegfa, and the Vegfr2 receptor to control heart field migration, indicating a Slit/miR-218/Robo/Vegf feedback regulatory loop regulating heart field migration. [score:3]
[71] miR-218 is able to repress expression of both robo1 and robo2 mRNA. [score:3]
Microrna-218 regulates vascular patterning by modulation of Slit-Robo signaling. [score:1]
Intriguingly, both slit2 and slit3 have a miRNA encoded within an intron, mir218-1, and mir218-2, respectively. [score:1]
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Uesugi A, Kozaki K, Tsuruta T, Furuta M, Morita K, Imoto I, Omura K and Inazawa J. The tumor suppressive microRNA miR-218 targets the mTOR component Rictor and inhibits AKT phosphorylation in oral cancer. [score:7]
Smoking was associated with the down-regulation of 27 plasma miRNAs (Fig.   7), including several previously identified as performing tumour suppressor-like functions; let-7i-5p [2], miR-148a-5p [22], miR-218-5p [17], miR-29-3p [20], miR-133a [4], miR-296-5p [10] and miR-370 [21]. [score:6]
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[+] score: 13
For example, hsa-miR-382, hsa-miR-31, and hsa-miR-149 are downregulated in medulloblastoma [51], hsa-miR-378 is downregulated in Alzheimer’s disease [52], and abnormal expression of hsa-miR-218 has been detected in samples from Parkinson’s disease patients [53]. [score:13]
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[+] score: 12
miR-218 is one of the commonly downregulated microRNAs in GSCs [76] which targets Bmi1. [score:6]
Cell migration and invasion declined as miR-218 expression levels increased, suggesting miR-218 functioned as a tumour suppressor. [score:5]
Cells with lower miR-218 levels presented increased tumour-like properties using both in vitro and in vivo experimental approaches [112]. [score:1]
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[+] score: 12
Other miRNAs from this paper: hsa-mir-203a, hsa-mir-218-2, hsa-mir-708, hsa-mir-203b
Given the discrepancy between mRNA (Figure 3b) and protein expression (Figure 2b), we sought to analyze potential differences in the expression of the miRNAs miR-218, mi-R203 and miR-708, which are among the best known miRNAs to target survivin. [score:7]
[21] We observed that whereas the expression levels of miR-218 and miR-708 were unchanged between lean- and obese-derived hASCs, the level of miR-203 was significantly decreased in obese-derived hASCs (Figure 3c). [score:3]
Real-time PCR (qPCR) was conducted on a 7900HT Fast Real-Time PCR System using TaqMan Gene Expression Assays (Applied Biosystems) for survivin (Hs 00426651_m1), leptin (Hs00174497_m1) and specific Taqman probes for hsa-miR-203, hsa-miR-218 and hsa-miR-708. [score:2]
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40
[+] score: 11
miR-218 regulates MEF2D expression by targeting 3’UTR of its mRNA and down-regulation of miR-218 in cardiac myxoma condition can increase MEF2D expression and promote cell cycle progression [78]. [score:11]
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[+] score: 11
Other miRNAs from this paper: hsa-mir-218-2, hsa-mir-324
This takes place by E6 -mediated downregulation of human miR-218, leading to upregulation of its target gene LAMB3, which is a component of the laminin-5 receptor expressed in the basal lamina [33]. [score:11]
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42
[+] score: 11
Other miRNAs from this paper: hsa-let-7a-1, hsa-let-7a-2, hsa-let-7a-3, hsa-let-7b, hsa-let-7c, hsa-let-7d, hsa-let-7e, hsa-let-7f-1, hsa-let-7f-2, hsa-mir-18a, hsa-mir-22, hsa-mir-29a, hsa-mir-30a, hsa-mir-93, hsa-mir-100, hsa-mir-29b-1, hsa-mir-29b-2, mmu-let-7g, mmu-let-7i, mmu-mir-1a-1, mmu-mir-29b-1, mmu-mir-30a, mmu-mir-30b, mmu-mir-124-3, mmu-mir-126a, mmu-mir-9-2, mmu-mir-133a-1, mmu-mir-146a, mmu-mir-200b, mmu-mir-203, mmu-mir-204, mmu-mir-205, hsa-mir-148a, hsa-mir-30c-2, hsa-mir-30d, mmu-mir-30e, hsa-mir-10a, hsa-mir-34a, hsa-mir-203a, hsa-mir-204, hsa-mir-205, hsa-mir-218-2, hsa-mir-221, hsa-mir-222, hsa-mir-200b, mmu-mir-34c, mmu-mir-34b, mmu-let-7d, hsa-let-7g, hsa-let-7i, hsa-mir-1-2, hsa-mir-30b, hsa-mir-124-1, hsa-mir-124-2, hsa-mir-124-3, hsa-mir-133a-1, hsa-mir-133a-2, hsa-mir-9-1, hsa-mir-9-2, hsa-mir-9-3, hsa-mir-126, hsa-mir-146a, mmu-mir-30c-1, mmu-mir-30c-2, mmu-mir-30d, mmu-mir-148a, mmu-mir-200a, mmu-let-7a-1, mmu-let-7a-2, mmu-let-7b, mmu-let-7c-1, mmu-let-7c-2, mmu-let-7e, mmu-let-7f-1, mmu-let-7f-2, mmu-mir-18a, mmu-mir-22, mmu-mir-29a, mmu-mir-29c, mmu-mir-93, mmu-mir-34a, hsa-mir-200c, hsa-mir-1-1, mmu-mir-1a-2, mmu-mir-10a, mmu-mir-100, mmu-mir-200c, mmu-mir-218-1, mmu-mir-218-2, mmu-mir-221, mmu-mir-222, mmu-mir-29b-2, mmu-mir-124-1, mmu-mir-124-2, mmu-mir-9-1, mmu-mir-9-3, hsa-mir-29c, hsa-mir-30c-1, hsa-mir-200a, hsa-mir-34b, hsa-mir-34c, hsa-mir-30e, hsa-mir-375, mmu-mir-375, hsa-mir-335, mmu-mir-335, mmu-mir-133a-2, hsa-mir-424, hsa-mir-193b, hsa-mir-512-1, hsa-mir-512-2, hsa-mir-515-1, hsa-mir-515-2, hsa-mir-518f, hsa-mir-518b, hsa-mir-517a, hsa-mir-519d, hsa-mir-516b-2, hsa-mir-516b-1, hsa-mir-517c, hsa-mir-519a-1, hsa-mir-516a-1, hsa-mir-516a-2, hsa-mir-519a-2, hsa-mir-503, mmu-mir-503, hsa-mir-642a, mmu-mir-190b, mmu-mir-193b, hsa-mir-190b, mmu-mir-1b, hsa-mir-203b, mmu-let-7j, mmu-mir-30f, mmu-let-7k, mmu-mir-126b, mmu-mir-9b-2, mmu-mir-124b, mmu-mir-9b-1, mmu-mir-9b-3
Expression of the MaSC/basal-specific miRNAs miR-34b, miR-204 and miR-218 is upregulated in luminal cells of Ezh2 -deficient samples compared to littermate controls. [score:5]
MiR-34b, miR-204 and miR-218 are expressed highly in the MaSC/basal subset. [score:3]
MiRNAs were extracted from MaSC/basal and luminal cells sorted from either control or Ezh2 -deficient mouse mammary glands, and quantitative RT-PCR was then performed for the MaSC/basal-specific miRNAs miR-34b, miR-204 and miR-218, as their promoter regions were enriched for H3K27me3 marks in the luminal subsets (Fig.   6a). [score:1]
a Track files or read coverage graphs for H3K4me3 and H3K27me3 marks present in the 3 kb upstream region of miR-34b (top panel), miR-204 (middle panel) and miR-218 (bottom panel) in each epithelial subset. [score:1]
Representative track file histograms for the MaSC/basal-specific miRs-34b/c, miR-204 and miR-218, highlighting the distribution of H3K27me3 and H3K4me3 peaks, are shown in Fig.   6a. [score:1]
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[+] score: 11
We previously demonstrated that several down-regulated miRNAs, such as miR-1, miR-133a, miR-145, miR-218 and miR-517a, have tumor suppressive function by targeting oncogenes. [score:8]
MiR-574-3p as well as miR-218, a tumor suppressive miRNA (17), are located on chromosome 4p (4p14 and 4p15), which was a typical chromosomal loss region in BC cell lines in our previous study (18). [score:3]
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[+] score: 11
Human slit1 is a top target of miR-218, which itself is transcribed from the intron of slit2, suggesting down-regulation of slit1 by transcription of slit2. [score:6]
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]
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[+] score: 11
It has been shown miR-218 could inhibit cancer cell migration and invasion by targeting focal adhesion pathway [23], impair tumor growth and increase chemo-sensitivity to cisplatin through regulating the AKT-mTOR signaling pathway [24] and suppress progression through downregulation of survivin and the SLIT2-ROBO1 pathway [25]. [score:11]
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46
[+] score: 10
Other miRNAs from this paper: hsa-mir-218-2, hsa-mir-200b, hsa-mir-15b, hsa-mir-30e
Both miR-15b and miR-200b regulate chemotherapy -induced EMT by downregulating Bmi1 in tongue squamous cell carcinomas, and miR-218 inhibits cell proliferation and cycle progression and promotes apoptosis by downregulating Bmi1 in colorectal cancer cells [30- 32]. [score:10]
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[+] score: 10
By direct regulating the key genes of glioma development, miR-218 suppresses the invasion and self-renewal of glioma [14]. [score:6]
Tu Y. Gao X. Li G. Fu H. Cui D. Liu H. Jin W. Zhang Y. MicroRNA-218 inhibits glioma invasion, migration, proliferation, and cancer stem-like cell self-renewal by targeting the polycomb group gene Bmi1 Cancer Res. [score:4]
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[+] score: 10
Tie J MiR-218 inhibits invasion and metastasis of gastric cancer by targeting the Robo1 receptorPLoS Genet. [score:4]
In this connection, we predicted that miR-218 could regulate axon guidance molecules in gastrointestinal cancers. [score:2]
SLIT-ROBO signaling, a major axon-guidance signaling axis, is also involved in miR-218 -mediated regulation of metastasis and invasion in gastric cancer [40]. [score:2]
Intriguingly, miR-218 -mediated regulation of SLIT-ROBO signaling has been shown to have crosstalk with vascular endothelial growth factor (VEGF) signaling in zebrafish [41]. [score:2]
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[+] score: 10
Maternal probiotic supplementation was associated with upregulation of let-7d-3p and downregulation of miR-574-3p, miR-340-5p and miR-218-5p, although the estimated FDR for each is 0.818 (Table 2). [score:7]
Maternal probiotic ingestion was associated with four differentially expressed miRNAs with low abundance (miR-574-3p, let-7d-3p, miR-340-5p and miR-218-5p). [score:3]
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[+] score: 10
Based on the collected miRNA-circRNA interactions and the deregulated RNA molecules, we collected several abnormally expressed miRNAs, including 11 downregulated miRNAs (miR-124-3p, miR-129-5p, miR-135a-5p, miR-153-3p, miR-204-5p, miR-208a-3p, miR-211-5p, miR-218-5p, miR-488-3p, miR-490-3p, and miR-504-5p) and 1 upregulated miRNA (miR-373-3p). [score:10]
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51
[+] score: 10
Other miRNAs from this paper: hsa-mir-27a, hsa-mir-96, hsa-mir-34a, hsa-mir-182, hsa-mir-218-2
Moreover, Jin et al demonstrated miR-218 acted as a tumor suppressor in osteosarcomas by down -regulating TIAM1, MMP2 and MMP9 expression[54]. [score:6]
miRNA-218 Inhibits Osteosarcoma Cell Migration and Invasion by Down -regulating of TIAM1, MMP2 and MMP9. [score:4]
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52
[+] score: 9
Expression of miR-218 remained unchanged in the bronchial epithelium of CF versus non-CF individuals [112], however it was found to be the most significantly down-regulated miRNA in bronchial epithelial cells of smokers vs. [score:6]
1[120] miR-133a Bronchial smooth muscle cells Human RhoA[97] miR-146a Lung alveolar epithelial cells Human IL-1β IL-8, RANTES[67] miR-218 Primary bronchial epithelial cells Human CSE MAFG[87] miR148a,b, Human miR-152 Primary bronchial epithelial cells HLA-G[24] # Let-7c miR-34c miR-222 Whole lung Rat CSE ND[86] miR-26b, 27a, miR-31*, 96, Primary bronchial epithelial cells Human DEP ND[88] miR-135b,274a, miR-338-5p, 494, miR-513a-5p, b, c, miR-923 Let-7a, b, f, Whole lung Mouse CSE ND[85] miR-26a, 30b, c, miR-34b, 99b, 122a, miR-124a, 125a, b, 140, miR-192, 431 CSE; cigarette smoke extract, ND; not determined, DEP; diesel exhaust particulate, # 3 of 24 down-regulated miR's validated by qRT-PCR The discovery of miRNA is considered one of the major breakthroughs of the last decade. [score:3]
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[+] score: 9
miR-218 was chosen for normalisation due to a high degree of similarity in expression levels between CF and non-CF brushings observed in the expression profiling screen. [score:5]
Expression of miRNAs relative to miR-218 was determined using the 2 [(−ΔΔCt)] method. [score:3]
Figure  2B shows the levels of these miRNAs, normalised to miR-218, in the samples studied here. [score:1]
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54
[+] score: 9
Other miRNAs from this paper: hsa-mir-20a, hsa-mir-218-2, hsa-mir-221
MiR-218 suppresses nasopharyngeal cancer progression through downregulation of survivin and the SLIT2-ROBO1 pathway. [score:5]
Finally, transfection of miR-218 in nasopharyngeal carcinoma cells reduced Cx43 expression and was associated with increased apoptosis. [score:3]
Moreover, miR-218 transfection reduced the tumor growth after intramuscular implantation of C666-1 cells in SCID mice (Alajez et al., 2011). [score:1]
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[+] score: 9
Moreover, Wang et al. demonstrated that miR-218 inhibited the proliferation, migration, and invasion and promotes apoptosis of gastric cancer cells by targeting LASP1 [28]. [score:5]
MiR-218 inhibits proliferation, migration, and EMT of gastric cancer cells by targeting WASF3 [3]. [score:4]
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Another example is a study that showed that miR-218 can suppress expression of cyclin -dependent kinase 4 (CDK4), a BMI1 downstream target, but increased p53 expression [22]. [score:9]
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[+] score: 8
Mir-218 exerts suppressing function to NPC by down -regulating survivin expression and SLIT2-BOBO1 pathway [20], and miR-26a acts the similar function for inhibiting cell growth and tumorigenesis through repression of EZH2miR [21]. [score:8]
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[+] score: 8
In particular, CUL3, over expressed in kidney and prostate cancers, is a target of several dysregulated MIRs: MIR22, MIR23A, MIR23B, MIR218-1, MIR218-2, and MIR301, which are down regulated in kidney cancers, and of MIR22, MIR23A, MIR181A, and MIR181C, which are down regulated in prostate cancers (Table 5). [score:8]
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Ma and colleagues have reported that CCAT1 upregulates the miRNA-218-5p target gene B cell-specific Moloney murine leukemia virus integration site 1 (Bmi1) by acting as miRNA-218-5p sponge, resulting in an increased proliferation and invasiveness of gallbladder cancer cells [135]. [score:6]
Ma M. Z. Chu B. F. Zhang Y. Weng M. Z. Qin Y. Y. Gong W. Quan Z. W. Long non-coding RNA CCAT1 promotes gallbladder cancer development via negative modulation of miRNA-218-5p Cell Death Dis. [score:2]
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60
[+] score: 8
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-23a, hsa-mir-30a, hsa-mir-92a-1, hsa-mir-92a-2, hsa-mir-103a-2, hsa-mir-103a-1, hsa-mir-196a-1, hsa-mir-148a, hsa-mir-30c-2, hsa-mir-30d, hsa-mir-181a-2, hsa-mir-181b-1, hsa-mir-181c, hsa-mir-196a-2, hsa-mir-210, hsa-mir-181a-1, hsa-let-7g, hsa-let-7i, hsa-mir-23b, hsa-mir-30b, hsa-mir-128-1, hsa-mir-145, hsa-mir-191, hsa-mir-181b-2, hsa-mir-128-2, hsa-mir-30c-1, hsa-mir-99b, hsa-mir-296, hsa-mir-30e, hsa-mir-361, hsa-mir-337, hsa-mir-148b, hsa-mir-196b, hsa-mir-425, hsa-mir-20b, hsa-mir-486-1, hsa-mir-488, hsa-mir-181d, hsa-mir-498, hsa-mir-519c, hsa-mir-520a, hsa-mir-526b, hsa-mir-520d, hsa-mir-506, hsa-mir-92b, hsa-mir-608, hsa-mir-617, hsa-mir-625, hsa-mir-641, hsa-mir-1264, hsa-mir-1271, bta-let-7f-2, bta-mir-103-1, bta-mir-148a, bta-mir-21, bta-mir-30d, bta-mir-128-1, bta-mir-145, bta-mir-181a-2, bta-mir-30b, bta-mir-181b-2, bta-mir-20b, bta-mir-30e, bta-mir-92a-2, bta-let-7d, bta-mir-148b, bta-mir-181c, bta-mir-191, bta-mir-210, bta-mir-23a, bta-mir-361, bta-mir-425, bta-let-7g, bta-mir-30a, bta-let-7a-1, bta-let-7f-1, bta-mir-30c, bta-let-7i, bta-mir-23b, bta-let-7a-2, bta-let-7a-3, bta-let-7b, bta-let-7c, bta-let-7e, bta-mir-103-2, bta-mir-99b, hsa-mir-890, hsa-mir-888, hsa-mir-889, hsa-mir-938, hsa-mir-1184-1, hsa-mir-1203, hsa-mir-1204, hsa-mir-1265, hsa-mir-103b-1, hsa-mir-103b-2, bta-mir-128-2, bta-mir-181d, bta-mir-196a-2, bta-mir-196a-1, bta-mir-196b, bta-mir-218-1, bta-mir-296, bta-mir-30f, bta-mir-486, bta-mir-488, bta-mir-92a-1, bta-mir-92b, bta-mir-1271, bta-mir-181a-1, bta-mir-181b-1, bta-mir-148c, hsa-mir-1184-2, hsa-mir-1184-3, hsa-mir-486-2, bta-mir-1264, bta-mir-148d
Moreover, miR-361-5p, miR-1184 and miR-218-1* were the top among the upregulated miRNAs while miR-1265, miR-20b*, miR-520d-5p and miR-506 were the top among the downregulated miRNAs in the SE animals. [score:7]
Among these, miR-938, miR-519c-3p, miR-1265, miR-498 and miR-488 were exclusively detected only in HE animals and 10 miRNAs including miR-608, miR-625*, miR-218-1*, miR-888*, miR-1184 and miR-1264 were detected only in SE and CE animal groups. [score:1]
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61
[+] score: 8
Previous studies have demonstrated that rifampin also inhibited anti-angiogenesis by regulating the expression of multiple miRNAs (miR-34b, miR-886-3p, miR-218, miR-576-3p, miR-200c, miR-616, miR-660, miR-335, miR-92a), and further induced the gene expression of BIRC3, CAV1, CAV2, FN1, ITGA1 and THBS1. [score:8]
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62
[+] score: 8
For example, hsa-miR-133a, hsa-miR-200b, hsa-miR-206, and hsa-miR-218 were considered as tooth tissue-specific miRNAs [4]; eight differentially expressed miRNAs were expressed during morphogenesis and seven were expressed in the incisor cervical loop containing the stem cell niche [1]; the three most highly expressed microRNAs in dental epithelium were identified as mmu-miR-24, mmu-miR-200c, and mmu-miR-205, while mmu-miR-199a-3p and mmu-miR-705 were found in dental mesenchyme [2]; and miR-200 was suggested to play an important role in the formation of incisor cervical loop during stem cell–fueled incisor growth [5]. [score:8]
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63
[+] score: 8
miR-218, a tumor suppressor miRNA, is downregulated in gastric cancer, which correlates with increased metastasis and cancer invasion [22]. [score:6]
Recently, Li et al. indicated that miR-21, miR-218, and miR-223 may be potential biomarkers for gastric cancer detection [23]. [score:1]
miR-218 is reduced significantly in gastric cancer tissues, H. pylori-infected gastric mucosa, and H. pylori-infected AGS cells [21]. [score:1]
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64
[+] score: 8
Among the differentially expressed miRNAs, 11 (miR-199a-5p, miR-218, miR-409a, miR-433, miR-511, miR-514, miR-551, miR-562, miR-556-3p, miR-1178 and miR-1205) were common to both doses (Figure 2D) and exhibited similar expression patterns (Tables 1A and C). [score:5]
The expression patterns of 10 of these (miR-146b, miR-193a, miR-193b, miR-218, miR-424, miR-450b-3p, miR-511, miR-573, miR-605 and miR-890) were similar at both time points. [score:3]
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65
[+] score: 8
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]
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66
[+] score: 7
Overexpression of miR-218 was implicated in cell growth and metastatic gastric cancer through direct targeting of ECOP and ROBO1 (Ref. [score:6]
Several miRNAs circulating in blood of gastric cancer patients can be applied as diagnosis biomarkers, including let-7a, miR-1, miR-17-5p, miR-21, miR-20a, miR-27a, miR-34, miR-106a/b, miR-196a, miR-199a-3p, miR-218, miR-221, miR-223, miR-370, miR-376c, miR-378, miR-421, miR-423-5p, miR-451 and miR-486 (Refs 64, 76, 111, 112, 113, 114, 115, 116, 117). [score:1]
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67
[+] score: 7
For examples, mir-218 (C46) is dynamically expressed in developing liver and pancreas, which targets Hepatocytes Nuclear Factor-6 (HNF-6/OC-1) and OC-2 to regulate liver and pancreas development [26]. [score:7]
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68
[+] score: 7
We have shown the top TFs and its related diseases for rhesus inter-species in Table  5. Besides these, mml-miR-338-5p, mml-miR-218, mml-miR-495, mml-miR-203, mml-miR-590-3p, mml-miR-596, mml-miR-548p, and mml-miR-524-5p have connection with “an auto immune disease like SIV” [52], Huntintong’s Disease [53], Age mediated skeletal muscle contamination [54], Enhances Coxsackievirus B3 replication [55], Neuro inflammation Disorder [56], Schizophernia [57], monkey hippocampus effected [58], and Amyotrophic lateral sclerosis [59], respectively. [score:7]
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69
[+] score: 7
Finally, Epigenetic silencing of miR-218 by overexpression of Rictor in oral squamous cell carcinoma (OSCC) inhibited the phosphorylation of Akt at Ser-473, resulting in cell growth inhibition [166]. [score:7]
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70
[+] score: 7
Other miRNAs from this paper: hsa-mir-218-2, hsa-mir-145, hsa-mir-448
For example, miR-145 and miR-218 suppress GC cell metastasis by inhibiting the expression of N-cadherin and Robo1, respectively [8]. [score:7]
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71
[+] score: 7
At LT, mmu-miR-29c and -98 are downregulated but upregulation of mmu-miR-125b-5p and -574-5p, and progressive normalization of the levels of mmu-miR-218, -690 and -805 would then be part of the reduction of the inflammatory process at the late stage of the asthma mo del through the modulation of TNFα receptors. [score:7]
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72
[+] score: 7
Thirteen miRNAs were overexpressed in exosomes from bulk cells: hsa-miR-218-5p, hsa-miR-7-5p, hsa-miR-1290, hsa-miR-17-5p, hsa-miR-20a-5p, hsa-miR-503-5p, hsa-miR-30c-5p, hsa-miR-125b-1, hsa-miR-21-5p, hsa-miR-93-5p, hsa-miR-378c, hsa-miR-378d and hsa-miR-25-3p (Table 2). [score:3]
In behalf of the premetastatic niche preparation, miR-21, miR-30 and miR-218 regulate osteoblast differentiation, increasing the production of RANKL, among other soluble factors. [score:2]
miR-100, together with miR-let7c and miR-218 is significantly overexpressed in localized PCa (similar to the type of cells that we analyzed in our study) when compared with metastatic carcinoma [35]. [score:2]
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73
[+] score: 7
A number of the miRNAs in this signature have been previously characterized in cervical cancer and other diseases, such as miR-218, which downregulates survivin (BIRC5) in nasopharyngeal carcinoma [29], and miR-21, which regulates PTEN expression in hepatocellular carcinoma [30]. [score:7]
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74
[+] score: 7
We found that IFN-γ and TNF-α resulted in up-regulation of miR-155–5p, miR-4485–3p, miR-218–5p, and miR-146a–5p and down-regulation of miR-582–5p, miR-582–3p, miR-93–5p, miR-217 and miR-125b–5p (supplemental Tables S1 and S2). [score:7]
[1 to 20 of 1 sentences]
75
[+] score: 7
In the present study, we verified the expression of CCAT1 and measured various miRNAs associated with cigarette smoking in HBE cells exposed to 20 μg/mL CSE for 0, 6, 12, or 24 h. With longer times of exposure to CSE, there were greater expressions of CCAT1, miR-21, and miR-155 and lower expressions of let-7c and miR-218 (Figure 2A and 2B). [score:5]
Figure 2HBE cells were exposed to CSE (0 or 20 μg/mL) for 0, 6, 12, or 24 h. The levels (means ± SD, n = 3) of CCAT1 (A) miR-21, let-7c, miR-125a, miR-125b, miR-155, and miR-218 (B) were determined by quantitative RT-PCR. [score:1]
HBE cells were exposed to CSE (0 or 20 μg/mL) for 0, 6, 12, or 24 h. The levels (means ± SD, n = 3) of CCAT1 (A) miR-21, let-7c, miR-125a, miR-125b, miR-155, and miR-218 (B) were determined by quantitative RT-PCR. [score:1]
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76
[+] score: 6
Parallel studies discussed miR-218 to be involved in LASP1 overexpression, as miR-218 is downregulated in prostate cancer [96]. [score:6]
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77
[+] score: 6
For instance, Cao et al. [19] revealed that downregulation of lncRNA CASC2 by microRNA-21 increased the proliferation and migration of renal cell carcinoma cells; Zhang et al. [20] illustrated that Antisense lncRNA FOXC2-AS1 promoted doxorubicin resistance in osteosarcoma by increasing the expression of FOXC2; and Liu et al. [21] related that epigenetic silencing of miR-218 by the lncRNA CCAT1, acting via BMI1, promoted an altered cell cycle transition in the malignant transformation of HBE cells induced by cigarette smoke extract. [score:6]
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78
[+] score: 6
miR-218 has been shown to be epigenetically (DNA hypermethylation) silenced in OSCC tissue specimens and to have a tumor suppressive function by regulating the expression of rapamycin-insensitive component of mTOR, Rictor [48]. [score:6]
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79
[+] score: 6
In particular, miR-218, the miR-200 family, and miR-29b were shown to inhibit glioblastoma invasion, migration, proliferation, and stemness through different targets 63, 64, 67, 72– 74. [score:5]
Such miRNAs included miR-218, miR-29b, all members of miR-200 family 63, 64, 67, 70– 74, and miR-21 75– 78. [score:1]
[1 to 20 of 2 sentences]
80
[+] score: 6
Downregulation of miR-218 in GC is implicated in metastasis resulting from the derepression of its target Robol, a transmembrane receptor for Slit, and thereby enhancing Slit/Robol signaling [83]. [score:6]
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81
[+] score: 6
No association of functional variant in pri-miR-218 and risk of congenital heart disease in a Chinese population. [score:3]
On the other hand, for the variant rs11134527, which is located 96 nt outside the MIR218-2 hairpin sequence, it was shown that it does change the expression of miR-218-5p significantly (Gao et al., 2013). [score:3]
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82
[+] score: 6
Other miRNAs from this paper: hsa-mir-218-2, hsa-mir-206, hsa-mir-155
A small regulatory miRNA (miR-218) has recently been identified as highly enriched in and exclusive to motor neurons; as miR-218 is detectable in the spinal tap biofluid of an ALS rat mo del, with the levels changing as the disease progressed, miR-218 may be a clinically useful marker of disease status [50]. [score:6]
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83
[+] score: 5
miR-218 inhibits the invasion and metastasis of gastric cancer by targeting the Robo1 receptor [39]. [score:5]
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84
[+] score: 5
For instance, CCAT1 could competitively bind miR-218-5p through intracellular “sponge-like” adsorption and promote the expression of target genes, leading to the proliferation of bladder cancer cells and invasion of blood vessels (27). [score:5]
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85
[+] score: 5
Ectopic expression of some miRs (such as miR-218, miR-145) inhibits invasion, angiogenesis, and metastasis [39, 40]. [score:5]
[1 to 20 of 1 sentences]
86
[+] 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]
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]
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]
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87
[+] score: 5
However, the expression changes in miR-3188 (p = 0.975), miR-218-5p (p = 0.213), and miR-590-5p (p = 0.193) were not statistical significant between the two groups. [score:3]
In another study, 9 miRNAs, including miR-218 and miR-21, were validated by qPCR between different stages of cervical neoplasm [20]. [score:1]
These miRNAs included miR-106b-5p, miR3653, miR-3188, miR-497-5p, miR-218-5p, miR-17-5p, miR-96, miR-15a-5p, miR-20a-5p, miR-21-5p, and miR-590-5p (Table 3). [score:1]
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88
[+] score: 5
Other miRNAs from this paper: hsa-let-7a-1, hsa-let-7a-2, hsa-let-7a-3, hsa-mir-15a, hsa-mir-18a, hsa-mir-33a, hsa-mir-103a-2, hsa-mir-103a-1, hsa-mir-107, mmu-mir-27b, mmu-mir-126a, mmu-mir-128-1, mmu-mir-140, mmu-mir-146a, mmu-mir-152, mmu-mir-155, mmu-mir-191, hsa-mir-10a, hsa-mir-211, hsa-mir-218-2, mmu-mir-297a-1, mmu-mir-297a-2, hsa-mir-27b, hsa-mir-128-1, hsa-mir-140, hsa-mir-152, hsa-mir-191, hsa-mir-126, hsa-mir-146a, mmu-let-7a-1, mmu-let-7a-2, mmu-mir-15a, mmu-mir-18a, mmu-mir-103-1, mmu-mir-103-2, mmu-mir-342, hsa-mir-155, mmu-mir-107, mmu-mir-10a, mmu-mir-218-1, mmu-mir-218-2, mmu-mir-33, mmu-mir-211, hsa-mir-374a, hsa-mir-342, gga-mir-33-1, gga-let-7a-3, gga-mir-155, gga-mir-18a, gga-mir-15a, gga-mir-218-1, gga-mir-103-2, gga-mir-107, gga-mir-128-1, gga-mir-140, gga-let-7a-1, gga-mir-146a, gga-mir-103-1, gga-mir-218-2, gga-mir-126, gga-let-7a-2, gga-mir-27b, mmu-mir-466a, mmu-mir-467a-1, hsa-mir-499a, hsa-mir-545, hsa-mir-593, hsa-mir-600, hsa-mir-33b, gga-mir-499, gga-mir-211, gga-mir-466, mmu-mir-675, mmu-mir-677, mmu-mir-467b, mmu-mir-297b, mmu-mir-499, mmu-mir-717, hsa-mir-675, mmu-mir-297a-3, mmu-mir-297a-4, mmu-mir-297c, mmu-mir-466b-1, mmu-mir-466b-2, mmu-mir-466b-3, mmu-mir-466c-1, mmu-mir-466e, mmu-mir-466f-1, mmu-mir-466f-2, mmu-mir-466f-3, mmu-mir-466g, mmu-mir-466h, mmu-mir-467c, mmu-mir-467d, mmu-mir-466d, hsa-mir-297, mmu-mir-467e, mmu-mir-466l, mmu-mir-466i, mmu-mir-466f-4, mmu-mir-466k, mmu-mir-467f, mmu-mir-466j, mmu-mir-467g, mmu-mir-467h, hsa-mir-664a, hsa-mir-1306, hsa-mir-1307, gga-mir-1306, hsa-mir-103b-1, hsa-mir-103b-2, gga-mir-10a, mmu-mir-1306, mmu-mir-3064, mmu-mir-466m, mmu-mir-466o, mmu-mir-467a-2, mmu-mir-467a-3, mmu-mir-466c-2, mmu-mir-467a-4, mmu-mir-466b-4, mmu-mir-467a-5, mmu-mir-466b-5, mmu-mir-467a-6, mmu-mir-466b-6, mmu-mir-467a-7, mmu-mir-466b-7, mmu-mir-467a-8, mmu-mir-467a-9, mmu-mir-467a-10, mmu-mir-466p, mmu-mir-466n, mmu-mir-466b-8, hsa-mir-466, hsa-mir-3173, hsa-mir-3618, hsa-mir-3064, hsa-mir-499b, mmu-mir-466q, hsa-mir-664b, gga-mir-3064, mmu-mir-126b, gga-mir-33-2, mmu-mir-3618, mmu-mir-466c-3, gga-mir-191
Out of the 26 miRNA/host gene pairs with coordinated expression, 11 have been found to be coordinately expressed in both, human and mouse [19], [27], [59], [61]– [64], [67]– [69], [71], [73]– [79]: mir-103/ PANK3, mir-107/ PANK1, mir-126/ EGFL7, mir-128-1/ R3HDM1, mir-140/ WWP2, mir-211/ TRPM1, mir-218-1/ SLIT2, mir-218-2/ SLIT3, mir-27b/ C9orf3, mir-33/ SREBF2, and mir-499/ MYH7B. [score:5]
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89
[+] score: 5
Studies have showed that miRNAs such as miR-27a [3], miR-106a [4], miR-133a [5], miR-145 [6], miR-181b [7], miR-218 [8], and miR-326 [5] may be involved in the development of drug resistance by regulating relative gene expression. [score:5]
[1 to 20 of 1 sentences]
90
[+] score: 5
Other miRNAs from this paper: hsa-mir-214, hsa-mir-218-2
In conclusion, we report for the first time that SLC34A2, target of miR-218, is overexpressed pervasively in BC, and it is correlated with poor prognosis, advanced T stage and larger tumor size. [score:5]
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91
[+] score: 5
Other miRNAs from this paper: hsa-mir-27a, hsa-mir-218-2, hsa-mir-451a, hsa-mir-451b
A549 cells were seeded into 6-well plates and transfected with the miR-415 -expressing vector or the control vector expressing a non-specific miR-NC using Lipofectamine 2000 (Invitrogen), and were selected with spectinomycin (100 μg/ml) to generate two stable monoclonal cell lines (a miR-218 stable cell line, A549/miR-451, and a control stable cell line, A549/miR-NC). [score:5]
[1 to 20 of 1 sentences]
92
[+] score: 5
The five most highly expressed miRNAs in ALL reported in [32] are miR-128b, miR-204, miR-218, miR-331, and miR-181b-1. In CLL, the five most highly expressed miRNAs are miR-331, miR-29a, miR-195, miR-34a, and miR-29c. [score:5]
[1 to 20 of 1 sentences]
93
[+] score: 5
MiR-218 inhibits invasion and metastasis of gastric cancer by targeting the robo1 receptor. [score:4]
Plasmas, miR-223, miR-21 and miR-218, as novel potential biomarkers for gastric cancer detection. [score:1]
[1 to 20 of 2 sentences]
94
[+] score: 5
miRNA expression profiling has also demonstrated reduced expression of several miRNAs in GB including miR-7, miR-128, miR124, miR137, and miR-218 which have been linked to alterations in proliferation, differentiation, invasion, and stem cell self-renewal [18], [22], [23]. [score:5]
[1 to 20 of 1 sentences]
95
[+] score: 5
Other miRNAs from this paper: hsa-mir-7-1, hsa-mir-7-2, hsa-mir-7-3, hsa-mir-218-2
Li Q. Zhu F. Chen P. MiR-7 and miR-218 epigenetically control tumor suppressor genes RASSF1A and claudin-6 by targeting HoxB3 in breast cancerBiochem. [score:5]
[1 to 20 of 1 sentences]
96
[+] score: 5
Fu WM Hotair mediates hepatocarcinogenesis through suppressing miRNA-218 expression and activating P14 and P16 signalingJ. [score:5]
[1 to 20 of 1 sentences]
97
[+] score: 5
Since miR-23 (JX994633), miR-218 (JX994383) and miR-338 (JX994406) are present in the elephant shark, these conserved miRNAs are likely to be involved in the regulation of Runx2 expression in elephant shark, possibly during chondrogenic differentiation through mechanisms similar to that in other jawed vertebrates. [score:4]
Of these, binding sites for miR-23, miR-218 and miR-338 were found conserved in the 3′UTR of elephant shark Runx2, while only that for miR-28 is present in zebrafish and fugu Runx2 (Fig. 8B). [score:1]
[1 to 20 of 2 sentences]
98
[+] score: 5
Li Q. Zhu F. Chen P. Mir-7 and mir-218 epigenetically control tumor suppressor genes rassf1a and claudin-6 by targeting hoxb3 in breast cancer Biochem. [score:5]
[1 to 20 of 1 sentences]
99
[+] score: 4
The most common down-regulated miRNAs were miR-30a-5p (6 profiles), followed by miR-139-5p, miR-187-3p, miR-551b-3p, miR-140-3p, miR-324-5p, miR-33-5p, miR-218-5p, miR-378a-3p and miR-29c-5p (Supplementary Table  S4). [score:4]
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100
[+] score: 4
Meanwhile, studies indicated that lnc CCAT1 could negatively regulate the expression of miRNA-218-5p and let-7 in gallbladder cancer [13] and hepatocellular carcinoma [11]. [score:4]
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