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96 publications mentioning mmu-mir-148a

Open access articles that are associated with the species Mus musculus and mention the gene name mir-148a. Click the [+] symbols to view sentences that include the gene name, or the word cloud on the right for a summary.

1
[+] score: 380
Since expression of miR-148a is down-regulated in 4T1 cells, we ectopically expressed miR-148a in 4T1 cells by viral infection (Figure 2C) and determined the effects of this manipulation on various aspects of cancer development. [score:9]
In the current study, we identified miR-148a as a suppressor of metastasis, particularly for TNBC, as its expression pattern is inversely correlated with tumor grade and metastatic potential, but directly correlated with prognosis of those patients since lower expression of miR-148 is associated with poor survival. [score:8]
To determine whether expression of miR-148a in the primary tumor and presence of distal metastasis are directly associated with patient outcome, we first correlated disease-specific survival with expression of miR-148a in patients with or without metastasis separately. [score:8]
In addition, miR-148a has been reported to suppress angiogenesis through down-regulation of ERBB3 and IGF1R [50, 51]. [score:6]
Consistent with this, our results show that miR-148a suppresses breast cancer metastasis possibly through down-regulation of WNT1. [score:6]
To directly determine whether the expression level of miR-148a is associated with metastatic development in breast cancer patients, we also analyzed a patient database annotated with time from initial diagnosis to metastasis development (GSE22220). [score:6]
In addition, correlation analysis between expression profiles of these mRNAs and miR-148a in TCGA database showed that expression of WNT1 and NRP1 is inversely correlated with levels of miR-148a (Figure 5D). [score:5]
Overexpression of miR-148a suppresses 4T1 lung metastasis. [score:5]
Theoretically, levels of target genes in human breast cancers should inversely correlate with miR-148a expression. [score:5]
4T1 control cells with expression of iRFP (VEC, red) and 4T1cells with expression of miR-148a and GFP (miR-148a, green) were mixed and implanted into the mammary fat pad of Balb/c mice. [score:5]
Figure 2(A) Expression levels of miR-148a were determined in M-I, M-II, M-III, and M-IV cells and normalized to the expression level in M-II. [score:5]
To directly test whether miR-148a suppresses extravasation of 4T1 cells in vivo, we administrated cancer cells directly into the blood system of the mouse through tail vein injection, and subsequently examined lung colonization. [score:5]
With expression of miR-148a in MDA-MB-231 cells being about 50% of its level in MCF7-Ras cells, we hypothesized that lower expression of miR-148a is correlated with TNBC metastasis. [score:5]
We utilized a microRNA sponge targeting miR-148a to decrease its expression in 4TO7 cells (Supplementary Figure 3). [score:5]
Through correlation analysis of gene expression profiles between candidate genes and miR-148a in the TCGA breast cancer patient database, we further narrowed down targets of miR-148a to four genes, INHBB, PIK3C2B, WNT1 and NRP1. [score:5]
Moreover, we identified WNT1 and NRP1 as potential targets of miR-148a involved in its tumor suppressive functions. [score:5]
Interestingly, overexpression of miR-148a caused at least a 50% reduction in the numbers of MDA-MB-231 cells present in the lung (Figure 4G), which supported our hypothesis that miR-148a likely suppresses cancer cells extravasation. [score:5]
Overexpression of miR-148a alters cancer cell propagation in vivo It has been reported that the tumor microenvironment contains many types of non-cancer cells that regulate cancer development and immune response [33, 34]. [score:5]
We therefore further analyzed multiple breast cancer patient databases annotated with both miRNA expression and metastatic status, and discovered that primary tumors from patients who were diagnosed with detectable distant metastasis have lower expression of miR-148a than primary tumors from patients without metastasis (Supplementary Table 3). [score:5]
Previous studies have shown that INHBB acts to suppress tumorigenesis and targeting PIK3C2B impairs cell proliferation in a cell-autonomous manner [37, 38], functions that are inconsistent with the theoretical characteristics of miR-148a target genes to modulate tumor microenvironment in our experimental setting. [score:5]
Although overexpression of miR-148a did not alter cell-autonomous behaviors in vitro, it suppressed breast cancer metastasis in vivo, achieved mainly through reducing cancer cell extravasation. [score:5]
Finally, we analyzed the expression of miR-148a in different subtypes, and found that patients with either Basal or Luminal B subtype primary tumors are more likely to be classified as having low miR-148a expression (Supplementary Table 2 and Figure 6C). [score:5]
Moreover, the correlation of miR-148a expression to metastatic development occurs in ER -negative patients but not ER -positive patients (Figure 7G and 7H). [score:4]
One possible explanation for this observation is that miR-148a regulates genes encoding proteins secreted or localized to the outer plasma membrane and interacting with the tumor microenvironment to suppress cancer metastasis. [score:4]
In this study, we show that miR-148a is down-regulated in breast cancer cell lines with high metastatic potential. [score:4]
Overexpression of miR-148a regulates cancer cell lung colonization. [score:4]
Based on the observation that overexpression of miR-148a did not alter tumor nodule size in the lung (Figure 4A, 4C, and 4E), we tested more directly if extravasation was altered. [score:4]
We first confirmed that expression of miR-148a was similar to that achieved in previous experiments (Supplementary Figure 2A), and that relative cell growth of the lines in vitro when mixed 1:1 was similar at multiple time points, indicating that miR-148a overexpression did not alter relative cell growth compared to control (Supplementary Figure 2B). [score:4]
MiR-148a overexpression suppresses TNBC metastasis. [score:4]
As discussed earlier, although many targets of miR-148a have been identified in various cancers, they mainly function in regulating cancer cell-autonomous behaviors [43, 47– 49]. [score:4]
We also tested if our findings on the suppressive effects of miR-148a on metastasis in the mouse cell lines were applicable to human cells. [score:3]
Low expression of miR-148a is associated with worse diagnosis of breast cancer patients. [score:3]
Consistent with the suppressive function of miR-148a in cancer cell lung colonization, decreasing in miR-148a promoted lung colonization of 4TO7 cells when they were inoculated intravenously (Figure 4C and 4D). [score:3]
Consistent with our postulation, miR-148a expression gradually decreased in this series in accordance with increased metastasis potential (Figure 2A). [score:3]
Taken together with the correlation of miR-148a expression to survival time of patients with metastasis, these results indicate that miR-148a might serve as a potential prognostic marker for TNBC patients. [score:3]
Consistently, lower expression of miR-148a in the primary tumor was correlated with shorter survival for patients with metastasis but not for patients without metastasis (Figure 7B and 7C). [score:3]
These results suggest that the extravasation process, in which circulating cancer cells penetrate the endothelial barrier of blood vessels and gain access to the lung, may be suppressed by miR-148a. [score:3]
The expression of miR-148a was significantly decreased in metastatic tissue (Figure 7A). [score:3]
Data was extracted from METABRIC data [55] (A) miR-148a expression was analyzed in patients stratified by tumor grade. [score:3]
Low expression of miR-148a correlates with poor breast cancer patient prognosis. [score:3]
These data indicated that low expression of miR-148a is correlated with higher metastatic potential in multiple independent TNBC cell lines. [score:3]
To investigate how miR-148a suppresses breast cancer metastasis, we took a systematic approach to identify target genes of miR-148a in MDA-MB-231 cells (Figure 5A). [score:3]
Identification of WNT1 and NRP1 as target genes of miR-148a in MDA-MB-231 cells. [score:3]
We next implanted 4T1 cells with or without miR-148a overexpression into the mammary fat pad of female Balb/c mice, and found that primary tumors formed and progressed with similar kinetics (Figure 2G). [score:3]
Instead, our results indicate that miR-148a likely suppresses cancer cell extravasation in vivo, which requires interactions with the tumor microenvironment. [score:3]
Only genes with mRNA levels decreased by at least 20% were selected for further validation as possible target genes of miR-148a. [score:3]
Moreover, overexpression of miR-148a did not affect primary tumor formation by MDA-MB-231 cells (Supplementary Figure 4G), but reduced lung colonization after their administration into the venous system of nude mice (Figure 4E and 4F). [score:3]
To further examine whether decrease in miR-148a level is a major factor promoting cancer cell metastasis, we manipulated expression of miR-148a in cancer cells with low metastatic potential and examined the lung metastasis of these cells. [score:3]
To test this, we utilized additional two series of mammary epithelial and TNBC cell lines and determined expression levels of miR-148a. [score:3]
E and F, MDA-MB-231 cells with over expression of miR-148a and control cells. [score:3]
Identification of WNT1 and NRP1 as potential target genes of miR-148a. [score:3]
Instead, we made the finding that in our system miR-148a targets WNT1 and NRP1. [score:3]
Two levels of miR-148a overexpression (150× and 20×) were achieved in MDA-MB-231 cells. [score:3]
Quantification of tumor burden by qRT-PCR also demonstrated that miR-148a overexpression caused a dramatic decrease in the lung colonization of cancer cells (Figure 4B). [score:3]
Plasmid DNA used for ectopic overexpression of miR-148a was constructed by inserting synthesized pri-miR-148a into pMSCV-Puro vector (Clontech) either alone or together with GFP open reading frame. [score:3]
Lower expression of miR-148a was detected in both 66c14 cells and 4T1 cells (Figure 2B). [score:3]
Importantly, low expression of miR-148a was significantly associated with worse overall survival in patients classified as ER -negative HER2 -negative (Figure 1C), which is consistent with our finding of reduced miR-148a level in the metastatic MDA-MB-231 cell line. [score:3]
Interestingly, the expression of miR-148a is significantly associated with the time to develop metastasis (Figure 7F). [score:3]
To rule out the possibility that the observation was due to different immune response to fluorescent proteins, we used GFP for vector control and BFP for miR-148a overexpression. [score:3]
Basal subtype (D) and LumB subtype (E) of patients with metastasis were further analyzed using Kaplan-Meier curves for high and low expression of miR-148a. [score:3]
Furthermore, we determined miR-148a expression level in patient tissue samples from primary tumors and metastasis. [score:3]
Therefore, miR-148a suppresses lung metastasis of 4T1 cells in this syngeneic mouse mo del. [score:3]
In our experimental setting, miR-148a did not appear to affect angiogenesis at the primary tumor site (Supplementary Figure 7), although we cannot rule out the possibility that miR-148a could suppress neo-angiogenesis in the lung during colonization. [score:3]
Quantitative RT-PCR was performed to validate these mRNA alterations by enhanced overexpression of miR-148a. [score:3]
Taken together, these results indicate NRP1 and WNT1 as molecular targets of miR-148a with biological functions relevant to TNBC metastasis. [score:3]
Therefore, we focused on validating NRP1 and WNT1 as targets of miR-148a in this study. [score:3]
By analyzing different subtypes of patients with metastasis, we found that the expression of miR-148a was significantly correlated with survival time only for patients with Basal or Luminal B subtype primary tumors (Figure 7D, 7E, and Supplementary Figure 5A–5C). [score:3]
Figure 3Overexpression of miR-148a alters 4T1 cancer cell propagation in vivo(A) Illustration of the procedure for tracking cancer cell propagation in vivo. [score:3]
NRP1 has recently been identified as a target gene of miR-148a in medulloblastoma [52]. [score:3]
Consistently, no correlation between patient tumor size and expression of miR-148a was observed (Supplementary Figure 6). [score:3]
The reduction of β-catenin and NRP1 proteins was confirmed in MDA-MB-231 cells with two different levels of miR-148a overexpression (Figure 5C). [score:3]
Therefore, although the macroscopic parameters of the primary tumors that arose from 4T1 cells with overexpression of miR-148a are similar to those of tumors derived from control cells, it is possible that miR-148a affects cancer cell propagation in vivo without presenting noticeable differences in tumor size. [score:3]
4T1 cells with overexpression of miR-148a formed fewer colonies in the lungs than control 4T1 cells (Figure 4A). [score:3]
In contrast, expression of miR-203 did not display a statistically significant association with patient prognosis in this cohort (Figure 1D), so we focused our study on the role of miR-148a in metastasis of breast cancer, in particular the triple -negative subtype. [score:3]
Previously we demonstrated that TNBC patients with low expression of miR-148a tend to have a worse prognosis (Figure 1C). [score:3]
Low expression of miR-148a is associated with poor prognosis of breast cancer patients. [score:3]
Furthermore, the 3′-UTRs of both NRP1 and WNT1 contain perfect binding sites for miR-148a (Figure 5E), as predicted by the TargetScan algorithm. [score:3]
In addition, we quantified the percentage of patients with low or high expression of miR-148a in each grade. [score:3]
Figure 5(A) Illustration of strategy used to identify target genes of miR-148a. [score:3]
We also examined miR-148a expression in the 4T1 series of murine breast cancer cell lines that also resemble TNBC cells. [score:3]
Overexpression of miR-148a alters cancer cell propagation in vivo. [score:3]
Therefore, we performed a microarray analysis to determine mRNA level alterations in an unbiased fashion in MDA-MB-231 cells with enhanced overexpression of miR-148a. [score:3]
4TO7 cancer cell line is well-known to have a low metastatic potential, as well as having a higher expression of miR-148a than the more metastatic 4T1 cell line, and is thus ideal for probing this issue (Figure 2B and [31]). [score:3]
Our discovery indicates that miR-148a suppresses breast cancer metastasis in multiple xenograft mouse mo dels. [score:3]
Although miR-148a does not alter cell-autonomous behaviors including cell growth, viability, or migration in vitro, it suppresses cancer cell extravasation in vivo. [score:3]
Low expression of miR-148a correlates with poor prognosis in breast cancer. [score:3]
Using statistical analysis of multiple databases of breast cancer patients, we found that low expression of miR-148a is associated with diagnosis of high-grade primary tumors and poor prognosis of breast cancer patients, particularly for patients with Basal and Luminal B subtypes. [score:3]
Figure 6Data was extracted from METABRIC data [55] (A) miR-148a expression was analyzed in patients stratified by tumor grade. [score:3]
Manipulation of miR-148a expression alters lung colonization of breast cancer cells. [score:3]
Figure 7(A) Levels of miR-148a expression were determined in primary (Tumor) and metastatic (Mets) tumor samples from breast cancer patients [19] and normalized to the levels of miR-148a in primary tumors. [score:3]
Therefore, we propose that the expression status of miR-148a could serve as a molecular biomarker for the diagnosis of primary tumors in breast cancer patients. [score:3]
Through statistical analysis, we found that the higher the grade of the primary tumor, the lower the expression of miR-148a (Figure 6A). [score:3]
To test this possibility, we labeled control 4T1 cells with iRFP (marked as red for convenience) and miR-148a -overexpressing cells with GFP (green) for engraftment in the same mouse with easy detection and quantification of different cells via flow cytometry. [score:3]
Overexpression of miR-148a alters 4T1 cancer cell propagation in vivo. [score:3]
Furthermore, after co-implantation of 4T1 cells into the mammary fat pad of recipient mice, we discovered that cancer cells with overexpression of miR-148a dominate the proportion of cancer cells in the primary tumor compared with control cancer cells (Figure 3B). [score:2]
Out of these 29 miRNAs detected at comparable levels, six miRNAs (miR-205, miR-200c, miR-200b, miR-148a, miR-203, miR-24) were found to be expressed at markedly lower levels in MDA-MB-231 cells compared to HMEC cells (top 6 miRNAs in Figure 1A). [score:2]
Four of these miRNAs, miR-148a, miR-203, miR-200b, and miR-200c, also displayed significantly reduced expression in the MDA-MB-231 cells compared to MCF7-Ras cells, suggesting that they may play roles in modulating metastasis (Figure 1B). [score:2]
In addition, miR-148a has been previously characterized as a tumor suppressor with functions in regulating cell proliferation, apoptosis, and migration/invasion, all of which are cell-autonomous behaviors [43, 47– 49]. [score:2]
Finally, we analyzed the impact of miR-148a on lung metastasis by counting macroscopic tumor nodules on the surface of the lungs and found approximately half as many tumor nodules with 4T1 cells overexpressing miR-148a compared with control 4T1 cells (Figure 2H and 2I). [score:2]
Figure 4(A– F) The lung colonization ability of cancer cells with manipulated levels of miR-148a and control cells were determined by quantification of lung nodules raised from cancer cells administered directly into the blood. [score:2]
Deregulation of miR-148a has been reported in several types of cancer, including non-small-cell lung cancer, osteosarcoma, gastric cancer, ovarian cancer, glioblastoma, pancreatic cancer, bladder cancer, hepatocellular carcinoma, and breast cancer [42– 46]. [score:2]
We first overexpressed miR-148a in MDA-MB-231 cells (Supplementary Figure 4A), and evaluated their cell-autonomous behaviors, including cell growth, viability in culture, and migration. [score:1]
On the other hand, several previous studies have implicated NRP1 and WNT signaling in various types of cancer growth and progression [39– 41], which are consistent with the expected characteristics of miR-148a target genes. [score:1]
Although 4T1-miR-148a cells were more abundant in the blood, they occupied a smaller proportion of the total cancer cells in the lung, comprising less than 20% of cancer cells in that tissue (Figure 3D). [score:1]
Patients with low miR-148a in the primary tumor occupied 31% of the pool in grade 1, 44% in grade 2, and about 60% in grade 3 (Figure 6B). [score:1]
4T1-miR-148a and 4T1-VEC cells were then mixed at a 1:1 ratio and implanted into the mammary fat pad of Balb/c mice. [score:1]
There were also more 4T1-miR-148a cells than control 4T1 cells in the blood at day 7, although the disparity was not as great as in the primary tumors (Figure 3C). [score:1]
In contrast to these reports, we did not detect cell-autonomous alterations mediated by miR-148a in TNBC in vitro. [score:1]
At day 7, the presence of 4T1-miR-148a remained dominant, with a slightly increased presence (Figure 3B). [score:1]
The cell-autonomous properties, including cell growth, viability in culture, and in vitro migration ability, of 4T1 cells with ectopically elevated miR-148a were indistinguishable from control 4T1 cells in these three aspects (Figure 2D, 2E, and 2F). [score:1]
Our previous results demonstrated that miR-148 does not strongly influence MDA-MB-231 cell-autonomous behaviors. [score:1]
Since two of these miRNAs (miR-148a and miR-203) have not been previously reported to affect metastasis, we determined their clinical relevance by analyzing the survival time of patients with low or high levels of these miRNAs in the TCGA breast cancer patient database (Figure 1C, 1D, and Supplementary Figure 1). [score:1]
At day 5, 4T1-miR148a cells dominate the primary tumor, constituting about 80% of the total cancer cell population. [score:1]
Consistently, the presence of 4T1-miR-148a remained dominant (Supplementary Figure 2C). [score:1]
Thus, miR-148a may be used as a prognostic biomarker for certain subtypes of breast cancer, including TNBC. [score:1]
Similar to the results found in 4T1 cells, overexpression of miR-148a did not alter cell-autonomous characteristics of MDA-MB-231 cells (Supplementary Figure 4B–4F). [score:1]
To determine whether miR-148a can be used as a potential biomarker for prognosis estimation, we analyzed the Metabric breast cancer patient database, which contains patient status with tumor grade and metastasis. [score:1]
Together with statistical analyses demonstrating that miR-148a may serve as a prognostic biomarker for TNBC metastasis, further efforts should be made to investigate whether administration of miR-148a could be therapeutically efficacious to suppress the metastasis of breast cancer. [score:1]
In agreement with this observation, mRNA abundance of ERBB3 or IGF1R was not affected by miR-148a in our microarray analysis. [score:1]
It will be interesting to test in the future whether the proliferation and viability of 4T1 cells are altered by miR-148a in vivo through changing the interactions between cancer cells and microenvironment. [score:1]
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2
[+] score: 346
Since over -expression of URG11 directly correlates with up-regulated expression of miR-148a (Figure 6), and miR-148a depresses PTEN protein expression (Figure 5), URG11 may activate β-catenin by suppressing PTEN. [score:13]
In addition, down-regulated expression of miR-148a by hypermethylation was associated with metastasis in many tumor types [54], and with up-regulation of metastasis associated genes such as subunit 1 of the general transcription factor IIH [55]. [score:9]
The results (Table 1) identified miR-148a as one of the up-regulated miRNAs in cells expressing HBx or over -expressing URG11. [score:8]
For HepG2X and HepG2URG11 cells expressing anti-miR-148a, tumor growth was partially inhibited (Table 3), suggesting that up-regulated miR-148a contributes to HBx and URG11 mediated tumor growth. [score:8]
The finding herein, that URG11 over -expression is associated with elevated expression of miR-148a, which then blocks the translation of PTEN, contributes importantly to understanding the centrality of URG11 in the activation of PI3K/Akt and β-catenin. [score:7]
To confirm that elevated miR-148a was associated with over-expressed URG11, HepG2 and Hep3B cells expressing HBx or over -expressing URG11 were transiently transfected with siURG11. [score:7]
To test whether the predicted miR-148a target site in the 3′UTR of PTEN mRNA was responsible for its regulation, the 3′UTR target site downstream from a luciferase reporter gene (pEZX-PTEN-3′UTR) was co -transfected with either anti-miR-148a or anti-miR control. [score:6]
These observations suggest that HBx and URG11 promote cell growth, in part, by up-regulated expression of miR-148a. [score:6]
Thus, the ability of HBx and URG11 to stimulate hepatocellular growth via up-regulated expression of β-catenin is modulated by miR-148a, which in turn, is associated with a decrease in PTEN activity. [score:6]
Hence, miR-148a was up-regulated in the presence of HBx or over-expressed URG11 in two different liver cell lines. [score:6]
Inhibition of up-regulated miR-148a partially blocked the ability of HBx and URG11 to promote tumorigenesis. [score:6]
Confirmation of Up-regulated miR-148a Expression. [score:6]
These results show that up-regulated expression of miR-148a in HBx positive cells is URG11 dependent. [score:6]
Thus, up-regulated miR-148a, through PTEN, may impact upon Akt signaling post-translationally. [score:6]
miR-148a stimulated cell viability, cell migration, anchorage independent cell growth and tumorigenesis in SCID mice (Table 3, Figure 3– 4) and appears to target the tumor suppressor PTEN (Figure 5). [score:5]
The same trends were observed in these cells at the G2/M transition, suggesting that miR-148a promotes cell cycle progression, especially in URG11 over -expressing and HBx expressing cells. [score:5]
Growth of HepG2X cells stably expressing anti-miR-148a was inhibited by an average of 68% by day 3 (P < 0.01). [score:5]
f. Negative ΔΔCt value  =  elevated expression of miR-148a in tumor; positive ΔΔCt value  =  elevated expression of miR-148a in non-tumor liver. [score:5]
These observations suggest that elevated miR-148a triggered changes in host gene expression that resulted in the appearance of more aggressive tumors despite the fact that miR-148a expression was not elevated in most tumors (Figure 2, Table 2). [score:5]
Since PTEN blocks PI3K activity, experiments were designed to test whether anti-miR-148a blocks Akt signaling by activating PTEN and thereby suppressing β-catenin expression. [score:5]
The results showed that anti-miR-148a significantly inhibited cell growth on all days post-transfection, and by day 3, inhibition was 60–70% (Figure 3A). [score:5]
Further work showed that miR-148a targeted inactivation of the tumor suppressor, phosphatase and tensin homolog (PTEN), which in turn, modulated β-catenin/Wnt signaling. [score:5]
Antagonists of endogenous miR-148a may be a useful therapeutic strategy for enhancing PTEN expression and suppressing Akt levels in the HBV infected liver. [score:5]
0035331.g008 Figure 8 miR148a increases β-catenin expression by inhibiting PTEN. [score:5]
Thus, HBx is associated with up-regulated expression of miR-148a in NT compared to T by an average of (14 ÷5) 2.8-fold. [score:5]
miR148a increases β-catenin expression by inhibiting PTEN. [score:5]
The function of miR-148a is also likely to be cell type dependent, since it is down-regulated in acute myeloid leukemia [52], [53]. [score:4]
Thus, HBx up-regulation of URG11 and miR-148a may be two mechanisms that block PTEN activity, resulting in the activation of β-catenin signaling (Figure 8). [score:4]
Since CLD involves tissue regeneration and remo deling, up-regulation of miR-148a in the chronically infected liver may promote the transition of hepatocytes into tumor cells. [score:4]
Similar inhibition was observed in Hep3BX and Hep3BURG11 cells stably expressing anti-miR-148a compared to control miRNA (data not shown). [score:4]
Parallel experiments using anti-miR-148a for transient transfection (as a positive control) showed that miR-148a levels were down-regulated by 1.92 ± 0.22-fold in HepG2X cells and by 1.71 ± 0.21-fold in Hep3BX cells (Figure 1B). [score:4]
Importantly, most HBx and up-regulated miR-148a were found in the NT compartment of clinical samples from tumor bearing patients (Figure 2, Table 2), suggesting that epigenetic changes involving hypermethylation occur prior to tumor appearance and may promote carcinogenesis. [score:4]
To determine whether HBxAg expression correlated with elevated miR-148a in vivo, the expression of HBx and miR-148a was compared in the tumor (T) and nontumor (NT) compartments in 19 patients. [score:4]
Among them, miR-148a was up-regulated by HBx and URG11. [score:4]
In this case, HepG2CAT cell migration was also modestly inhibited (P < 0.05), suggesting that miR-148a promotes cell migration to a greater extent in HBx or over-expressed URG11 cells compared to control. [score:4]
In 19 T/NT tissue pairs from as many patients with HBV associated HCC, miR-148a was up-regulated an average of 14-fold in NT tissue from 13 patients. [score:4]
However, the fact that up-regulated miR-148a was found in mostly NT herein, combined with its ability to stimulate viability, proliferation, migration and growth in soft agar (Figure 3– 4), suggest that tissue remo deling and metastasis are early events in HBV associated HCC instead of late events associated with tumor progression. [score:4]
For HepG2URG11, anti-miR-148a inhibited growth an average of 69% by day 3 (P < 0.01) (Figure 3B). [score:3]
Effect of anti-miR-148a upon the expression levels of Akt, GSK3β, and β-catenin. [score:3]
These observations suggest that miR-148a, at least in part, drives tumor growth mediated by HBx, and in particular, by over -expression of URG11. [score:3]
0035331.g004 Figure 4(A) Migration of HepG2CAT, HepG2X, and HepG2URG11 cells stably expressing anti-miR-148a or control anti-miR. [score:3]
PTEN is suppressed by miR-148a in HBV associated HCC (Figure 5) although other mechanisms may also be operative. [score:3]
The expression of miR-148a was then determined by SYBR Green qRT-PCR. [score:3]
Effect of anti-miR-148a on PTEN expression. [score:3]
0035331.g001 Figure 1 (A) Endogenous levels of miR-148a were determined in the indicated cell lines, and their levels normalized to miR-148a in CAT expressing cells. [score:3]
Taken together, these data suggest that the binding of miR-148a to the 3′UTR of PTEN is specific, and that PTEN is a target of miR-148a. [score:3]
Relationship between HBx, URG11 and miR-148a expression levels. [score:3]
Once accomplished, miR-148a (and HBx) is no longer selected for, and their expression levels decrease. [score:3]
These results suggest that anti-miR-148a inhibits Akt signaling, which results in lower levels of active β-catenin. [score:3]
The difference in miRNA expression between tumor (T) and non-tumor (NT) was determined by qRT-PCR and determination of ΔΔCT, where ΔΔCt  =  ΔCt of miR-148a in tumor – ΔCt of miR-148a in non-tumor. [score:3]
Expression of miR-148a in tumor and non-tumor liver tissues. [score:3]
Stably expressed anti-miR-148a was associated with essentially stable levels of total Akt but significantly decreased levels of activated Akt (p-Akt; P < 0.005). [score:3]
Neither control miRNA introduced into HepG2X or HepG2URG11 cells, nor introduction of anti-miR-148a into HepG2CAT cells, inhibited growth at any point in time. [score:3]
To test this hypothesis, total and active β-catenin, phosphorylated-GSK3β (p-GSK3β, Ser9), as well as total and phosphorylated-Akt (p-Akt, Ser473) levels, were determined in Hep3BX and Hep3BURG11 cells stably expressing anti-miR-148a. [score:3]
To see if elevated miR-148a also promotes cell cycle progression, Hep3BCAT, Hep3BX, Hep3BURG11 stably expressing anti-miR-148a or control anti-miR were synchronized by serum starvation, released by addition of serum, and then subjected to flow cytometry. [score:3]
Anti-miR-148a Inhibits Cell Growth and Viability. [score:3]
miR-148a was also up-regulated 1.68 ± 0.11-fold in Hep3BX and by 2.33 ± 0.21-fold in Hep3BURG11 cells compared to Hep3BCAT cells (Figure 1A). [score:3]
miR-148a was up-regulated 1.59 ± 0.12-fold in HepG2X cells and 2.73 ± 0.46-fold in HepG2URG11 cells compared to HepG2CAT cells (Figure 1A). [score:3]
miR-148a expression was quantified in HepG2X, HepG2URG11 and HepG2CAT cells by using SYBR green qRT-PCR. [score:3]
Day 3 results show that anti-miR-148a suppressed cell cycle progression into S phase in Hep3BX (P < 0.005) (Figure 3C). [score:3]
miR-148a Expression in Clinical Specimens. [score:3]
Thus, elevated miR-148a expression appears to be an early event in the pathogenesis of HCC, since it was observed most often in infected liver tissues from which tumor nodules developed. [score:3]
miR-148a Targets PTEN. [score:3]
Anti-miR-148a Inhibits Cell Migration. [score:3]
In contrast, inhibition of miR-148a in HepG2CAT cells had little impact upon tumorigenicity. [score:3]
Since PXR contributes to the detoxification of xenobiotics in the liver [49]– [51], the inverse relationship between miR-148a and PXR in chronic liver disease (CLD) may promote toxic liver damage. [score:3]
Likewise, total levels of β-catenin were minimally altered by stable expression of anti-miR-148a, while the levels of active β-catenin were depressed in Hep3BX cells (P < 0.05), and in Hep3BURG11 cells (P < 0.01), compared to controls (Figure 6). [score:2]
miR-148a was first shown to block apoptosis [47] by modulating the levels of cytochrome P450 3A4 via post-transcriptionally regulating the 3′UTR of the Pregnane X Recepter (PXR) mRNA [48]. [score:2]
Three additional constructs, identical to pEZX-PTEN-3′UTR but each containing unique point mutations in one or both miR-148a binding sites, were also made (Genecopoeia) and tested. [score:2]
Parallel experiments using reporter plasmids containing these mutations resulted in little increase in luciferase activity, suggesting that the mutant PTEN 3′UTRs did not bind to miR-148a (Figure 5C). [score:2]
In the present work, up-regulated miR-148a in the liver was associated with the appearance of aggressive tumors (Edmonson grade III-IV) characterized by venous invasion (Figure 2, Table 2) and by the ability of elevated miR-148a to promote tumorigenesis (Table 3). [score:2]
In contrast, anti-miR-148a did not suppress HepG2CAT cell growth in soft agar compared to control miRNA treatment. [score:2]
HBx expression in NT was associated with chronic hepatitis (P < 0.02), cirrhosis (P < 0.01) and elevated levels of miR-148a (P < 0.001) compared to uninfected liver. [score:2]
Anti-miR-148a suppressed colony formation of HepG2X cells by an average of 11.8-fold, and that of HepG2URG11 cells by an average of 2.7-fold, compared to control anti-miR (Figure 4B, P < 0.01). [score:2]
mirVana qRT-PCR miRNA Detection Kit, reverse transcriptase and PCR primer sets (hsa-miR-148a and U6), miR -negative control 1, and hsa-miR-148a inhibitor (anti-miR-148a) were all purchased from Ambion. [score:2]
Lentiviral based anti-mir-148a construct (pmiRZip-148a) and control vector (pGreenPuro Scramble Hairpin Control), pPACKF1™ Lentivector Packaging Kit and the 293TN producer cell line were all purchased from System Biosciences (Mountain View, CA). [score:1]
In this report, miR-148a, which was up-regulated 1.64 -fold in HepG2X and 6.49-fold in HepG2URG11 compared to HepG2CAT cells, was chosen for further characterization. [score:1]
This corresponds to an average of 14-fold change in miR-148a levels in NT in 13 patients and an average of 5-fold change in T from the remaining 6 patients (Table 2). [score:1]
To test whether HBx and URG11 stimulated cell growth is at least partially dependent upon miR-148a, HepG2X and HepG2URG11 cells were transiently transfected with anti-miR-148a. [score:1]
qRT-PCR analysis of Akt, GSK3β, and β-catenin mRNAs showed no differences in cells treated with anti-miR-148a or control anti-miR (data not shown). [score:1]
Effect of anti-miR-148a on cell phenotype. [score:1]
Growth of HepG2CAT cells was not altered by anti-miR-148a. [score:1]
The impact of miR-148a upon tumorigenicity was then assessed by xenotransplantation. [score:1]
To test whether miR-148a contributed to tumorigenesis, HepG2CAT, HepG2X, HepG2URG11 cells stably expressing anti-miR-148a or control anti-miR were evaluated for anchorage independent growth in soft agar. [score:1]
HepG2CAT, HepG2X and HepG2URG11 cells were (A) transiently transfected with anti-miR-148a or (B) stably transduced with recombinant lentivirus encoding anti-miR-148a. [score:1]
0035331.g003 Figure 3 HepG2CAT, HepG2X and HepG2URG11 cells were (A) transiently transfected with anti-miR-148a or (B) stably transduced with recombinant lentivirus encoding anti-miR-148a. [score:1]
The relationships between HBx, miR-148a, and histopathology were assessed by 2×2 Chi-square analysis. [score:1]
Use of a control siRNA (as a negative control) yielded 0.16 ± 0.02-fold and 0.18 ± 0.018-fold lower levels of miR-148a in HepG2X and Hep3BX cells, respectively (Figure 1B). [score:1]
0035331.g005 Figure 5(A) Homology between the PTEN 3′UTR and anti-miR-148a. [score:1]
Anti-miR-148a Blocks Colony Formation in Soft Agar and Tumor Formation in SCID Mice. [score:1]
Effect of anti-miR148a on cell migration and anchorage independent growth. [score:1]
The pEZX-PTEN-3′UTR construct (Genecopoeia, Rockville, MD), which contains the PTEN 3′UTR sequence, has the putative binding site for miR-148a downstream of the firefly luciferase stop codon. [score:1]
Further, the inactive form of GSK3β, p-GSK3β, was depressed by treatment with anti-miR-148a (P < 0.05). [score:1]
Given that the PTEN 3′UTR contains two miR-148a binding sites, the wild type pEZX-PTEN-3′UTR was mutated at each or both of these sites (Table S1). [score:1]
Cells were plated (5,000 cells/well) in 96 well plates and co -transfected with 100ng of the pEZX-PTEN-3′UTR and 100 ng of anti-miR-148a, using DharmaFECT1. [score:1]
The indicated cell lines were stably transfected with anti-miR-148a (or control miRNA) and then analyzed for total and active β-catenin, p-GSK3β, as well as total and p-Akt by western blotting. [score:1]
The homology between miR-148a and PTEN from miRanda is shown in Figure 5A. [score:1]
Further, elevated miR-148a in NT was associated with Edmond III-IV stage tumor (P < 0.001) and venous invasion (P < 0.001) but not with a tumor capsule (P > 0.25). [score:1]
miR-148a was also shown to repress DNA methyltransferase 1 (DNMT1) and DNMT3B [56], [57]. [score:1]
Dependence of Elevated miR-148a Upon URG11. [score:1]
The ΔΔCt values showed that miR-148a was elevated in 13 out of the 19 NT samples (68%) and in 6 out of 19 tumors (31%) (Table 2). [score:1]
Additional work will be needed to investigate whether miR-148a targets other proteins in addition to PTEN that are important to pathogenesis of HBV -mediated HCC. [score:1]
These findings again suggest that HBx and URG11 stimulate cell growth, at least in part, in a miR-148a dependent manner. [score:1]
Cells were then transiently transfected with 100 ng of anti-miR-148a (Ambion) using DharmaFECT1. [score:1]
miR-148a and Akt Signaling. [score:1]
The results showed that anti-miR-148a, but not control anti-miR, partially blocked the ability of HBx and URG11 to promote migration of HepG2 cells after 72 hr (P < 0.01) (Figure 4A). [score:1]
In the remaining 6 patients, miR-148a was elevated an average of 5-fold in T (Table 2, Figure 2). [score:1]
Mo del of miR148a associated signaling pathway. [score:1]
The results showed that miR-148a levels were depressed by 1.54 ± 0.24-fold in HepG2X cells and depressed by 1.85 ± 0.19-fold in Hep3BX cells (Figure 1B). [score:1]
0035331.g006 Figure 6 The indicated cell lines were stably transfected with anti-miR-148a (or control miRNA) and then analyzed for total and active β-catenin, p-GSK3β, as well as total and p-Akt by western blotting. [score:1]
Role of miR-148a in tumorigenesis. [score:1]
Thus, miR-148a may promote tumorigenesis from the non-tumor compartment but is no longer active once tumor appears. [score:1]
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[+] score: 292
Other miRNAs from this paper: hsa-mir-20a, mmu-mir-182, hsa-mir-148a, hsa-mir-182, mmu-mir-20a
Meanwhile, IHC and immunoblotting revealed that MMP9 and VEGF expression was upregulated in miR-148a–overexpressing tumors, while that of QKI was downregulated; the effects were attenuated in miR-148a–inhibited tumors (Figure  6A and B). [score:13]
Ectopically expressing miR-148a had no effect on GFP–γ-tubulin expression, but robustly inhibited the expression of GFP with a complete, wild-type QKI-3′UTR in glioblastoma cells (Figure  2D). [score:9]
Herein, we report that miR-148a was induced by NF-κB and directly targeted and suppressed the 3′ untranslated regions (3′ UTRs) of multiple genes that function as negative regulators of TGF-β, leading to TGF-β hyperactivation and GBM aggressiveness. [score:9]
Lastly, but no less importantly, analyzing miR-148a expression and TGF-β–regulated gene signatures via GSEA of published TCGA patient expression profiles allowed us to confirm that miR-148a expression levels were positively correlated with the TGF-β–activated gene signatures (Figure  3I). [score:8]
Here, we report microRNA-148a (miR-148a) overexpression in glioblastoma and that miR-148a directly suppressed Quaking (QKI), a negative regulator of TGF-β signaling. [score:7]
Analysis using three publicly available algorithms (TargetScan, PicTar, miRanda) revealed that the QKI-3′UTR contains conserved critical nucleotides that may serve as a legitimate target of miR-148a (Figure  2A), which is substantially overexpressed in glioblastoma [34]. [score:7]
Taken together, our result indicates that the NF-κB pathway induced miR-148a expression by directly targeting the MIR148A promoter. [score:6]
Expression and correlation of miR-148a with MMP9 and VEGF mRNA expression, p-Smad3 expression, and NF-κB activity (detected by an EMSA assay) in 10 human glioblastoma samples. [score:6]
The key finding of the present study is that NF-κB increases miR-148a expression to sustain the TGF-β/Smad signaling pathway by downregulating QKI and SKP1. [score:6]
It is notable that miR-148a expression also correlated with the expression of NF-κB–regulated gene signatures (Additional file 3: Figure S3A). [score:6]
Notably, the luciferase reporter assay showed that miR-148a inhibitor abolished the inhibitory effect of miR-148a linked with QKI-3′UTR, whereas miR-148a into which a mutation had been introduced lost the ability to reduce luciferase activity despite the presence of QKI-3′UTR (Figure  2E). [score:5]
MiRNA expression was defined based on the comparative threshold (Ct); relative expression levels were calculated as 2 - (Ct miR-148a - Ct U6) after normalization with reference to the quantification of U6 small nuclear RNA expression. [score:5]
More importantly, Kaplan–Meier analysis demonstrated that mice bearing miR-148a–overexpressing glioblastomas had significantly shorter survival than control animals; in contrast, mice bearing miR-148a–inhibited tumors survived longer than the control mice (Figure  6C). [score:5]
Furthermore, miR-148a overexpression increased Smad luciferase reporter activity of Smad2/3 phosphorylation, while miR-148a inhibition reduced it (Figure  3E and F). [score:5]
Importantly, miR-148a expression also correlated with the expression of glioblastoma progression–related gene signatures (Figure  4E), suggesting that miR-148a plays significant roles in glioblastoma progression and that its levels are associated with poor overall survival in patients with glioblastoma. [score:5]
As predicted, ectopic expression of miR-148a in U87 and U138MG cells decreased SKP1 expression and ROC1-SCF [Fbw1a] ubiquitination activity (Figure  3B and C). [score:5]
Interestingly, we found that NF-κB activation increased the expression of miR-148a, whose promoter contains NF-κB target elements. [score:5]
Interestingly, there was a marked increased in miR-148a expression in glioblastoma cells treated with tumor necrosis factor-α (TNF-α), whereas TGF-β had minimal effects on miR-148a expression (Figure  8A). [score:5]
From the above results, we conclude that NF-κB signaling is probably hyperactivated in glioblastoma, thereby inducing miR-148a expression but reducing QKI expression. [score:5]
Furthermore, miR-148a overexpression reduced the luciferase activity of SKP1-3′UTR in a consistent and dose -dependent manner, but miR-148a inhibition increased it. [score:5]
We demonstrate that NF-κB binds directly to the miR-148a promoter to regulate miR-148a expression. [score:5]
Notably, the borders of miR-148a–overexpressing tumors exhibited spike-like structures invading into the surrounding brain tissues, whereas the control tumors exhibited sharp edges (Figure  6A), indicating that miR-148a overexpression induced glioblastoma cell invasion into the brain. [score:5]
Consistent with this, microarray analysis showed that miR-148a was significantly upregulated in glioblastoma (Figure  4C). [score:4]
Analyses using publicly available algorithms and the present results identified QKI as a direct target of miR-148a in glioblastoma. [score:4]
Immunoblotting analysis showed that QKI expression was decreased in miR-148a–transduced cells and increased in miR-148a inhibitor–transfected cells compared to the negative control cells (Figure  2B). [score:4]
Here, we showed that miR-148a directly repressed QKI and SKP1, which inhibited the TGF-β pathway. [score:4]
Figure 2 miR-148a directly targets QKI. [score:4]
Importantly, pyrrolidine dithiocarbamate (PDTC, a NF-κB inhibitor) and a TNF-α–neutralizing antibody prevented the stimulatory effect of TNF-α on miR-148a (Figure  8B). [score:3]
From analysis using a published microarray -based high-throughput assessment, we found that miR-148a expression is significantly higher in GBM tissues than in normal brain tissue. [score:3]
Furthermore, QKI and SKP1 are bona fide targets of miR-148a. [score:3]
In the attempt to understand the role of QKI and SKP1 repression in miR-148a–induced invasiveness and angiogenesis, the effects of QKI and SKP1 (without and with the 3′ UTRs) were examined in miR-148a–overexpressing cells. [score:3]
Collectively, these results demonstrate that QKI is a bona fide target of miR-148a. [score:3]
Interestingly, we found that NF-κB induced miR-148a expression, leading to enhanced-strength and prolonged-duration TGF-β/Smad signaling. [score:3]
These findings suggest that miR-148a expression could be sufficient for activating TGF-β/Smad signaling. [score:3]
These results support the notion that hyperactive NF-κB signaling induces miR-148a expression, resulting in TGF-β/Smad pathway activation and consequently leading to the promotion of malignant phenotypes of glioblastoma and poor clinical prognosis of clinical glioblastoma. [score:3]
As shown in Figure  8F, p-Smad2/3 were also elevated in TNF-α–treated cells, but miR-148a inhibitor halted the effect. [score:3]
Figure 8 NF-κB induces miR-148a expression. [score:3]
NC2 is a chemically synthesized single-stranded RNA molecule used as negative control for miR-148a inhibitor. [score:3]
Figure 3 MiR-148a directly targets SKP1 and activates TGF-β signaling. [score:3]
As both QKI and SKP1 are bona fide targets of miR-148a, we suspect that miR-148a is involved in TGF-β activation. [score:3]
However, ectopically expressing miR-148a had no effect on the NF-κB luciferase reporter activity (Additional file 3: Figure S3B). [score:3]
MiR-148a upregulation augmented glioblastoma aggressiveness in vitroand in vivo. [score:3]
Thus, these results support the view that miR-148a overexpression is linked to glioblastoma progression. [score:3]
These findings uncover a plausible mechanism for NF-κB–sustained TGF-β/Smad activation via miR-148a in glioblastoma, and may suggest a new target for clinical intervention in human cancer. [score:3]
Taken together, our results suggest that suppressing QKI and SKP1 plays an important role in miR-148a promotion of invasiveness and angiogenesis. [score:3]
Stable cell lines expressing miR-148a and miR-148a sponge were generated via retroviral infection using HEK293T cells as described by Li et al. [52] and selected with 0.5 μg/mL puromycin for 10 days. [score:3]
Real-time PCR analysis of miR-148a expression in (A) three normal brain tissues and 12 glioma tissues, and (B) NHAs and seven glioblastoma cell lines. [score:3]
As shown in Figure  5A and B, miR-148a overexpression dramatically increased both LN18 and U138MG cell migration and invasiveness. [score:3]
Interestingly, we also found that NF-κB induced miR-148a expression. [score:3]
Interestingly, SKP1 is the theoretical target gene of miR-148a (Figure  3A). [score:3]
As shown in Figure  9, there was positive correlation between the miR-148a levels in 10 freshly collected glioblastoma samples with MMP9 (r = 0.674, P < 0.001) and VEGF mRNA levels (r = 0.748, P < 0.001), the DNA -binding activity of NF-κB (r = 0.895, P < 0.001), and p-Smad3 expression (r = 0.754, P = 0.001). [score:3]
Taken together, our results demonstrate that SKP1 is also a bona fide target of miR-148a in glioblastoma. [score:3]
Ectopic miR-148a expression dramatically promoted glioblastoma aggressiveness both in vitro and in vivo. [score:3]
We used a stable miRNA sponge to inhibit miR-148a in vivo. [score:3]
Meanwhile, miR-148a overexpression strongly promoted the ability of glioblastoma cells to induce vessel formation (CAM, Figure  5C and D). [score:3]
Moreover, suppressing miR-148a yielded results to the contrary (Additional file 2: Figure S2A and S2D). [score:3]
Understanding the precise role played by miR-148a in GBM progression will not only increase our knowledge of the pathogenesis of gliomas, but also will enable the development of novel therapeutic strategies and the identification of an effective biomarker for predicting outcomes for patients with malignant gliomas. [score:2]
MiR-148a upregulation augmented glioblastoma aggressiveness in vitroand in vivoAs glioblastomas are highly angiogenic and generally kill via invasiveness, we investigated whether miR-148a could modulate glioblastoma cell angiogenesis and invasiveness. [score:2]
We synthesized cDNA using a TaqMan MicroRNA Reverse Transcription Kit (Applied Biosystems, Foster City, CA, USA) and quantified miR-148a expression using a miRNA-specific TaqMan MiRNA Assay Kit (Applied Biosystems). [score:2]
MiR-148a overexpression correlated with glioblastoma progression. [score:2]
Immunoblotting analysis and immunofluorescence (IF) staining revealed that miR-148a–expressing cells exhibited a marked increase in nuclear Smads, which was confirmed by the cellular fraction assays (Figure  3G and H). [score:2]
Our findings suggest an essential role of miR-148a in regulating GBM cell progression. [score:2]
Figure 4 MiR-148a is overexpressed in gliomas. [score:2]
MiR-148a expression correlated with NF-κB activity and TGF-β/Smad pathway hyperactivation in clinical glioblastoma. [score:2]
However, transfection of the miR-148a-mut, containing mutations in the miR-148a seed region, did not decrease the luciferase activity of SKP1-3′UTR (Figure  3D). [score:2]
MiR-148a targeted SKP1 and activated TGF-β signaling. [score:2]
MiR-148a targeted QKI. [score:2]
Co-transfecting QKI or SKP1 with miR-148a significantly reduced glioblastoma cell invasiveness and decreased the ability of glioblastoma cells to induce HUVEC tube formation (Figure  7A and B). [score:1]
Figure 7 QKI and SKP1 play important roles in miR-148a promotion of the aggressive phenotypes of glioblastoma. [score:1]
Thus, it is plausible that miR-148a modulates NF-κB–mediated TGF-β activation through multiple mechanisms. [score:1]
QKI and SKP1 played important roles in miR-148a–induced glioblastoma cell invasiveness and angiogenesis. [score:1]
Taken together, our results suggest that miR-148a induced glioblastoma cell invasiveness and angiogenesis in vitro and in vivo. [score:1]
On the other hand, analysis of the TCGA datasets indicated that miR-148a promotes glioblastoma aggressiveness. [score:1]
miR-148a QKI NF-κB TGF-β Aggressiveness Glioblastomas Glioblastoma multiforme (GBM) is the most common and lethal primary brain tumor in adults; it has a spectrum of aberrantly aggressive phenotypes [1]. [score:1]
Cells were cotransfected with a plasmid that encodes hemagglutinin-tagged (HA)-Ago1 and miR-148a (100 nM), followed by HA-Ago1 immunoprecipitation (IP) using an anti-HA antibody. [score:1]
These results indicate that miR-148a was involved in TNF-α–mediated TGF-β/Smad activation. [score:1]
Figure 9 Clinical relevance of the NF-κB/miR-148a/TGF-β/Smad axis in human glioblastoma. [score:1]
NF-κB induced miR-148a in glioblastoma. [score:1]
The human MIR148A gene was PCR-amplified from genomic DNA and cloned into a pMSCV-puro retroviral vector. [score:1]
Figure 6 miR-148a promotes the aggressive phenotype of glioblastoma cells in vivo. [score:1]
Hence, the NF-κB/miR-148a/TGF-β pathway represents a critical mechanism for promoting glioblastoma aggressiveness. [score:1]
Via TCGA database analysis, we found that miR-148a was significantly associated with shorter overall survival in patients with glioblastoma, and correlated positively with TGF-β/Smad signaling activity (P < 0.05). [score:1]
Analysis of the MIR148A promoter region using ConSite (http://consite. [score:1]
Real-time PCR analysis revealed that miR-148a was markedly overexpressed in the eight primary glioblastoma tissues compared to that of the normal brain tissues, and in the seven glioblastoma cell lines compared with the NHAs (Figure  4A and B). [score:1]
Importantly, the significant correlation detected among miR-148a levels, NF-κB, and TGF-β/Smad signaling hyperactivation was confirmed in a cohort of human glioblastoma samples. [score:1]
In summary, the present study provides an important link between NF-κB and TGF-β signaling via miR-148a in glioblastoma. [score:1]
Lastly, we examined whether activation of the NF-κB/miR-148a/TGF-β/Smad axis identified in our glioblastoma cell mo dels would also be evident in clinical glioblastoma tumors. [score:1]
The biological role of miR-148a in promoting the aggressive phenotype of glioblastoma was further examined in vivo by stereotactically implanting engineered glioblastoma cells into the brains of nude mice. [score:1]
MiR-148a sponge was constructed by annealing, purifying, and cloning oligonucleotides containing six tandem “bulged” miR-148a–binding motifs into the pMSCV vector. [score:1]
Furthermore, statistical analysis revealed that miR-148a levels were inversely correlated with survival (P < 0.001, Figure  4D). [score:1]
Negative control 1(NC1) is a chemically synthesized double-stranded small RNA used as negative control for miR-148a mimic. [score:1]
Notably, these findings were consistent with the significant correlation between miR-148a levels with NF-κB hyperactivation and activated TGF-β/Smad signaling in a cohort of human glioblastoma specimens. [score:1]
We found that miR-148a enhances the strength and prolongs the duration of TGF-β/Smad signaling. [score:1]
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[+] score: 276
Downregulation of endogenous Wnt1 (Fig. 5B) also promoted adipogenesis in hMSCs-Ad (Fig. 5C, Fig. S5) and increased the expression of the adipocyte-related genes PPARγ2 (Fig. 5D), C/EBP-α (Fig. 4E), and Fabp4 (Fig. 5F), consistent with the results of miR-148a overexpression in hMSCs-Ad (Fig. 2). [score:8]
However, previous studies on hMSCs-Ad undergoing adipogenesis reported that miR-21 13, miR-22 14, miR-196 15, miR-27b 20, and miR-138 31 were either upregulated or downregulated, and miR-148a was not reported in hMSCs-Ad. [score:7]
Wnt1 or Wnt10b inhibits the differentiation of mesenchymal stem cells 40 and blocks adipogenesis in vivo 41; thus, miR-148a expression rescued the negative effect of Wnt1 expression in hMSCs-Ad. [score:7]
We further identified Wnt1 as a direct translational target of miR-148a, where it directly bound to the 3′-UTR of Wnt1 and not to the related Wnt10b, which is also consistent with previous studies 36. [score:7]
Overexpression of miR-148a partially restored differentiation in Wnt1 -suppressed hMSCs-Ad as assessed by lipid accumulation (Fig. 5C, last two columns; Fig. S5), as well as PPARγ2 (Fig. 5G), C/EBP-α (Fig. 5H), and Fabp4 (Fig. 4I) mRNA expression. [score:7]
miR-148a was highly expressed in hMSCs-Ad during adipogenesis relative to its negative regulatory effect on Wnt1 expression. [score:6]
Meanwhile, knockdown of miR-148a obviously inhibited adipogenesis, as indicated by the expression of adipocyte-specific factors PPARγ2, C/EBP-α, and FABP4 (Figs. 3B–D), triacylglycerol content (Fig. 3E), and oil red O staining (Fig. 3F). [score:6]
Overexpression (D) and knockdown (E) CREB in hMSC-Ad were used to examine the expression level of miR-148a by qRT-PCR. [score:6]
To further understand the mechanism underlying the regulation of adipogenesis by miR-148a, candidate target genes were examined by bioinformatics analysis using TargetScan, miRanda, and PicTar. [score:6]
Exogenous expression of miR-148a in hMSCs-Ad significantly increased TG content, GPDH activity, and adipogenesis relative to an increase in differentiation-specific factors at both transcriptional and translational levels. [score:5]
The miR-148a lentiviral expression vector pGLV3-H1-GFP-puro-miR-148a, miR-148a sponge (four repeat complimentary sequences) lentiviral expression vector, and the negative control vector pGLV3-H1-GFP-puro were purchased from GenePharma (Shanghai, China). [score:5]
In our study, we examined the effect of miR-148a on TLX-2 reporter gene, which is a downstream target for BMP signaling in the primitive streak where BMP-4 and other TGF-related factors are expressed. [score:5]
Bioinformatics analysis using TargetScan, miRanda, and PicTar revealed that the Wnt (Wnt1, Wnt10b), cell cycle (E2F3), and DNA methylation pathways (DNMT1, DNMT3B) were candidate targets of miR-148a. [score:5]
However, other studies have found little or no change in Wnt1 or Wnt10b expression by miR-148a or miR-148b in gastric cancer cells 38 39, suggesting that inhibition is dependent on cellular context. [score:5]
miR-148a was highly expressed in CREB overexpressed hMSC-Ad (n = 3). [score:5]
Interestingly, miR-148a can inhibit the Wnt1 expression at post-transcriptional level. [score:5]
To determine whether miR-148a directly affected adipocyte differentiation, hMSCs-Ad were transduced with a lentivirus expressing miR-148a or an empty virus for 48 h before transferring to differentiation medium. [score:4]
Therefore, we examined whether endogenous miR-148a expression was regulated by CREB in hMSCs-Ad. [score:4]
miR-148a was also upregulated sixfold in hMSCs-Ad. [score:4]
Qin et al. 32 found that miR-148a was downregulated in activation of Wnt signaling in 3T3-L1 cells. [score:4]
We tested whether miR-148a levels were altered in brown adipose tissues and observed downregulated levels, opposite to the changes observed in epididymal white adipose tissues. [score:4]
This hypothesis was first proved by identification of a direct miR-148a target protein. [score:4]
Knockdown miR-148a in hMSCs-Ad inhibits adipogenic differentiation. [score:4]
Mutation of the miR-148a binding site abolished its inhibitory effect on Wnt1 reporter activity (Fig. 4C). [score:4]
To determine whether miR-148a can rescue Wnt1 -suppressed adipogenesis, hMSCs-Ad was co-infected with Wnt1 and miR-148a. [score:3]
We then examined the role of these differentially expressed miRNAs in adipocyte differentiation by PPREx3-TK report gene, representing PPAR -dependent transcription as a major factor in adipogenesis 23. miR-148a increased PPREx3-TK activity by about twofold (Fig. S1A). [score:3]
Bioinformatics and identification of miR-148a target sites. [score:3]
As control, the expression of miR-152, which belongs to the same family of miR-148a, as well as miR-1908 and let-7a, was unchanged (Fig. S2B), suggesting that miR-148a did not disrupt other endogenous miRNA pathways. [score:3]
org) were used to predict the target consensus sequences for miR-148a. [score:3]
HEK-293T cells were transfected with lentiviral packaging vectors (ABM, Richmond, BC, CA) and lentiviral vectors expressing miR-148a, CREB, or Wnt1 by Lipofectamine 2000. [score:3]
Additionally, qRT-PCR (Fig. 2E) and Western blot (Fig. 2F) analyses indicated that the adipocyte-specific factors PPARγ2, C/EBP-α, and FABP4 increased significantly after transduction with the miR-148a -expressing lentivirus. [score:3]
Canonical Wnt signaling was repressed following miR-148a expression, as indicated by the marked reduction of Wnt1 protein (Fig. 5A, Day 0), increased phosphorylation of GSK-3β (p-GSK-3β) (Fig. 5A, Day 10), and reduced nuclear β-catenin (Fig. 5A, Day 10). [score:3]
Expression of miR-148a during hMSC-Ad differentiation was quantitated by TaqMan miR -based qRT-PCR. [score:3]
Overexpression of miR-148a promoted adipogenesis as indicated by oil red O staining (Fig. 2B), triacylglycerol content (Fig. 2C), and GPDH activity (Fig. 2D). [score:3]
Differential miR-148a expression in obese mice and human subjects. [score:3]
Identification of miR-148a -binding sequence in target genes. [score:3]
Expression of miR-148a increased in these subjects in proportion to increasing BMI (Fig. 7B, r = 0.63, P < 0.001, Pearson’s correlation). [score:3]
The expression of miR-148a was increased 38-fold at Day 0 and remained high throughout differentiation (Fig. 2A). [score:3]
Additionally, miR-148a decreased the expression of Wnt1 protein but not Wnt1 mRNA in hMSCs-Ad (Figs. 4D and 4E), suggesting that miR-148a modulated Wnt1 post-transcriptionally. [score:3]
Overexpression (F) and knockdown (G) CREB in HEK293 were used to examine the promoter activity of miR-148a by Luciferase assay. [score:3]
Further research may elucidate whether miR-148a can modulate adipogenesis in vivo and possibly provide a novel therapeutic target for the management of obesity. [score:3]
This new role for miR-148a was only previously recognized as modulator function of tumor suppressor genes in gastrointestinal tumors 30. [score:3]
miR-148a expression gradually increased after induction of adipocyte differentiation in hMSCs-Ad and peaked after 10 d (Fig. 1C). [score:3]
Differential miR-148a expression in lean and obese human subjects and mice. [score:3]
CREB is bound to miR-148a promoter in hMSCs-Ad, and CREB is required for miR-148a expression. [score:3]
Our results revealed that human and mouse adipocyte differentiation-related molecules, namely, Wnt (Wnt1, Wnt10b), cell cycle (E2F3), and DNA methylation (DNMT1, DNMT3B), were the candidate targets of miR-148a (Figs. S4A and S4B). [score:3]
This finding is also supported by the high expression of miR-148a in diet -induced obese mice, as well as our finding that miR-148a levels in human adipose tissues achieve proportion to an increase in BMI, providing new insights into the roles of miRNAs in obesity and related metabolic disorders. [score:3]
By contrast, miR-148a inhibited activity of Wnt1 but not Wnt10b by 50% (Fig. 4B). [score:3]
miR-148a expression levels also increased 10-fold in murine 3T3-L1 preadipocytes undergoing differentiation (Fig. S1B), further suggesting that miR-148a is associated with adipocyte differentiation. [score:3]
Overexpression of miR-148a promotes adipogenesis in hMSCs-Ad. [score:3]
Overexpression of miR-148a in hMSCs-Ad enhances adipogenic differentiation. [score:3]
By contrast, brown adipose tissues from mice fed HFD decreased in miR-148a expression compared with animals fed SD (Fig. S7D). [score:2]
As mentioned above, whether miR-148a acted as an additional adipogenic regulator in hMSCs-ad or differentiation factor should be elucidated. [score:2]
By contrast, the level of miR-148a decreased by about 70% upon CREB knockdown (Fig. 7E). [score:2]
Epididymal adipose tissues from mice fed HFD significantly increased in miR-148a expression compared with animals fed SD (Fig. 8A). [score:2]
Following transduction of hMSCs-Ad with a lentivirus expressing CREB, the level of miR-148a increased 2.6-fold compared with control cells (Fig. 7D). [score:2]
These findings suggested that miR-148a may function differently in brown fat tissues to influence the occurrence and development of mouse obesity. [score:2]
Thus, these data in both mouse mo del and human subjects suggested a correlation between miR-148a and development of obesity. [score:2]
miR-148a regulates adipogenesis in hMSC-Ad via Wnt. [score:2]
These findings suggest that miR-148a is an upstream regulator rather than an effector of adipogenesis. [score:2]
Considering these results suggested miR-148a as a positive regulator of adipogenesis, possible mechanisms were explored by reporter gene analysis. [score:2]
miR-148a regulates adipogenesis in hMSCs-Ad via Wnt. [score:2]
miR-148a and miR-26b were highly expressed in differentiated hMSCs-Ad by over fivefold compared with undifferentiated hMSCs-Ad. [score:2]
Thus, our findings provide a basis for the role of miR-148a in adipogenesis, which may underlie the development of obesity and associated metabolic disorders. [score:2]
Four sets of primers were designed to target different regions of the pri-miR-148a promoter (Supplementary Table 3). [score:2]
The miR-148a -binding sites in the reporter vector were mutated using the Quick Change Site-Directed Mutagenesis Kit (Agilent Technologies Inc. [score:2]
The expression of miR-148a was decreased by about 60% at Day 0 compared with the control (Fig. 3A). [score:2]
The upstream region of miR-148a was examined using the UCSC genome browser (http://genome. [score:1]
By contrast, TGF-β (Fig. S3B) and BMP signaling (Fig. S3C) were unchanged by miR-148a. [score:1]
Analysis revealed potential miR-148a binding sites in the 3′-UTRs of Wnt1, Wnt10b, E2F3, and DNMT1, as well as in the coding sequence of DNMT3B (Fig. 4A). [score:1]
The effects of miR-148a (miRNA sponge) loss on adipogenesis were also determined. [score:1]
Importantly, miR-148a as a biomarker of obesity was elevated in adipose tissues of obese mice, as well as in human subjects. [score:1]
Identification of miR-148a promoter. [score:1]
Knockdown of miR-148a also significantly influenced adipogenesis compared with the control. [score:1]
To assess the utility of miR-148a as a biomarker in the development of obesity, miR-148a expression was measured in adipose tissues from obese eight-week-old C57BL/6J mice fed high-fat diet (HFD) and compared with age-matched controls fed standard diet (SD). [score:1]
In summary, our data provide the first evidence of miR-148a as a CREB- dependent and adipogenic-specific miRNA in hMSCs-Ad, which mediates this effect through modulation of Wnt signaling. [score:1]
Our results showed that miR-148a cannot bind to the 3′-UTRs of E2F and DNMT1/3B. [score:1]
miR-148a represses Wnt signaling. [score:1]
To further examine the interaction of CREB and E2F with the miR-148a promoter region in vivo, ChIP analysis was performed in hMSCs-Ad (Fig. 7C). [score:1]
The miR-148a minigenes, including the upstream and downstream sequences of the pre-miRNA and open reading frame of CREB and Wnt1, were amplified by PCR and ligated into the BamHI and EcoRI sites of pGLV3-H1-GFP-puro. [score:1]
The UCSC browser identified a putative promoter region in the miR-148a locus at Chr7p15.2: 25,986,556–25,989,530 (Fig. 6A). [score:1]
Promoter analysis of the miR-148a locus indicated it as an intergenic miRNA with putative CREB binding sites in the core promoter region. [score:1]
Changes in miR-148a, miR-26b, miR-30, and miR-199a-3p were confirmed by qRT-PCR (Fig. 1B), and these findings closely mirrored the array data. [score:1]
After 24 h, the cells were transfected with 100 ng of pGLV3-H1-GFP-puro-miR-148a or control vector and 100 ng of the reporter genes PPRE × 3-TK (Addgene, Cambridge, MA) 23, Super 8x TOPFlash/Super 8x FOPFlash (Super 8x TOPFlash mutant) (Addgene, Cambridge, MA) 26, SBE4 (Addgene, Cambridge, MA) 27, and TLX-2 (Addgene, Cambridge, MA) 28, as well as 2.5 ng of Renilla luciferase vector (pRL-TK), using Lipofectamine 2000 in accordance with the manufacturer’s instructions. [score:1]
EMSA and ChIP analyses demonstrated that CREB bound to the miR-148a promoter in hMSCs-Ad, suggesting interplay between CREB and the pri-miR-148a proximal promoter. [score:1]
com/scientificreports How to cite this article: Shi, C. et al. miR-148a is associated with obesity and modulates adipocyte differentiation of mesenchymal stem cells through Wnt signaling. [score:1]
Our results showed that TLX-2 luciferase activity was unchanged by miR-148a. [score:1]
In comparison, sequences −2146 to −1984 (CREB), −1734 to −1566 (CEBP), and −1566 to −800 (E2F) did not bind to the miR-148a promoter region (Fig. S6). [score:1]
The predicted pre-miR-148a promoter region of 2,974 bp was cloned into the pTB-Cherry vector to generate plasmids pTB-miR-148a1-Cherry (−1752 to −1) and pTB-miR-148a2-Cherry (−2974 to −1752), and the activity was detected by fluorescence microscopy upon transfection of HEK293 cells (Fig. 6B). [score:1]
A recent study demonstrated that miR-148a silencing resulted in Wnt10b -mediated stimulation of tumor cell motility in cancer -associated fibroblasts 36 37. [score:1]
CREB bound to the promoter region of miR-148a in hMSCs-Ad (lane 5). [score:1]
Luciferase activity of HEK293 cells cotransfected with reporter vector containing either wild-type (B) or mutant Wnt1 3′-UTR and miR-148a or control (C). [score:1]
After 24 h, the cells were transfected with 50 ng of pSi-CHECK-2 and 100 ng of pGLV3-H1-GFP-puro-miR-148a or the control virus using 0.3 μl of Lipofectamine 2000 (Invitrogen, Life Technologies Corporation, Carlsbad, CA). [score:1]
Among these miRNAs, miR-148a exhibited the most effects on increasing PPRE luciferase activity. [score:1]
Our data also showed a 10-fold increase in miR-148a in differentiated 3T3-L1 preadipocytes in accordance with the study of Xie et al. 16, which supported our thesis that miR-148a may play a key role in adipogenesis. [score:1]
The levels of miR-148a, miR-26b, miR-30, and miR-199a were increased in differentiating hMSCs-Ad. [score:1]
Thus, the role of miR-148a in obesity was clarified in the present study. [score:1]
CREB is bound to miR-148a promoter in hMSC-Ad. [score:1]
Reporter activity of E2F3, DNMT1, and DNMT3B was unaffected by miR-148a (Fig. 4B). [score:1]
The minimum match is the conservation reached in at least 80% of sites, and the minimum match number of sites is 5. The predicted promoter regions, namely, pTB-miR-148a1-Cherry (−1 to −1752) and pTB-miR-148a2-Cherry (−1752 to −2974) of miR-148a (chr7p15.2: 25,986,556–25,989,530, 2974 bp), were cloned into pTB-Cherry constructed from pTA-Luc (Clontech, Mountain View, CA) and pTB-Cherry 53 using the NsiI and XhoI restriction sites. [score:1]
To determine the adipogenesis-related transcription factors associated with the miR-148a promoter region, putative response elements were identified using TFSEARCH (http://mbs. [score:1]
Thus, miR-148a may play a critical role in adipocyte differentiation and be identified as the robust candidate miRNA for further research. [score:1]
To verify miR-148a binding, the 3′-UTRs of Wnt1, Wnt10b, E2F3, and DNMT1 and the DNMT3B cDNA were cloned into pSi-Check2, then cotransfected with miR-148a or control vector into HEK293 cells. [score:1]
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[+] score: 233
Other miRNAs from this paper: mmu-mir-148b
Indeed, enforced miR-148 expression inhibited the activity of these targets 3′UTR reporter vector in dual luciferase reporter assays, while mutation in miR-148a binding sites abrogated this repression; Suppression of miR-148a-3p and 5p using their respective sponge or inhibitor enhanced the activity of Pgc1 α, Sirt7 and HMGCR, YBX1 3′-UTR reporter vector in the same assays,respectively, while mutation in miR-148a-3p/5p -binding sites abrogated this upregulation (Figure 5c). [score:14]
This is likely mediated by the ability of miR-148a to directly and indirectly inhibit the expression of multiple, functionally related genes, which encode key factors that promote HCC progression such as c-Myc, Dnmt1, Wnt1, Ybx1, Sirt7 and Pgc1 α. Restoration of miR-148a expression is sufficient to inhibit DEN -induced hepatocarcinogenesis in mice. [score:11]
To determine whether these targets represent direct targets of miR-148a-3p/5p, luciferase reporter assays were conducted to examine whether the putative miR-148a -binding sites in the 3′UTR of these targets were important for miR-148a -mediated suppression. [score:9]
Because FHCC98 and HepG2 HCC cell lines show high and low levels of miR-148a-3p expression, respectively, FHCC98 cells stably expressing forced miR-148a-3p sponge and HepG2 cells stably expressing Pri-miR-148a were established. [score:7]
The expression of genes involved in lipogenesis and fatty acid uptake [24] were also significantly upregulated in miR-148a KO mice (Figure 3c and d). [score:6]
13, 14, 15, 16, 17, 18, 19, 20 In cultured HCC cells and mouse xenograft mo dels, miR-148a suppressed growth, epithelial-to-mesenchymal transition, invasion and metastasis through inhibition of different oncoprotein signaling pathways. [score:5]
As shown in Supplementary Figure 2d–f, miR-148a-3p inhibition in FHCC98 cells increased lung colonization whereas Pri-miR-148a overexpression in HepG2 cells significantly decreased lung colonization incidence. [score:5]
In accordance with the above results, miR-148a-3p/5p expression in HCCs was significantly lower than that in normal hepatic tissues (Figure 1e) and the significant association between decreased miR-148a-3p/5p expression and advanced tumor stage was also validated (Figure 1f). [score:5]
Inhibition and overexpression of miR-148a-3p were confirmed by (Supplementary Figure 2a). [score:5]
These data further identify miR-148a as a potential therapeutic target for certain liver diseases, including cancer. [score:5]
To identify potential targets of miR-148a-3p/5p, database prediction combined with biological function analyses were performed on candidate target genes involved in lipid metabolism and hepatocarcinogenesis. [score:5]
These results suggested that the mRNAs of these targets are directly regulated by miR-148a-3p/5p via seeding-matching sequences. [score:5]
In HCC patients, those with low expression of miR-148a3p/5p had significantly worse survival than those with high miR-148a-3p/5p expression (Figure 1g). [score:5]
miR-148a downregulation predicts poor HCC patient clinical outcomes. [score:4]
Taken together, these data indicated that miR-148a-3p/5p directly targets these molecules. [score:4]
miR-148a is downregulated in HCCs and is associated with poor prognosis as we and others have shown previously. [score:4]
Recently it has been shown that miR-148a -mimetic treatment in Pten null mice markedly suppressed tumor development and growth rates. [score:4]
miR-148a deletion also resulted in increased expression of several key factors involved in hepatic lipid metabolic transcriptional regulation, including Pgc1 α and Sirt7. [score:4]
These include Hmgcr the rate-limiting enzyme of cholesterol biosynthesis and a direct miR-148a target, and other enzymes downstream of Hmgcr. [score:4]
The results showed that most genes in this pathway were more highly expressed in miR-148a KO animals, including those encoding sterol regulatory element binding transcription factor 2 (Srebf2) and the rate-limiting enzyme, 3-hydroxy-3-methylglutaryl-CoA reductase (Hmgcr; Figure 4c). [score:4]
Many studies including ours have shown that miR-148a performs a tumor suppressor function in human HCCs. [score:3]
Furthermore, decreased miR-148a expression was significantly associated with advanced stage tumors in HCC patients (Figure 1c). [score:3]
These findings suggest that decreased miR-148a-3p/5p expression is involved in the pathogenesis of HCC. [score:3]
21, 31 The targets of miR-148a 3′-UTRs were amplified from cDNAs, inserted into pGL3-basic vector under the control of the HSV-TK promoter. [score:3]
28, 29 To study the effect of miR-148a-3p/5p on endogenous expression of these targets, their mRNA and protein levels in the livers of WT and miR-148a KO mice were measured and found to be elevated in the latter group (Figure 5a and b). [score:3]
To study the clinical significance of miR-148a expression in HCC, Pri/Pre-miR-148a and miR-148a-3p expression levels were measured in total RNA derived from normal hepatocytes HL7702, four HCC cell lines, 78 HCCs and paired normal hepatic tissues using. [score:3]
28, 29To study the effect of miR-148a-3p/5p on endogenous expression of these targets, their mRNA and protein levels in the livers of WT and miR-148a KO mice were measured and found to be elevated in the latter group (Figure 5a and b). [score:3]
We investigated whether miR-148a inhibits HCC progression as suggested by its patterns of expression in human HCC patients with different survival statistics. [score:3]
miR-148a targets Hmgcr, Pgc1 α, Sirt7 and Ybx1. [score:3]
[22] The cutoff values for high and low miR-148a-3p and 5p expression groups were 88639 and 97.73 per million in TCGA data set, respectively. [score:3]
miR-148a inhibits tumor growth and lung colonization. [score:3]
20, 21 The miR-148a locus encodes two miRNAs, miR-148a-3p/5p, which are members of a family of evolutionarily conserved miRNAs that are highly expressed in most mouse tissues, including liver (Figure 1a and Supplementary Figure 1a). [score:3]
First, miR-148a deficiency promoted DEN -induced hepatocarcinogenesis through multiple complex mechanisms in mice and the re -expression of miR-148a via lentivirus infection reversed this tumor susceptibility. [score:3]
As shown in Supplementary Figure 2b and c, the tumors formed by miR-148a-3p sponge -expressing FHCC98 cells were bigger than those formed by control FHCC98 cells. [score:3]
miR-148a-5p inhibitor was purchased from RiboBio Co. [score:3]
In our previous studies, miR-148a significantly inhibited HCC cell growth. [score:3]
HCC patients were assigned to two groups based upon their miR-148a-3p/5p expression levels using the minimum P-value approach, which is a comprehensive method to identify the optimal risk separation cutoff point in continuous gene expression measurements for survival analysis. [score:3]
miR-148a targets Hmgcr, Pgc1 α, Sirt7 and Ybx1As described above, miR-148a deletion enhances lipid metabolism and hepatocarcinogenesis. [score:3]
34, 35 MiR-148a expression data were assessed and Kaplan–Meier curves were analyzed in human HCC tissues from the TCGA miR-seq data set (n=355). [score:3]
These results suggest that miR-148a inhibited both tumor growth and lung colonization. [score:3]
As shown in Figure 5d and e, the above target RNAs were significantly enriched in WT liver extracts versus those from miR-148a KO mice. [score:3]
Also Pri/Pre-miR-148a and miR-148a-3p were significantly downregulated in HCC samples compared with paired normal hepatic tissues (Figure 1b). [score:3]
HCC samples were assigned to two groups based on miR-148a-3p/5p expression level using the minimum P-value approach. [score:3]
org/) were used to predict miR-148a targets. [score:3]
In contrast, tumors formed by Pri-miR-148a expressing HepG2 cells were significantly smaller than the tumors formed by control HepG2 cells. [score:3]
To further study the clinical significance of miR-148a expression, the survival rates in TCGA data set of HCC were assessed. [score:3]
Histologically poorly differentiated HCC also showed a significant association with decreased miR-148a-3p expression relative to well differentiated tumors (Figure 1d). [score:3]
13, 14, 15, 16, 17, 18, 19, 20 In the current study, miR-148a exerted an intrinsic tumor suppressor effect as shown by several pieces of evidence. [score:3]
Pparg co-activator 1 alpha (Pgc1 α), sirtuin 7 (Sirt7) and Hmgcr, Y-box binding protein 1 (Ybx1) which are involved in the processes of lipid metabolism and hepatocarcinogenesis were all identified as potential targets of miR-148-3p and 5p, respectively. [score:3]
Moreover, restoring Pri-miR-148a expression reduced the size of tumor nodules and also tumor growth rates (Figure 2b–e) in miR-148a KO liver. [score:3]
The experiments showed that Pri/Pre-miR-148a and miR-148a-3p expression were both significantly lower in HepG2, BEL-7402 and Huh7 compared with HL7702 and FHCC98 (Supplementary Figure 1b). [score:2]
Mutations in the miR-148a seed-matching sequences were generated by overlap extension PCR. [score:2]
Wild type (WT) and miR-148a knockout (KO) male mice were treated with DEN at postnatal day 15 on either RCD or HFD (Figure 2a). [score:2]
As described above, miR-148a deletion enhances lipid metabolism and hepatocarcinogenesis. [score:1]
miR-148a-3p sponge vector containing ten repeats of anti-sense miR-148a-3p was designed following the principles previously described, [30] synthesized by GENEWIZ (Suzhou, China) and then cloned into the lentiviral vector pHAGE-CMV-GFP. [score:1]
miR-148a deletion promotes DEN -induced hepatocarcinogenesis in mice. [score:1]
For DEN -induced mouse HCC, 15 day old WT or miR-148a KO mice were intraperitoneally injected once with 25 mg/kg DEN (Sigmal-Aldrich, St. [score:1]
These findings strongly support that miR-148a deficiency increases cholesterol biosynthesis. [score:1]
miR-148a deficiency enhances hepatic steatosis. [score:1]
As hepatic and serum TC levels were increased without a significant change in TG levels in miR-148a KO mice, the increase of TC levels could be the result of increased TC biosynthesis in miR-148a KO mice. [score:1]
Conventional miR-148a KO mice were ordered from Mo del Animal Research Center of Nanjing University (Nanjing, China). [score:1]
[19] Therefore, miR-148a may represent a promising candidate for miRNA replacement therapy in HCC patients. [score:1]
Human Pri-miR-148a, ~400 bp stem-loop structures, was amplified from genomic DNA and inserted into the lentiviral vector pHAGE-CMV-GFP. [score:1]
Then miR-148a KO mice were randomly divided into two groups. [score:1]
These findings suggested that miR-148a deletion promotes hepatic tumor progression in mice. [score:1]
Similarly, DEN -treated miR-148a KO mice also exhibited significantly elevated serum and hepatic TC without significantly changing TG levels on either RCD or HFD (Figure 2a and Figure 4a and b, Supplementary Table 2). [score:1]
Our study also revealed that genetic deletion of miR-148a results in hepatic lipid accumulation and increased serum and liver TC levels. [score:1]
Therefore, miR-148a KO mice have abnormal hepatic lipid metabolism. [score:1]
2, 23 In summary, we show that miR-148a deletion exerts crucial roles on lipid metabolism and hepatocarcinogenesis. [score:1]
Strikingly, the number of tumor nodules per liver were significantly higher in miR-148a KO mice than in WT mice (Figure 2b–d) and tumor sizes were bigger (Figure 2e) irrespective of the animals’ diet. [score:1]
2, 23 Given that miR-148a deficiency also enhances hepatocarcinogenesis, hepatic steatosis in these animals was assessed by quantification of hepatic neutral lipid by ORO staining in hepatic tissues. [score:1]
One group was treated with concentrated pHAGE-Pri-miR-148a lentivirus and the other group was treated with concentrated pHAGE-GFP lentivirus (Figure 2a). [score:1]
As shown in Figure 3a and b, miR-148a KO mice exhibited significantly increased hepatic steatosis as indicated by lipid accumulation. [score:1]
Regardless of the diet, miR-148a deletion led to significant increases in serum and hepatic total cholesterol (TC) without significantly altering triglyceride (TG) levels (Figure 4a and b, Supplementary Table 2). [score:1]
To determine the effect of miR-148a deletion on hepatocarcinogenesis, a was used. [score:1]
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[+] score: 159
When both binding sites were functional miR-148 downregulated reporter gene expression to 50–60% compared to expression from the vector alone in 501mel cells (p = 0.0140) (Fig. 3A). [score:7]
P-values are: miR-148a expression in 501mel  = 0.0940 and in MeWo  = 0.0148. miR-148b expression in 501mel  = 0.0023 and in MeWo  = 0.0065. miR-152 expression in 501mel  = 0.0054 and in MeWo =  0.9316. [score:7]
However, when the 148/152B binding site was mutated, miR-148 was no longer able to downregulate reporter gene expression (p = 0.3929). [score:6]
When the 148/152A binding site was mutated, miR-148 downregulated reporter gene expression to 47% (p = 0.0049). [score:6]
These results indicate that miR-148 is able to downregulate Mitf expression by binding to the 148/152B binding site. [score:6]
Higher endogenous expression in HEK293 cells might explain why transfected miR-148 had no effect on reporter gene expression in HEK293 cells, except at the highest concentration. [score:5]
miR-148 and affect expression of the endogenous MITF In order to test if these miRNAs affect the level of endogenous MITF mRNA in melanoma cells, we used qRT-PCR to determine MITF mRNA expression after transfecting MeWo melanoma cells with the miRNAs miR-124, and miR-148. [score:5]
Of these potential target genes, 66 are common targets of both and miR-148. [score:5]
The microRNAs and miR-148 have many other potential target genes according to online prediction programs (Targetscan). [score:5]
Expression of miR-152 in 501mel was 2.7 fold lower than in HEK293 cells and was much lower then the expression of miR-148a and miR-148b in all cell types (see Table 2). [score:5]
Low expression of miR-148a, 148b and 152 in the melanoma cell lines is therefore consistent with the relatively high level of MITF expression in these cells. [score:5]
Simultaneous transfection with and miR-148 did not result in further effects on MITF expression as it reduced expression to 67% (Cp value 22.3, p = 0.0051), which is similar to the reduction seen with alone (Fig. 4A). [score:5]
miR-148 expression has been shown to be downregulated in tissue samples from undifferentiated gastric cancer compared to normal tissue [49]. [score:5]
The microRNAs miR-148a and miR-148b have similar expression levels in all the cell types tested. [score:3]
Similarly, the effects of and miR-148 on endogenous MITF mRNAs are inhibited when MeWo cells were co -transfected with anti-miRNAs (Fig. 5B). [score:3]
miR-148 affected reporter gene expression more significantly in 501mel cells. [score:3]
miR-148 has 536 conserved targets, with a total of 581 conserved sites and 134 poorly conserved sites. [score:3]
0011574.g006 Figure 6. Expression of endogenous miRNAs miR-148a, miR-148b and miR-152 in HEK293, 501mel and MeWo cells. [score:3]
The mutations are shown in Fig. 1C and the primers used for mutagenesis in Table 1. There are two target sites for miR-148/152 in the mouse Mitf 3′UTR sequence. [score:3]
miR-148 and affect expression of the endogenous MITF. [score:3]
There are two target sites for miR-148/152 in the mouse Mitf 3′UTR sequence. [score:3]
Consistent with previous results, cells simultaneously transfected with the luciferase vector construct, the miR-148 and the anti-miR-148 showed that the anti-miR148 molecule effectively inhibited the effects of miR-148 (Fig. 5A). [score:3]
In 501mel cells, miR-148 had significant effects on expression of the mouseMitf-3′UTR-luciferase reporter (Fig. 2A). [score:3]
The mutations are shown in Fig. 1C and the primers used for mutagenesis in Table 1. There are two target sites for miR-148/152 in the mouse Mitf 3′UTR sequence. [score:3]
Role of the miR-148/152 target sites. [score:3]
This indicates a possible negative feedback loop where higher amounts of MITF would lead to more miR-148 expression which in turn adjusts MITF protein at desirable levels. [score:3]
Expression of endogenous miRNAs miR-148a, miR-148b and miR-152 in HEK293, 501mel and MeWo cells. [score:3]
In order to test if these miRNAs affect the level of endogenous MITF mRNA in melanoma cells, we used qRT-PCR to determine MITF mRNA expression after transfecting MeWo melanoma cells with the miRNAs miR-124, and miR-148. [score:3]
It has not been shown previously that miR-148 and/or miR-152 can target Mitf. [score:3]
of anti-miR-148 and miR-148 simultaneously with the Mitf-3′UTR-luciferase vector inhibits the effect of miR-148. [score:3]
A. of anti-miR-148 and miR-148 simultaneously with the Mitf-3′UTR-luciferase vector inhibits the effect of miR-148. [score:3]
A. Expression of human MITF mRNA in MeWo cells transfected with miR-124,, miR-148 or and miR-148 combined. [score:3]
The effects of and miR-148 when transfected seperatly, are blocked when the cells are transfected with and miR-148 inhibitors. [score:3]
These results show that the and miR-148 have the same effects on expression of the endogenous MITF gene as seen using the luciferase reporter assay. [score:2]
In melanoma cells, Mitf is regulated by and miR-148/152. [score:2]
We show that and miR-148 negatively affect Mitf mRNA in melanoma cells through conserved binding sites in the 3′UTR sequence. [score:1]
Combining both and miR-148 did not result in added effects on endogenous MITF mRNA levels. [score:1]
anti-microRNA where purchased from Ambion and are the following: anti-miR-137 (Product ID: AM10513) and anti-miR-148 (Product ID: AM10263). [score:1]
A. The line indicates the 3′ UTR region of the mouse Mitf gene, including the coding region of exon 9. Potential binding sites for miR-27, miR-124/506, miR-25/32/92/363/367, miR-148/152, and miR-101/144 in the mMitf 3′UTR sequence are indicated below the line and potential PAS sites above. [score:1]
Black bars: miR-124/506 binding sites, dark grey bars: binding sites, light grey bars: miR-148/152 binding sites, white bars: miR-27, miR-25/32/92/363/367 and miR-101/144. [score:1]
In the case of one of the miR-148 binding site, 148/152A, only 4 bases were mutated as a clone with the fully mutated binding site was not generated successfully. [score:1]
miR-148/152 affects mMitf RNA in melanoma cells. [score:1]
We tested the effects of microRNAs which have conserved binding sites in the 3′UTR region of Mitf, including miR-27a (located at 229–235 in the mouse Mitf 3′UTR sequence), miR-25/32/92/363/367 (1491–1497), miR-101/144 (3023–3029), miR-124/506 (1639–1646) and miR-148/152 (1674–1680 and 2931–2937) (Fig. 1A and 1B). [score:1]
When the 148/152B binding sites were mutated, the effects of miR-148 were eliminated. [score:1]
The roles of and miR-148 were analysed further by mutating the binding sites in the mouseMitf-3′UTR-luciferase reporter construct. [score:1]
A. Effects of miR-148 on the mouseMitf-3′UTR-luciferase reporter when the potential binding sites are mutated. [score:1]
The 3′UTR sequences of Mitf in 11 vertebrate species all contain the two conserved miR-148/152 binding sites. [score:1]
miR-148/152 affects mMitf RNA in melanoma cellsTo test the functionality of the miRNA binding sites, the mouse Mitf 3′UTR sequence was cloned downstream of a luciferase reporter gene. [score:1]
When the cells were transfected with either, miR-148 or simultaneously with both and miR-148, MITF protein levels were reduced. [score:1]
and are the following: hsa-miR-27a (Product ID:PM10939), hsa-miR-32 (Product ID:PM10124), hsa -miR-101 (Product ID:PM10537), mmu-miR-124a (Product ID:PM10691), mmu-miR-137 (Product ID: PM10513), hsa-miR-148a (Product ID:PM10263), hsa-miR-182. [score:1]
B. analysis on MITF protein levels in MeWo cells, when transfected with miR-124,, miR-148 or and miR-148 combined. [score:1]
Similarly, hypermethylation of the miR-148, 124a3 and miR-152 genes was found in 34-86% of primary human breast cancer specimens [50]. [score:1]
miR-148 affected the reporter only when transfected at the highest concentration (1pmol) (Fig. 2B). [score:1]
ND (1/9) ND (0/9) 34.69 (7/9) 37.39 (1/3) miR-124 34.37 (9/9) 34.73 (5/9) 35.09 (2/9) 32.68 (3/3) miR-506 35.19 (2/9) 34.73 (3/9) 32.87 (9/9) ND (0/9) miR-148a 27.90 (9/9) 28.29 (9/9) 28.82 (9/9) 33.12 (3/3) miR-148b 28.37 (9/9) 28.65 (9/9) 29.37 (9/9) 35.19 (1/3) miR-152 34.08 (9/9) 35.12 (9/9) 34.26 (9/9) 35.05 (2/3) miR-16 contr. [score:1]
and miR-148 both led to reduced levels of MITF mRNA and protein. [score:1]
miR-148 and miR-152. [score:1]
P-values are: Scramble  = 0.0396; miR-124 = 0.2228; = 0.0069; miR-148 = 0.0051;+148 = 0.0051. [score:1]
The p-values are; miR-neg  = 0.14 miR-148 = 0.007, miR-148+anti-miR-148 = 0.119. [score:1]
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[+] score: 126
It is worth to note that the observed liver detargeting effects will not only account from miR-148a binding to the inserted target sites but also from the recognition by all the miR-148/152 family members, since miR148a, miR-148b and miR-152 can recognize miR-148a target sites and downregulate transgenes with engineered target sites [8]. [score:12]
No downregulation of fiber expression was observed in RWP-1 and PANC-1 pancreatic cancer cells that do not express miR-148a (Fig. 1C, Supplementary Table S1). [score:8]
To further evaluate the detargeting effects of miR-148a-regulated viruses, we analyzed the mRNA content of the early gene E1A, the L3 (hexon) and L5 (fiber) gene expression in liver and pancreas, two organs in which miR-148a is expressed, and in kidney where there is no expression (Supplementary Table S2). [score:8]
Analysis of the E1A gene expression revealed a downregulation in E1A levels in miR-148a expressing cells at 72h after infection but not at 24h (Fig. 1B). [score:8]
Fiber expression is directly or indirectly regulated, in miR-148a positive tissues, following Ad-L5-8miR148aT or Ad-E1A-8miR148aT systemic delivery. [score:6]
We observed a robust suppression of the fiber protein (L5 protein product) in cells expressing miR-148a infected with Ad-L5-8miR148aT. [score:5]
In this study we have focused on miR-148a, however L5-miRNA targeting could be applied to other miRNAs, such as miR-122, let-7 or miR-199, which have also shown great success in excluding gene expression from the hepatocytes in E1A-miRNA adenoviruses [5, 7, 19- 21]. [score:5]
We have recently shown that the inclusion of 8 target sites downstream E1A recognizing miR-148a/miR-152 family members efficiently detargeted adenovirus from mouse liver and normal pancreas while maintained its antitumoral activity in pancreatic tumors [8]. [score:5]
Here, we generated a miR-148a targeted adenovirus regulating the L5 gene by insertion of 8 copies of perfect complementarity for miR-148a downstream the stop codon generating a new regulatory 3′UTR and designated as Ad-L5-8miR148aT (Fig. 1A). [score:5]
miR-148a regulates fiber expression from cells infected with Ad-L5-8miR148aT. [score:4]
An interesting feature of the current approach is the feasibility to achieve independent control of late genes, as shown by the strong downregulation of the fiber mRNA (L5) but not of the hexon mRNA (L3) after Ad-L5-8miR148aT infection of miR-148a positive tissues. [score:4]
The downregulation of miR-148a initiates in early stages of pancreatic tumorigenesis, in the preneoplasic lesions PanIN-1B, -2 and -3 [23, 24]. [score:4]
However, an interesting aspect of using miR-148a is that it has been proposed as one of the three miRNAs (together with miR-217 and miR-375) which downregulation is a signature of PDAC [22]. [score:4]
MiR-148a reduces fiber gene expression and decreases Ad-L5-8miR148aT viral production. [score:3]
RT-qPCR expression of miR-148a from non-tumor human pancreas (n=11) and from RWP-1 xenograft (n=4) and CP13 (n=4), CP15 (n=4) PDX. [score:3]
Furthermore, adenoviral replication of Ad-L5miR148aT is strongly impaired both, in vitro and in vivo, in miR-148a expressing cells and tissues, but it retained full efficacy against pancreatic xenografts. [score:3]
However, a significant reduction in fiber content was detected in MIA PaCa-2 miR-148a that received Ad-L5-8miR148aT, suggesting a miR-148a control of fiber expression. [score:3]
Next, we analyzed the antitumor efficacy of Ad-L5-8miR148aT in three tumor mo dels with loss of miR-148a expression: xenografts from RWP-1 cells and PDXs from patients CP13 and CP15 (Fig. 5C). [score:3]
MIA PaCa-2 cells stably expressing miR-148a (MIA PaCa-2 miR-148a), or a seed-scrambled miR-148a sequence (MIA PaCa-2 miR-SC) (Supplementary Table S1) were transduced with Ad-wt or Ad-L5-8miR148aT; and the L5 protein product fiber was analyzed by western blot 72 hours later. [score:3]
Our data shows that miR-148a attenuates the expression of the fiber protein in cells or tissues infected with the Ad-L5-8miR148aT engineered virus. [score:3]
In line with high miR-148a expression in the mouse liver, we observed reduced fiber protein and mRNA content in livers of mice receiving Ad-L5-8miR148aT. [score:3]
miR-148a regulates viral release from cells infected with Ad-L5-8miR148aT. [score:2]
Dose–response curves were constructed for MIA PaCa-2 miR-148a, MIA PaCa-2 miR-SC, PANC-1, MIA PaCa-2 and RWP-1. Cells were transduced with doses ranging from 0.001 vp/cell to 10000 vp/cell of Ad-wt, Ad-E1A-8miR148aT or Ad-L5-8miR148aT. [score:1]
Thus, lost of miR-148a in PDAC is a highly frequent and early event. [score:1]
Total cell lysates from MIA PaCa-2 miR-SC/miR-148a and liver homogenates were obtained at 72 hours post-infection and progeny production was assessed by titration in HEK293 cells by hexon immunostaining. [score:1]
When the cytopathic effect was observed, supernatants were harvested and used to infect new wells of MIA PaCa-2 miR-SC/miR-148a cultures. [score:1]
Moreover, we have recently shown that miR-148a prevents from liver and pancreas replication to Ad-E1A-8miR148aT but not to Ad-wt. [score:1]
Therefore this will assure the antitumor activity of miR-148a engineered adenoviruses in PDAC, in line with the strong antitumor effects triggered by Ad-L5-8miR148aT in RWP-1 xenografts and in CP13 and CP15 PDX mo dels. [score:1]
Noticeably, after 7-rounds of infection the amount of viral particles in the supernatants of infected miR-148a positive cells was almost negligible, most probably as a result of accumulative reduction of viral particles in each replication cycle. [score:1]
Nevertheless cytotoxicity was highly impaired in the miR-148a positive cells (MIA PaCa-2 miR-148a), showing miR-148a dependency of the Ad-L5-8miR148aT lytic activity (Fig. 5B). [score:1]
The reduction in E1A at 72h in miR-148a positive cells could be the consequence of decreased viral particles production in Ad-L5-8miR148aT infected cultures. [score:1]
To test this hypothesis, we first analyzed the virus progeny in cellular supernatants of MIA PaCa-2 miR-148a and MIA PaCa-2 miR-SC infected with either Ad-wt or Ad-L5-8miR148aT. [score:1]
We have recently shown that miR-148a can selectively control adenovirus activity when the 3′UTR of the E1A gene was genetically engineered with miRNA binding sites recognizing miR-148a [8]. [score:1]
Reduced viral genomes were only detected in Ad-E1A-8miR148aT treated mice, in miR-148a positive tissues (Fig. 4A). [score:1]
Cytotoxic effects of Ad-wt, Ad-E1A-8miR148aT and Ad-L5-8miR148aT supernatants obtained after 7 consecutives passages of amplification in MIA PaCa-2 miR-148a and MIA PaCa-2 miR-SC cells. [score:1]
In vitro cell survival studies Dose–response curves were constructed for MIA PaCa-2 miR-148a, MIA PaCa-2 miR-SC, PANC-1, MIA PaCa-2 and RWP-1. Cells were transduced with doses ranging from 0.001 vp/cell to 10000 vp/cell of Ad-wt, Ad-E1A-8miR148aT or Ad-L5-8miR148aT. [score:1]
B, C. (Upper panels) Representative Western blots of E1A and Fiber from (B) MIA PaCa-2 miR-148a and MIA PaCa-2 miR-SC or (C) PANC-1 and RWP-1 cells infected with 50 vp/cell of Ad-wt and Ad-L5-8miR148aT for 24 and 72h. [score:1]
Both viral infective particles and viral genomes from MIA PaCa-2 miR-148a cultures infected with Ad-L5-8miR148aT were significantly lower than those treated with Ad-wt whereas no differences between the two viruses were detected in MIA PaCa-2 miR-SC infected cells (Fig. 2A, 2B). [score:1]
Similar reduction in the viral release was observed with the E1A miR-148a controlled adenovirus Ad-E1A-miR148aT (Fig. 2D). [score:1]
With this view, we hypothesized that in the first round of infection the viral genomes within miR-148a rich cells would not be substantially different between Ad-wt and Ad-L5-8miR148aT since the miRNA control takes place at a late structural protein whereas, the assembly and release of viral particles would be highly impaired. [score:1]
The impairment of Ad-L5-8miR148aT to release viral particles in miR-148a cells was maximized when cells were exposed to consecutive rounds of infection (Fig. 2D). [score:1]
MIA PaCa-2 miR-148a and MIA PaCa-2 miR-SC cells were obtained in the laboratory as previously described [8]. [score:1]
The comparative analysis of intracellular and extracellular viral genomes between Ad-wt and Ad-L5-8miR148aT in miR-148a positive or negative cells revealed a reduction of viral particles only in the supernatant of miR-148a positive cells (Fig. 2C). [score:1]
from several passages was assessed in the supernatant of MIA PaCa-2 miR-SC/miR-148a cells infected with Ad-L5-8miR148aT, Ad-E1A-8miR148aT and Ad-wt. [score:1]
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[+] score: 86
Other miRNAs from this paper: mmu-mir-152, mmu-mir-148b
We also showed that alcohol -induced upregulation of both miR-148 and miR-152 play a key role in downregulating their common targets Dnmt1 and Dnmt3b. [score:9]
Taken together, these results suggest that upregulation of both miR-148 and miR-152 plays a causal role in suppressing their common targets, Dnmt1 and Dnmt3b, in mice fed a liquid alcohol diet. [score:8]
miR-148 and miR-152, which target Dnmt1 and Dnmt3b, are upregulated in the livers of the wild type mice fed the liquid alcohol diet. [score:6]
Ethanol feeding caused pronounced decrease in hepatic Dnmtase activity in Dnmt1 [+/+] mice due to decrease in Dnmt1 and Dnmt3b protein levels and upregulation of miR-148 and miR-152 that target both Dnmt1 and Dnmt3b. [score:6]
miR-148 and miR-152 that Target Dnmt1 and Dnmt3b are Upregulated in the Livers of Mice Fed Alcohol Diet. [score:6]
These results suggest that co-ordinate upregulation of miR-148/152 is likely to be involved in down regulation of hepatic Dnmt1/3b in alcohol fed mice. [score:5]
The lack of inhibition of relative luciferase activity in cells transfected with the mutant psiCHECK2-Dnmt1-3′UTR vector lacking the miR-148/152 cognate site validated Dnmt1 as a true target of these two miRs. [score:5]
We focused on miR-148/152 because only these two miRs have a common site on Dnmt1 3′-UTR, which is conserved in mammals, and miR-148 and miR-152 have been previously shown to target Dnmt1 by interacting through its 3′-UTR [41], [42], whereas miR-148 targets Dnmt3b by binding to its cognate site in the coding region [36]. [score:5]
C. qRT-PCR analysis confirmed upregulation of hepatic miR-148&152 in mice fed alcohol. [score:4]
F. Endogenous DNMT1 and DNMT3b protein levels were reduced in cells expressing ectopic miR-148/152. [score:3]
Similar results were obtained after ectopic expression of miR-148a (data not shown). [score:3]
Interestingly, miR-148 has been shown to target Dnmt3b by complementary base pairing with two conserved sites located in its coding region [36]. [score:3]
B. Northern blot analysis demonstrated increased expression of miR-148 in mice fed alcohol. [score:3]
0041949.g002 Figure 2 A. miR-148/152 cognate site predicted by TargetScan in the 3′-UTR of Dnmt1. [score:3]
E. Upregulation of miR-148/152 in Hepa cells transfected with the respective miRs compared to the controls (NC RNA transfected cells). [score:3]
D. Dnmt1 is a validated target of miR-148&152. [score:3]
A. miR-148/152 cognate site predicted by TargetScan in the 3′-UTR of Dnmt1. [score:3]
qRT-PCR analysis confirmed 40% increase in miR-148 level whereas miR-152 expression (not detectable by Northern blotting) increased by 85% in the livers from mice fed the liquid alcohol diet compared to controls (Figure 2C ). [score:2]
We then investigated whether Dnmt1 is a target of miR-148 and/or miR-152. [score:1]
Next, we examined whether endogenous Dnmt1 and Dnmt3b protein level could be modulated by miR-148 and miR-152 by transfecting these miRs or respective NC RNAs into H293T cells. [score:1]
Total RNA (5 µg) was separated in 15% acrylamide-8 M urea gel, transferred to nylon membrane and subjected to Northern blotting using [32]P-labeted anti-miR-148 oligo as probe, washed and subjected to autoradiography. [score:1]
H293T cells obtained from ATCC, were transfected with 50 nM miR-148/152 mimic or NCRNA were harvested after 48 h and 72 h, harvested, and whole cell extracts prepared in cell lysis buffer were subjected to imunoblotting with Dnmt1,3a,3b and Gapdh antibodies. [score:1]
org/mmu_50/) [35] search revealed that 3′-UTR of Dnmt1 harbors only one conserved site for miR-148 and miR-152 (Figure 2A ). [score:1]
Briefly, growing Hepa (hepatoma) cells (1×10 [5] cells/well), obtained from ATCC, were plated in 24-well plates the day before and transfected with 100 ng of psiCKECK2 harboring Dnmt1 3′-UTR, together with 50 nM miR-148a (Sigma) or miR-148b (Invitrogen), miR-152 (Invitrogen) mimics or respective negative control RNAs (NCRNAs) (Sigma/Invitrogen). [score:1]
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[+] score: 46
Other miRNAs from this paper: hsa-let-7a-1, hsa-let-7a-2, hsa-let-7a-3, hsa-let-7b, hsa-let-7c, hsa-let-7d, hsa-let-7e, hsa-let-7f-1, hsa-let-7f-2, hsa-mir-22, hsa-mir-29a, hsa-mir-30a, hsa-mir-29b-1, hsa-mir-29b-2, mmu-let-7g, mmu-let-7i, mmu-mir-1a-1, mmu-mir-29b-1, mmu-mir-30a, mmu-mir-127, mmu-mir-132, mmu-mir-133a-1, mmu-mir-136, mmu-mir-144, mmu-mir-146a, mmu-mir-152, mmu-mir-155, mmu-mir-10b, mmu-mir-185, mmu-mir-190a, mmu-mir-193a, mmu-mir-203, mmu-mir-206, hsa-mir-148a, mmu-mir-143, hsa-mir-10b, hsa-mir-34a, hsa-mir-203a, hsa-mir-215, mmu-mir-34c, mmu-mir-34b, mmu-let-7d, hsa-let-7g, hsa-let-7i, hsa-mir-1-2, hsa-mir-132, hsa-mir-133a-1, hsa-mir-133a-2, hsa-mir-143, hsa-mir-144, hsa-mir-152, hsa-mir-127, hsa-mir-136, hsa-mir-146a, hsa-mir-185, hsa-mir-190a, hsa-mir-193a, hsa-mir-206, mmu-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-22, mmu-mir-29a, mmu-mir-29c, mmu-mir-34a, mmu-mir-337, hsa-mir-1-1, mmu-mir-1a-2, hsa-mir-155, mmu-mir-29b-2, hsa-mir-29c, hsa-mir-34b, hsa-mir-34c, hsa-mir-378a, mmu-mir-378a, hsa-mir-337, mmu-mir-133a-2, mmu-mir-133b, hsa-mir-133b, mmu-mir-215, mmu-mir-411, mmu-mir-434, hsa-mir-486-1, hsa-mir-146b, hsa-mir-193b, mmu-mir-486a, mmu-mir-540, hsa-mir-92b, hsa-mir-411, hsa-mir-378d-2, mmu-mir-146b, mmu-mir-193b, mmu-mir-92b, mmu-mir-872, mmu-mir-1b, mmu-mir-3071, mmu-mir-486b, hsa-mir-378b, hsa-mir-378c, hsa-mir-378d-1, hsa-mir-378e, hsa-mir-378f, hsa-mir-378g, hsa-mir-378h, hsa-mir-378i, mmu-mir-378b, hsa-mir-203b, mmu-mir-3544, hsa-mir-378j, mmu-mir-133c, mmu-let-7j, mmu-mir-378c, mmu-mir-378d, mmu-let-7k, hsa-mir-486-2
Down-regulated miRNAs Up-regulated target genes mmu-mir-148a ARL6IP1, ARPP19, ATP2A2, CCNA2, CSF1, EGR2, ERLIN1, ERRFI1, FIGF, GADD45A, GMFB, ITGA5, KLF4, KLF6, LIMD2, MAFB, NFYA, PDIA3, PHIP, PPP1R10, PPP1R12A, PTPN14, RAI14, RSBN1L, SERPINE1, SIK1, SLC2A1, TMEM127, TMSB10, TMSB4X mmu-mir-411 APOLD1, SPRY4 mmu-mir-136 RYBP, ARL10, GLIPR2, UGGT1 Up-regulated miRNAs Down-regulated target genes mmu-mir-34a/c DAB2IP, DMWD, EVI5L, FAM107A, MAZ, SPEG, TFRC, TTC19 mmu-mir-92b COL1A2, DAB2IP, G3BP2, HOXC11, LBX1, NFIX, PKDCC, PRKAB2 mmu-mir-132 ACTR3B, AMD1, GPD2, HBEGF, KBTBD13, KCNJ12, PRRT2, SREBF1, TLN2 mmu-mir-146a IRAK1, TLN2 mmu-mir-152 EML2, GPCPD1, NFIX, RPH3AL, SH3KBP1, TFRC, TRAK1, UCP3 mmu-mir-155 DUSP7, G3BP2 mmu-mir-185 DAB2IP, FAM134C, SYNM, TMEM233 mmu-mir-203 APBB2, CACNG7, FKBP5, GDAP1, HBEGF, KCNC1, SIX5, TMEM182 mmu-mir-206 DMPK, G3BP2, GPD2, KCTD13, MKL1, SLC16A3, SPEG mmu-mir-215 KLHL23 Figure 5The network displays the predicted interactions between age-related miRNAs and mRNAs from the sequencing and was generated using Cytoscape (version 3.0, www. [score:17]
Down-regulated miRNAs Up-regulated target genes mmu-mir-148a ARL6IP1, ARPP19, ATP2A2, CCNA2, CSF1, EGR2, ERLIN1, ERRFI1, FIGF, GADD45A, GMFB, ITGA5, KLF4, KLF6, LIMD2, MAFB, NFYA, PDIA3, PHIP, PPP1R10, PPP1R12A, PTPN14, RAI14, RSBN1L, SERPINE1, SIK1, SLC2A1, TMEM127, TMSB10, TMSB4X mmu-mir-411 APOLD1, SPRY4 mmu-mir-136 RYBP, ARL10, GLIPR2, UGGT1 Up-regulated miRNAs Down-regulated target genes mmu-mir-34a/c DAB2IP, DMWD, EVI5L, FAM107A, MAZ, SPEG, TFRC, TTC19 mmu-mir-92b COL1A2, DAB2IP, G3BP2, HOXC11, LBX1, NFIX, PKDCC, PRKAB2 mmu-mir-132 ACTR3B, AMD1, GPD2, HBEGF, KBTBD13, KCNJ12, PRRT2, SREBF1, TLN2 mmu-mir-146a IRAK1, TLN2 mmu-mir-152 EML2, GPCPD1, NFIX, RPH3AL, SH3KBP1, TFRC, TRAK1, UCP3 mmu-mir-155 DUSP7, G3BP2 mmu-mir-185 DAB2IP, FAM134C, SYNM, TMEM233 mmu-mir-203 APBB2, CACNG7, FKBP5, GDAP1, HBEGF, KCNC1, SIX5, TMEM182 mmu-mir-206 DMPK, G3BP2, GPD2, KCTD13, MKL1, SLC16A3, SPEG mmu-mir-215 KLHL23 Figure 5The network displays the predicted interactions between age-related miRNAs and mRNAs from the sequencing and was generated using Cytoscape (version 3.0, www. [score:17]
Of the down-regulated miRNAs, miR-148a-3p and -127-3p belonged to the 50 most abundant miRNAs in skeletal muscle (Fig. S4, Asterisk). [score:4]
MiR-148a, one of the down-regulated miRNAs, was identified as a myogenic miRNA that promotes myogenic differentiation through the ROCK1 gene. [score:4]
Thus, in accordance with their expression and role in myogenesis, miR-148a and miR-155 might be involved in the aging process through muscle differentiation or regeneration. [score:3]
miRNA Fold Change P-value mmu-miR-337-5p −5.2 0.0149 mmu-miR-3544-3p −5.1 0.0147 mmu-miR-540-5p −4.9 0.0200mmu-miR-337-3p [a] −3.0 0.0324mmu-miR-3544-5p [a] −3.0 0.0308 mmu-miR-434-3p −2.1 0.0001 mmu-miR-3071-5p −2.0 0.0004mmu-miR-136-3p [a] −2.0 0.0004mmu-miR-3071-3p [a] −1.6 0.0000 mmu-miR-136-5p −1.6 0.0000 mmu-miR-143-5p −1.2 0.0004 mmu-miR-190a-5p −1.0 0.0139 mmu-miR-872-3p −0.9 0.0152 mmu-miR-193a-3p −0.9 0.0164 mmu-miR-144-3p −0.8 0.0298 mmu-miR-127-3p −0.7 0. 0002mmu-miR-434-5p [a] −0.6 0.0082 mmu-miR-148a-3p −0.6 0.0130 mmu-miR-411-5p −0.6 0.0091 a miRNA* (passenger) strand processed from opposite arm of the mature miRNA. [score:1]
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[+] score: 43
The finding of increased miR-148a in female mice at 30 wks of age is significant since miR-148a was reported to be highly upregulated in both human and murine lupus T cells, which contributed to DNA hypomethylation and induction of autoimmune -associated genes by targeting DNA methyltransferase 1 (DNMT1) [36]. [score:6]
We initially analyzed the expression of lupus -associated miRNAs including the miR-96-182-183 cluster, miR-155, miR-31, miR-127, miR-379, and miR-148a in splenocytes from male and female NZB/W [F1] mice at 17–18 wks old, an age before the onset of disease in NZB/W [F1] mice. [score:5]
The estrogen -upregulated miRNA miR-148a was increased in CD4 T cells from human lupus patients and positively correlated with lupus activity [49]. [score:4]
miR-148a was the only miRNA that displayed the increased expression in pre-diseased female NZB/W [F1] mice when compared to those in NZW controls [34]. [score:4]
In this study, we observed that short-term estrogen treatment (4 wks) did not increase miR-148a (Figure  4A), which has been shown to be upregulated by estrogen in orchidectomized wild-type B6 mice [42]. [score:4]
miR-148a showed increased expression in female NZB/W [F1] even before the onset of lupus [34]. [score:3]
Our finding of increased miR-182 cluster, miR-155, miR-31, and miR-148a expression in female NZB/W [F1] mice at an age after the onset of lupus validates our previous report of the association of these miRNAs with lupus manifestation in this mo del. [score:3]
However, our data tends to support that estrogen treatment promoted the expression of selected lupus -associated miRNAs such as the miR-182 cluster, miR-379, and miR-148a in orchidectomized male NZB/W [F1] mice. [score:3]
As shown in Figure  1A, there was no significant difference in the expression of miR-182-96-183 cluster, miR-155, miR-31, and miR-148a between male and female mice. [score:3]
Among the above lupus -associated miRNAs, miR-31 and miR-148a were reported to be dysregulated in human lupus patients and contributed to human lupus pathogenesis by affecting IL-2 production and by causing CD4 [+] T cell hypomethylation and induction of autoimmune -associated genes, respectively [35, 36]. [score:2]
Impressively, we found that after the onset of lupus, the expressions of lupus -associated miRNAs (miR-182-96-183, miR-31, miR-127, miR-379, and miR-148a, miR-155) were significantly increased in female NZB/W [F1] mice when compared to those in age-matched male mice. [score:2]
We noticed that the expression of miR-96, miR-379, and miR-148a was significantly increased in 30-wk-old female mice, but not in 23-wk-old female mice when compared to that in age-matched male mice (Figure  2A). [score:2]
The sex differences in the expression of lupus -associated miRNAs, including the miR-182-96-183 cluster, miR-155, miR-31, miR-148a, miR-127, and miR-379, were markedly evident after the onset of lupus, especially at 30 wks of age when female NZB/W [F1] mice manifested moderate to severe lupus when compared to their male counterparts. [score:2]
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[+] score: 34
Pathways analysis predicted that miR-101a is targeting TGFBR1 and SMAD3, miR-582 is targeting TGFB2, SMAD1, miR-425 is targeting TGFBR2 and FST, miR-199a is targeting ACVR2a, miR-148 is targeting ACVR1, and miR-103 is targeting BMP2 in TGF- β signaling pathway. [score:13]
Predicted target and pathway analysis concluded that miR-101a is targeting TGFBR1 and SMAD3, miR-425 is targeting TGFBR2 and FST, miR-582 is targeting SMAD1 and TGFB2, miR-148 is targeting ACVR1, and miR-199a is targeting AcvR1a gene in the TGF- β signaling pathway. [score:13]
miR-148a promotes myogenic differentiation and downregulates ROCK1 gene at the translational level and plays a positive role in skeletal muscle development through the RhoA/ROCK pathway [58]. [score:7]
MiR-133a [23, 38], miR-378a [50], miR-26a [51], miR-27b [52, 53], miR-21a [56], miR-29a [44], miR-148 [58], and miR-103 are skeletal muscle specific miRNAs and play a vital role in muscle differentiation and proliferation as reported in previous studies. [score:1]
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[+] score: 32
The quantitative PCR results confirmed the expression of two most upregulated (hsa-miR-361-5p and hsa-miR-214) and downregulated (hsa-miR-1225-5p and hsa-miR-148a) miRNAs in the same 35 GC pairs (Figure 1B). [score:9]
B. Validation of two most differentially upregulated (miR-214 and miR-361-5p) and downregulated (miR-148a and miR-1225-5p) miRNAs in tumor and corresponding nontumorous pairs used for microarray analysis. [score:7]
Two most upregulated (hsa-miR-361-5p and hsa-miR-214) and two most downregulated (hsa-miR-1225-5p and hsa-miR-148a) miRNAs were further validated using qRT-PCR in GC tissue pairs. [score:7]
The average mRNA expression levels in cancerous tissues were increased by 2.81- and 1.92-fold (p < 0.01 for both) for hsa-miR-361-5p and hsa-miR-214, but decreased by 4.76- and 6.25-fold (p < 0.01 for both) for hsa-miR-148a and hsa-miR-1225-5p relative to those in the adjacent normal tissues. [score:3]
For example, miR-148a has been shown to serve as a tumor suppressor in cancers of the liver [24, 25], prostate [26, 27], colon [28, 29], stomach [30], pancreas [31, 32], bladder [33], ovary [34] and breast [35, 36]. [score:3]
MiR-148a was significantly downregulated in both GC cell lines and GC tissue samples compared to the adjacent normal gastric tissues [37– 39] which is consistent with our findings in this study. [score:2]
Among them, previous reports have established the association of hsa-miR-148a, 214 and 361-5p with human cancers. [score:1]
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Moreover, Katada et al. and our previous work studied the expression of miR-148a and miR-152 in gastric cancer tissues and found they were down-regulated compared with non-tumor adjacent tissues [53, 14]. [score:5]
Duursma et al. studied the target of miR-148 in the protein coding region and found that human miR-148 represses the expression of the DNA methyltransferase 3b (Dnmt3b) gene, which is the primary mediator of establishment and maintenance of DNA methylation in mammals [22]. [score:5]
Our previous studies have revealed that miR-148a and miR-152 are down-regulated in gastrointestinal cancers [14]. [score:4]
Our previous studies have revealed that miR-148a and miR-152 are significantly down-regulated in gastrointestinal cancers. [score:4]
We also found CCKBR was a putative target of miR-148a and miR-152 previously [14]. [score:3]
Interestingly, a recent study showed that the coding sequence of DNA methyltransferase 3b (Dnmt3b) mediated regulation by the miR-148 family (miR-148a and miR-148b) [22]. [score:2]
However, the regulation processes of miR-148b, as well as the relationship between miR-148a, miR-148b and miR-152, need further study. [score:2]
Therefore, miR-148a, miR-148b and miR-152 may play the same role in gastric cancer by regulating the same targets, and the relationship among them need further investigation. [score:2]
Interestingly, miR-148b has the same "seed sequences" as miR-148a and miR-152. [score:1]
As shown on the miRbase website, miR-148a, miR-148b and miR-152 have the same "seed sequences". [score:1]
Moreover, bioinformatics shows that miR-148b has the same "seed sequences" as miR-148a and miR-152, however, its pathophysiologic role and relevance to tumorigenesis are still largely unknown. [score:1]
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Table 1 The role of miRNAs in autoimmune diseases miRNA Predicted/Identified targets Function Related diseases miR-22 IRF8Enhances CD11c [+]CD11b [+]B220 [−] cDC generation at the expense of pDCs miR-142 IRF8Plays a pivotal role in the maintenance of CD4 [+] DCs miR-142-3p IL-6 Specifically inhibits IL-6 expression by moDC MS miR-21 IL-12p35, Wnt1 Negatively regulates the production of IL-12 by moDC; negatively regulate the development of moDC SLE, IBD, UC, MS miR-10a IL-12/IL-23p40 Suppress the production of IL-12 and IL-23 by moDC SLE miR-148/152 Calcium/Calmodulin- dependent protein kinase IIa Suppress the production of IL-12 and IL-6 SLE miR-23b Notch1, NF-κB Inhibits the production of IL-12 while promotes IL-10 production UC miR-155 SOCS1, SHIP1, TAB2 Positively regulates the production of several pro-inflammatory cytokines including IL-6, IL-23, IL-12, and TNF-α RA, IBD miR-146a IRAK1, TRAF6 Negatively regulates TLR4-NF-κB pathway in monocytes RA, SLE, IBD miR-34a JAG1 Negatively regulates the development of moDC MS miR-223 C/EBPβNegatively regulates LCs -mediated antigen-specific CD8 [+] T cell proliferation, production of inflammatory cytokine TNFα, IL-1β, and IL-23 by intestinal DCs. [score:25]
For example, miR-148/152 suppressed IL-12 as well as IL-6 production; miR-23b suppressed IL-12 production while enhancing IL-10 production (Liu et al., 2010). [score:5]
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miR-21 and miR-148a overexpression could result in increased signaling by targeting PTEN [32], [33] and miR-96 and miR-155 overexpression could increase signaling by targeting FOXO3a [34], [35]. [score:9]
This analysis confirmed the trends observed previously in the Nanostring analysis (i. e. overexpression of miR-21, miR-146a and miR-148a and underexpression of miR-181a in LAT Y136F CD4 [+] T cells compared to wild type CD4 [+] T cells) using a different method and multiple replicates. [score:4]
Four miRNAs (miR-21, miR-181a, miR-146a and miR-148a) have a greater than 10-fold difference in expression between LAT Y136F and naïve C57BL/6 CD4 [+] T cells and five additional miRNAs have greater than 5-fold differences (Table 1; miR-669f, miR-155, miR-466a/b, miR-125a and miR-96). [score:3]
RNAs from three groups of wild type mice (each containing sorted naïve or memory CD4 [+] T cells from pools of five to eight C57BL/6 mice per group) and four individual LAT Y136F mice were analyzed for levels of miR-21, miR-146a, miR148a and miR-181a (miRNAs with more than ten-fold differences in expression between LAT Y136F and C57BL/6 naïve CD4 [+] T cells). [score:3]
Three miRNAs had altered expression in LAT Y136F CD4 [+] T cells and in CD4 [+] T cells undergoing homeostatic proliferation (miR-181a, miR148a and miR-96). [score:3]
In addition we can compose a list of other miRNAs that are differentially regulated more than 5-fold among various combinations of the three proliferative states: miR-96, miR-125a, miR-139, miR-148a, miR-155, miR-181a, miR-361, miR-466a/b and miR669f. [score:2]
Three miRNAs showed more than 10-fold differences of expression in CD4 [+] T cells from mice undergoing homeostatic proliferation compared to naïve C57BL/6 CD4 [+] T cells (miR-21, miR-181a and miR-146a, Table S1) and two additional miRNAs showed greater than 5-fold differences (miR148a and miR-96, Table 1). [score:2]
H poly mmu-miR-150 mmu-miR-181a ↓↓ ↓↓ mmu-miR-669f ↓ ↓ mmu-miR-29c ↑ mmu-miR-155 ↑ ↑ mmu-miR-467f mmu-miR-466a/b-3p ↓ ↓ mmu-miR-361 ↑↑ ↓ mmu-miR-547 mmu-miR-1949 mmu-miR-345-3p ↓ ↑ mmu-miR-101b mmu-miR-340-5p ↓ mmu-miR-148a ↑ ↑ mmu-miR-139-5p ↓↓ ↓ mmu-miR-132 ↑ ↑ mmu-miR-539 ↓ mmu-miR-125a-5p ↑↑ ↑ ↓ mmu-miR-130b *miRNAs with Nanostring counts that passed the minimum intensity filter and have >2-fold differences among any two-way comparison. [score:1]
After reverse transcription, qPCR was performed using TaqMan® Universal PCR Master Mix II (No UNG), cDNA, and TaqMan® hydrolysis probes, hsa-miR-21, hsa-miR-146a, hsa-miR-148a, hsa-miR-181a, and snoRNA202. [score:1]
For biological replicates within groups, the samples did not differ significantly by one-way ANOVA among different mice or pools of mice, with the exception of miR148a. [score:1]
However, miR-148a showed small variation between mice within all conditions. [score:1]
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MiR-148a downregulates HLA-G expression by binding its 3′UTR, and this downregulation of HLA-G affects leukocyte immunoglobulin-like receptor subfamily B member 1 (LILRB1) recognition, and consequently abolishes the LILRB1 -mediated inhibition of NK cell killing. [score:10]
The suppression of miR-148a by strong TCR signal leads to depression of DNMT1 mRNA translation, which then modulates the expression of foxp3 epigenetically 58. [score:7]
In the placenta, miR-148a is expressed at relatively low levels, compared to that in other healthy tissues, and the mRNA levels of HLA-G are particularly high in the placenta, suggesting that this might enable the tissue-specific expression of HLA-G 59. [score:4]
The hepatocyte-derived miRNA analysis of the serum samples from healthy controls and liver transplant recipients and peritransplant liver allograft biopsy samples demonstrated that the expression of miR-148a in the liver tissue was significantly reduced by prolonged graft warm ischemia times 57. [score:3]
These studies demonstrated that miR-148a has a major role in immune regulation. [score:2]
This study showed that miR-148a is involved in liver injury. [score:1]
The levels of miR-148a closely correlate with the AST and ALT levels during posttransplant liver injury and acute rejection. [score:1]
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Other miRNAs from this paper: hsa-let-7a-1, hsa-let-7a-2, hsa-let-7a-3, hsa-let-7b, hsa-let-7c, hsa-let-7d, hsa-let-7e, hsa-let-7f-1, hsa-let-7f-2, hsa-mir-18a, hsa-mir-22, hsa-mir-29a, hsa-mir-30a, hsa-mir-93, hsa-mir-100, hsa-mir-29b-1, hsa-mir-29b-2, mmu-let-7g, mmu-let-7i, mmu-mir-1a-1, mmu-mir-29b-1, mmu-mir-30a, mmu-mir-30b, mmu-mir-124-3, mmu-mir-126a, mmu-mir-9-2, mmu-mir-133a-1, mmu-mir-146a, mmu-mir-200b, mmu-mir-203, mmu-mir-204, mmu-mir-205, hsa-mir-148a, hsa-mir-30c-2, hsa-mir-30d, mmu-mir-30e, hsa-mir-10a, hsa-mir-34a, hsa-mir-203a, hsa-mir-204, hsa-mir-205, hsa-mir-218-1, hsa-mir-218-2, hsa-mir-221, hsa-mir-222, hsa-mir-200b, mmu-mir-34c, mmu-mir-34b, mmu-let-7d, hsa-let-7g, hsa-let-7i, hsa-mir-1-2, hsa-mir-30b, hsa-mir-124-1, hsa-mir-124-2, hsa-mir-124-3, hsa-mir-133a-1, hsa-mir-133a-2, hsa-mir-9-1, hsa-mir-9-2, hsa-mir-9-3, hsa-mir-126, hsa-mir-146a, mmu-mir-30c-1, mmu-mir-30c-2, mmu-mir-30d, mmu-mir-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
The top negatively correlated (conserved) mouse miRNAs include miR-30a/d (targets Runx2) [57], miR-148a (targets Met/Snail) [58], miR-503 (targets Bcl-2 and Igf1r, implicated in involution) [59], miR-203 (targets the transcription factor p63) [60] and miR-34a (targets Dll1 and CD44, important for stem cell activity) [61, 62]. [score:11]
Luminal-restricted miRNAs included miR-10a (targets KLF4 and PIK3CA) [41, 42], miR-200a/b (targets EMT (epithelial mesenchymal transition) genes) [43], miR-148a (targets Bim) [44] and miR-375 (targets PDK1) [45]. [score:9]
Zhang JP Zeng C Xu L Gong J Fang JH Zhuang SM MicroRNA-148a suppresses the epithelial-mesenchymal transition and metastasis of hepatoma cells by targeting Met/Snail signalingOncogene. [score:4]
In the context of miRNAs that potentially control these pathways, we identified several luminal-restricted miRNAs, including miR-10a, miR-200a/b, miR-203, miR-148a. [score:1]
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18
[+] score: 24
By analyzing regulation of miRNA expression in wild type cells and cells expressing a GR with impaired dimerization 11, we found several miRNAs up-regulated including let-7, miR-146a, miR-148a, miR-148b and miR-152 by GC treatment, some of them exclusively in wildtype cells, and not in GR [dim] cells. [score:9]
In the total pool of differentially expressed miRNAs in Dex -treated wild type and GR [dim] mesenchymal cells we found eight identical miRNAs that were up regulated (let-7a, let-7c, let-7f, let-7g, let-7i, miR-148a, miR-148b and miR-152) indicating GR monomer dependent GC regulation of miRNA expression (Table S1). [score:7]
Venn analyses revealed sixteen differentially expressed miRNAs in wildtype primary mesenchymal cells that were treated with dexamethasone (Fig. 1A), of which eleven were up regulated (let-7 family, miR-125b, miR-146a, miR-148a + b, miR-152, miR-423) (Table S1) and five were down regulated (miR-1724a, miR-23a+b, miR-24-1,-2, miR-29a) (Table S1). [score:5]
Among the GR monomer dependent miRNAs were miR-148a and let-7i, whose expression was reported to be involved in differentiation of mesenchymal stromal cells towards osteoblasts 34. [score:3]
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Analysis of global profiles of miRNA expression in skeletal muscle with microarray shows that expression of 4 miRNAs (miR-29a, miR-29b, miR-29c and miR-150) are up-regulated [23], whereas expression of 11 miRNAs (miR-379, miR-127, miR299-5p, miR-434-3p, miR-335, miR130a, miR-19b, miR-451, miR-148a, miR-199a and miR-152) are down-regulated in skeletal muscle of type 2 diabetic rats [23]. [score:13]
For example, it has been shown that expression of 4 miRNAs (miR-29a, miR-29b, miR-29c and miR-150) is up-regulated [23], whereas expression of 11 miRNAs (miR-379, miR-127, miR299-5p, miR-434-3p, miR-335, miR130a, miR-19b, miR-451, miR-148a, miR-199a and miR-152) is down-regulated in skeletal muscle of type 2 diabetic rats [23]. [score:11]
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[+] score: 23
Intriguingly, miR-148a directly downregulated DNMT1 expression by targeting the protein coding region of its transcript. [score:9]
miR-21 and miR-148a downregulated DNA methyltransferase 1 (DNMT1) expression in vitro and in vivo, decreasing DNMT1 production in T cells. [score:6]
In addition, miR-21 and miR-148a induced the overexpression of methylation-sensitive, autoimmune -associated genes in CD4 [+] T cells including CD70 and LFA-1. Furthermore, the investigators found that the effects were reversed when inhibitors of either miR-21 or miR-148a were transfected into CD4 [+] T cells isolated from SLE patients, implying that hypomethylation in CD4 [+] T cells can potentially be alleviated by inhibiting these miRNAs [71]. [score:5]
While a putative miR-148a binding site has been predicted in the 3′ UTR of DNMT1, there are no predicted binding sites for miR-21. [score:1]
The overexpression of miR-148a has also been investigated in CD4 [+] T cells from patients with lupus as well as lupus-prone mice. [score:1]
Due to the importance of DNA methylation abnormalities in SLE pathogenesis, Pan et al. examined the roles of mir-21 and miR-148a in aberrant CD4 [+] T cell DNA hypomethylation [71]. [score:1]
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21
[+] score: 22
In the present study, we showed that the expression of several miRNAs is altered during the development of PC and that licofelone reverses the altered expression of the majority of these miRNAs with up-regulation of miR-21, miR-222, Let-7, miR-125, miR-142 and down-regulation of miR-1, miR-122 and miR-148. [score:12]
MicroRNA-148a is down-regulated in human PDAC and regulates cell survival by targeting CDC25B [49]. [score:6]
Most importantly, the miRNAs most strongly implicated in regulation of arachidonic acid metabolism via COX-2 and 5-LOX — like miR-199a, miR-21, miR-146, miR-29, miR148 — were tremendously modulated by licofelone treatment, clearly demonstrating targeted effects of this agent (Fig. 7C–7G, Supplementary Table 1). [score:4]
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22
[+] score: 20
[21] Out of the nine miRNAs that were screened, four were upregulated (miR-135b, miR-155, miR-205 and miR-206: Figure 1a) and five were downregulated (miR-31, miR-148a, miR-181c, miR-200b and miR-210: Figure 1b). [score:7]
[21]Out of the nine miRNAs that were screened, four were upregulated (miR-135b, miR-155, miR-205 and miR-206: Figure 1a) and five were downregulated (miR-31, miR-148a, miR-181c, miR-200b and miR-210: Figure 1b). [score:7]
[30] Three of the downregulated miRNAs (miR-148a, miR-181c and miR-210) are normally highly expressed during lactation in the mouse mammary gland. [score:6]
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23
[+] score: 18
MiR-148a is an established inhibitor of Dnmt1 expression [34], thus Dnmt1- KO SMCs, through increased miR-148a, likely create even further repression of Dnmt1 expression. [score:7]
Nan W MicroRNA-21 and microRNA-148a contribute to DNA hypomethylation in lupus CD4+T cells by directly and indirectly targeting DNA methyltransferase 1J. [score:5]
Furthermore, both miR-10b and miR-148a expression are known to regulated by genomic CpG methylation 31, 35. [score:4]
We also noted increases in miRNAs associated with regulating cellular identity and proliferation including, miR-10b [31], miR-21a [32], miR-486a [33], and miR-148a. [score:2]
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24
[+] score: 18
To further determine whether our finding as described above can be translated into a clinical application, three upregulated (miR-193a, miR-126 and miR-148a) and one downregulated miRNA (miR-196b) found in the exosomes isolated from metastatic liver in a mouse colon cancer were analysed in samples from colon cancer patients by qPCR. [score:9]
However, we demonstrated that knockout of MVP in CT26 cells leads to miR-193a accumulation in the cells without affecting the levels of miR-126a or miR-148a, suggesting that MVP selectively targets miR-193a. [score:4]
qPCR analysis of miR-193a, miR-126a and miR-148a expression in colon cancer tissue and adjacent non-tumour tissue from the same patients (right panel). [score:3]
Although miR-148a increased in the plasma of colon cancer patients, no difference in miR-148a level between tumour tissue and adjacent tissue was evident (Fig. 6c, right panel). [score:1]
The results generated from qPCR show that miR-126a, miR-148a and miR-193a are significantly higher in the exosomes released from metastatic CT26 cells and circulating in the peripheral blood of metastatic colon cancer in the liver, but not from primary colon cancer or subcutaneous xenografts. [score:1]
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25
[+] score: 18
Members of the miR-148 family (miR-148a, miR-148b, and miR-152) are upregulated upon DC stimulation by LPS, and their overexpression reduces MHC II expression on DC surface, inhibits the secretion of some proinflammatory cytokines, and reduces DC -mediated CD4 [+] T cell expansion. [score:10]
Correspondingly, MHC II expression, cytokine production, and CD4 [+] T cell proliferation increase when LPS-stimulated DCs are treated with miR-148 family inhibitors [35]. [score:5]
MicroRNAs regulate DC activation (let-7i, miR-142-3p, miR-146a, the miR-148 family, and miR-155), as well as cytokine production and development of DCs (miR-155) [28, 29]. [score:3]
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26
[+] score: 16
Other miRNAs from this paper: mmu-mir-7a-1, mmu-mir-7a-2, mmu-mir-7b
Furthermore, increased expression of miR-148a leads to lethal autoimmune disease in a mouse mo del of lupus [151]. [score:5]
Molecular studies revealed that miR-148a functions by suppressing the expression of Gadd45α, PTEN and the pro-apoptotic protein Bim. [score:5]
Furthermore, increased expression levels of miR-148a were reported in patients with lupus and also in lupus-prone mice [151]. [score:3]
Functional screening of a microRNA library also revealed that another miR, miR-148a, is a potent regulator of B cell tolerance [151]. [score:2]
Elevated miR-148a levels impair B cell tolerance through enhancing the survival of immature B cells following BCR engagement by self-antigens [151]. [score:1]
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27
[+] score: 14
In PyMT mice, miR-200a and miR-148a can regulate their expression, and thus changes in the expression of these miRNAs will probably also drive changes in the expression of both PPAR genes. [score:8]
For example, miR-182 and miR-148a are differentially expressed in weeks 6 and 8, and they regulate ENPEP, EFNB2, S1PR1, and MMP19 - four genes related to blood vessel morphogenesis or vascular endothelial growth factor (VEGF) signaling. [score:4]
MiRNAs persistently regulating these genes in our mo del are miR-143, miR-27b, miR-141, miR-200a, and miR-148a (Fig.   6b). [score:2]
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28
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Further, p53 appears to regulate the expression of Dicer through its transcriptional target miRs, such as miR-192, 215, miR29a/b/c, miR-148, miR-15/16a, miR-206, and miR-103 [Table 2], suggesting that p53/p63/p73 could regulate the expression of dicer both at the transcriptional and the post-transcriptional level. [score:9]
Among the p53-miRs that target the components of the miRNA processing complexes, miR-15/16/195, miR-103, miR-107, let-7, miR-124, miR-181, miR-148a/b, miR-30a/c, miR-27, miR-17, and miR-20 appear to target more than five components of the miRNA-processing pathway [Table 4, Table S3], suggesting the conserved nature of p53-miRs. [score:5]
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In TM4 cells exposed to NP, Ppara was down-regulated at both 3 and 24 h. We thus surmised that miRNAs regulated by Ppara may include miR-378, miR-125a-3p, and miRNA-148a at 3 h, and miR-20a, miR-203, and miR-101a at 24 h. Figure 3 Network analysis of miRNAs the expression of which in TM4 cells was altered by NP (A) 3 h. (B) 24 h. Network analysis was performed using an algorithm supported by IPA. [score:7]
In TM4 cells exposed to NP, Ppara was down-regulated at both 3 and 24 h. We thus surmised that miRNAs regulated by Ppara may include miR-378, miR-125a-3p, and miRNA-148a at 3 h, and miR-20a, miR-203, and miR-101a at 24 h. Figure 3 Network analysis of miRNAs the expression of which in TM4 cells was altered by NP (A) 3 h. (B) 24 h. Network analysis was performed using an algorithm supported by IPA. [score:7]
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30
[+] score: 14
The analysis for the KC animals compared to controls revealed that miR-150, miR-494, miR-138, miR-148a*, miR-216a, and miR-217 (p-value = 0.01) were significantly downregulated (Table 1), whereas, miR-146b, miR-205, miR-31, miR-192, and miR-21 (p-value = 0.01) were significantly upregulated (Table 2). [score:6]
Similarly, another study showed that the expression of miR-148a/b and miR-375 were significantly downregulated in the PC developed from p48Cre;Kras [G12D] transgenic animals compared to the normal controls [59]. [score:5]
The also revealed decreased expression of miR-148a and miR-451 in mouse PC, an observation consistent with other reports [40, 41, 55– 58]. [score:3]
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[+] score: 13
The miRNAs are clustered into five groups: (1: turquoise) The most highly expressed miRNAs in all samples, which are primarily made up of the mGliomiRs and the shared miRNAs; (2, gray) a cluster of miRNAs not expressed in vivo, but with very high expression levels in the cultured MG; (3: black) a “cluster” with miR-21 alone, which is moderately expressed in vivo but increased substantially in vitro; (4: pink) a cluster with miRNAs expressed at low levels in the FAC-sorted MG and which decline further in vitro (including miR-146a, miR-20a+b) and lastly (5: purple) a cluster of miRNAs that are moderately expressed in freshly isolated samples and also decline in vitro (including miR-148a, miR-106/miR-17, and miR-191). [score:13]
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32
[+] score: 12
miR-145, miR-148a, miR-190 and miR-335 however showed different expression pattern in and HD cell mo del [33]. [score:3]
Expression of miR-148a, which was increased in STHdh [Q111]/Hdh [Q111] cells, was however decreased in all the four cell mo dels. [score:3]
However, miR-148a which was up regulated in HD cell mo del [33] had been shown to be down regulated in all other mo dels. [score:3]
Other miRNAs which showed a consistent expression pattern across the mo dels were miR-100, miR-214, miR-299, miR-335, miR-34a and miR-148a. [score:3]
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33
[+] score: 12
Based on these findings, upregulation of miR-9, miR-9*, miR-22, miR-34b, miR-125b, miR-137, miR-146a, miR148a, miR-150, miR-196a, and miR-214 may have therapeutic potential against mutant HTT, REST, HDAC4, apoptosis, and other pathobiological factors in HD. [score:4]
HTT gene expression is regulated by miR-137, miR-148a, and miR-214, with HTT mRNA concentrations reduced by 40%–50% in HEK293T cells after transfection with each of these microRNAs [101]. [score:4]
These functional data support some (miR-22, miR-125b, miR-146a, miR-150) and contradict other (miR-34b, miR-148a, and miR-214) Table 2 miRNA targets. [score:3]
The effects of psychotropics on the other miRNAs listed in Table 2, particularly miR-9, miR-9*, miR-22, miR-34b, miR-125b, miR-137, miR-146a, miR148a, miR-150, miR-196a, and miR-214, as well as on REST, deserve study in HD mo dels. [score:1]
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34
[+] score: 12
Following chronic CS exposure, 12 miRNAs (miR-146a, miR-148a, miR-152, miR-21, miR-26a, miR-30a-5p, miR-30c, miR-31, miR-31*, miR-342-3p, miR-376b* and miR-449) were differentially expressed in both lung tissue and BAL supernatant of which 10 showed concordant up- or down-regulation. [score:6]
Only miR-449 and miR-148a displayed different expression patterns in the two compartments (Fig.   3b). [score:3]
By focusing on the overlap between subacute and chronic CS exposure within the same compartment, or the overlap between miRNAs with altered expression levels in BAL and lung, we narrowed the pool of interesting miRNAs down to 18: let-7b, let-7c, miR-135b, miR-138, miR-146a, miR-148a, miR-152, miR-155, miR-21, miR-26a, miR-30a-5p, miR-30c, miR-31, miR-31*, miR-322*, miR-342-3p, miR-376b* and miR-449. [score:3]
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35
[+] score: 11
For experimental validation in oral tumors, we narrowed down that candidate miRNAs to six (miR-137, miR-148a-3p, miR-30a-5p, miR-30b-5p, miR-338-3p and miR-22-3p) by reviewing the functional evidence present in the literature, analyzing their expression in HNSCC datasets from TCGA and correlating with OIP5-AS1 expression (Supplementary Table  S2). [score:5]
Out of the 8 selected miRNAs, miR-137, miR-140–5p, miR-148a-3p, miR-30a-5p and miR-338-3p were significantly downregulated in the tumors compared with normal tissue (P < 0.001, <0.001, 0.001, 0.001 and 0.0003, respectively) (Fig.   3a). [score:3]
Six miRNAs miR-137, miR-148a-3p, miR-338-3p, miR-30a/b-5p and miR-22-3p known to be associated with several cancers were chosen to study the expression levels in oral tumors 20, 25, 26. [score:3]
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[+] score: 10
The differentially expressed miRNAs in earlier studies appeared consistently in mouse skeletal muscle from our study; for example, the expression pattern of miR-146a-5p, miR-146b-5p, miR-434-3p, miR-127-3p, and miR-148a-3p are similar to previous studies. [score:5]
The array uncovered the induction of 117 miRNAs with the signal intensity ≥500 (the fluorescence amount of each miRNA probe is measured by a photo multiplier tube or charge-coupled device and signal scaled across the range of detection for the platform) in GA muscle (Table 1, Fig. 1A and 1B), including the highly downregulated miRNAs (≥1.5-fold) miR-194-5p, miR-101b-3p, miR-148a-3p, miR-199b-5p, miR-335-5p, miR-127-3p, miR-379-5p, miR-541-5p, miR-382-5p, miR-329-3p, miR-299-5p and miR-434-3p, and the highly up-regulated miRNAs (≥1.5 fold), miR-146b-5p and miR-146a-5p (Fig. 1C). [score:5]
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[+] score: 10
We found that miR-152 expression, but not miR-148a and miR-148b expressions, was obviously increased by Sal B (Fig. 8A). [score:5]
Using the computer-aided algorithms, TargetScan, miRanda and miRDB, we predicted a group of miRNAs that have sequence complementarity to the 3′-UTR of DNMT1, namely miR-148a, miR-148b and miR-152. [score:3]
To detect miR-148a, miR-148b and miR-152 expression, the RT reaction was performed using the TaqMan MicroRNA Assay (Applied Biosystems, Foster City, CA, USA) according to the manufacturer's instructions. [score:2]
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38
[+] score: 10
Our validated colitis signature was therefore composed of nine miRNAs: the up-regulated miRNAs, miR-29b-3p, -122-5p, -192-5p, -194-5p, -375-3p, -150-5p, and -146a-3p, and the down-regulated miRNAs, miR-148a-3p and -199a-3p (Fig.   2B). [score:7]
miRNA nameIL10 [−/−] mice mo del Intestinal Inflammation Inflammation mmu-miR-29b-3p x mmu-miR-122-5p x x x mmu-miR-148a-3p x mmu-miR-150-5p x x mmu-miR-192-5p x mmu-miR-194-5p x mmu-miR-146a-5p x mmu-miR-375-3p x x x mmu-miR-199a-3p x We showed that our nine-miRNA signature could discriminate between the different forms of colitis and arthritis, as well as between non-colitic mice with and without a genetic predisposition to develop the disease (WT mice versus non-colitic IL10 [−/−] mice). [score:3]
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[+] score: 10
Two were upregulated (miR-492 and miR-224) and six were downregulated (miR-191, miR-122, miR-192, miR-101, miR-302b, miR-148a) (Figure  1A). [score:7]
In our study, the expressions of other miRNAs such as miR-224, miR-148a has been found to either increase or decrease in HCC. [score:3]
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[+] score: 9
Inhibition of FGF signaling through SU5402 -treated primitive streak regions of chick embryos identified up-regulation of let-7b, miR-9, miR-19b, miR-107, miR-130b, miR-148a, miR-203, and miR-218 and down-regulation of miR-29a and miR-489 (Bobbs et al. 2012). [score:9]
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[+] score: 9
Several human miRs, including miR-29 family, miR-148, and miR-200b/c have been found to be frequently downregulated in human cancers and lead to increase expression of DNMT1 and DNMT3a/b because they directly target the 3′-UTR of DNMTs [30, 35, 36]. [score:9]
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[+] score: 8
Additionally, activation of repair -mediated DNA demethylation (Barreto et al. 2007) and decreased expression and/or functioning of Dnmt1 caused by a number of factors, including direct effects of BD and its metabolites on Dnmt1 protein, aberrant expression of microRNAs (e. g., miR-29b, miR-148, and miR-152), and expression of chromatin-modifying proteins (Garzon et al. 2009; Huang et al. 2010; Vire et al. 2006; Wang et al. 2009), may further contribute to the loss of DNA methylation. [score:8]
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[+] 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-17, hsa-mir-18a, hsa-mir-20a, hsa-mir-21, hsa-mir-22, hsa-mir-26a-1, hsa-mir-99a, hsa-mir-103a-2, hsa-mir-103a-1, hsa-mir-106a, hsa-mir-107, mmu-let-7g, mmu-let-7i, mmu-mir-99a, mmu-mir-101a, mmu-mir-125a, mmu-mir-125b-2, mmu-mir-126a, mmu-mir-127, mmu-mir-145a, mmu-mir-146a, mmu-mir-129-1, mmu-mir-206, hsa-mir-129-1, hsa-mir-148a, mmu-mir-122, mmu-mir-143, hsa-mir-139, hsa-mir-221, hsa-mir-222, hsa-mir-223, mmu-let-7d, mmu-mir-106a, hsa-let-7g, hsa-let-7i, hsa-mir-122, hsa-mir-125b-1, hsa-mir-143, hsa-mir-145, hsa-mir-125a, hsa-mir-125b-2, hsa-mir-126, hsa-mir-127, hsa-mir-129-2, hsa-mir-146a, hsa-mir-206, mmu-let-7a-1, mmu-let-7a-2, mmu-let-7b, mmu-let-7c-1, mmu-let-7c-2, mmu-let-7e, mmu-let-7f-1, mmu-let-7f-2, mmu-mir-18a, mmu-mir-20a, mmu-mir-21a, mmu-mir-22, mmu-mir-26a-1, mmu-mir-129-2, mmu-mir-103-1, mmu-mir-103-2, rno-let-7d, rno-mir-335, rno-mir-129-2, rno-mir-20a, mmu-mir-107, mmu-mir-17, mmu-mir-139, mmu-mir-223, mmu-mir-26a-2, mmu-mir-221, mmu-mir-222, mmu-mir-125b-1, hsa-mir-26a-2, hsa-mir-335, mmu-mir-335, rno-let-7a-1, rno-let-7a-2, rno-let-7b, rno-let-7c-1, rno-let-7c-2, rno-let-7e, rno-let-7f-1, rno-let-7f-2, rno-let-7i, rno-mir-17-1, rno-mir-18a, rno-mir-21, rno-mir-22, rno-mir-26a, rno-mir-99a, rno-mir-101a, rno-mir-103-2, rno-mir-103-1, rno-mir-107, rno-mir-122, rno-mir-125a, rno-mir-125b-1, rno-mir-125b-2, rno-mir-126a, rno-mir-127, rno-mir-129-1, rno-mir-139, rno-mir-143, rno-mir-145, rno-mir-146a, rno-mir-206, rno-mir-221, rno-mir-222, rno-mir-223, hsa-mir-196b, mmu-mir-196b, rno-mir-196b-1, hsa-mir-20b, hsa-mir-451a, mmu-mir-451a, rno-mir-451, hsa-mir-486-1, hsa-mir-499a, mmu-mir-486a, mmu-mir-20b, rno-mir-20b, rno-mir-499, mmu-mir-499, mmu-mir-708, hsa-mir-708, rno-mir-17-2, rno-mir-708, hsa-mir-103b-1, hsa-mir-103b-2, mmu-mir-486b, rno-mir-126b, hsa-mir-451b, hsa-mir-499b, mmu-mir-145b, mmu-mir-21b, mmu-let-7j, mmu-mir-130c, mmu-mir-21c, mmu-mir-451b, mmu-let-7k, hsa-mir-486-2, mmu-mir-129b, mmu-mir-126b, rno-let-7g, rno-mir-148a, rno-mir-196b-2, rno-mir-486
By 18 wks of E [2] treatment, the mammary glands were characterized by lobular involution and hyperplasia, and only 1 miRNA was down-regulated (miR-139) and 5 miRNAs were up-regulated (miR-20b, miR-21, miR-103, mir-107, miR-129-3p, and miR-148a). [score:5]
E [2] decreased miR-146a, miR 125a, miR-125b, let-7e, miR-126, miR-145, and miR-143 and increased miR-223, miR-451, miR-486, miR-148a, miR-18a, and miR-708 expression in mouse splenic lymphocytes [199]. [score:3]
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44
[+] score: 8
Other miRNAs from this paper: hsa-let-7c, hsa-let-7d, hsa-mir-16-1, hsa-mir-21, hsa-mir-24-1, hsa-mir-24-2, hsa-mir-28, hsa-mir-29a, hsa-mir-30a, hsa-mir-31, hsa-mir-99a, hsa-mir-101-1, hsa-mir-16-2, mmu-let-7g, mmu-let-7i, mmu-mir-27b, mmu-mir-30a, mmu-mir-99a, mmu-mir-101a, mmu-mir-125b-2, mmu-mir-126a, mmu-mir-128-1, mmu-mir-9-2, mmu-mir-142a, mmu-mir-144, mmu-mir-145a, mmu-mir-151, mmu-mir-152, mmu-mir-185, mmu-mir-186, mmu-mir-24-1, mmu-mir-203, mmu-mir-205, hsa-mir-148a, hsa-mir-34a, hsa-mir-203a, hsa-mir-205, hsa-mir-210, hsa-mir-221, mmu-mir-301a, mmu-let-7d, hsa-let-7g, hsa-let-7i, hsa-mir-27b, hsa-mir-125b-1, hsa-mir-128-1, hsa-mir-142, hsa-mir-144, hsa-mir-145, hsa-mir-152, hsa-mir-9-1, hsa-mir-9-2, hsa-mir-9-3, hsa-mir-125b-2, hsa-mir-126, hsa-mir-185, hsa-mir-186, mmu-mir-200a, mmu-let-7c-1, mmu-let-7c-2, mmu-mir-16-1, mmu-mir-16-2, mmu-mir-21a, mmu-mir-24-2, mmu-mir-29a, mmu-mir-31, mmu-mir-34a, mmu-mir-148b, mmu-mir-339, mmu-mir-101b, mmu-mir-28a, mmu-mir-210, mmu-mir-221, mmu-mir-9-1, mmu-mir-9-3, mmu-mir-125b-1, mmu-mir-128-2, hsa-mir-128-2, hsa-mir-200a, hsa-mir-101-2, hsa-mir-301a, hsa-mir-151a, hsa-mir-148b, hsa-mir-339, hsa-mir-335, mmu-mir-335, hsa-mir-449a, mmu-mir-449a, hsa-mir-450a-1, mmu-mir-450a-1, hsa-mir-486-1, hsa-mir-146b, hsa-mir-450a-2, hsa-mir-503, mmu-mir-486a, mmu-mir-542, mmu-mir-450a-2, mmu-mir-503, hsa-mir-542, hsa-mir-151b, mmu-mir-301b, mmu-mir-146b, mmu-mir-708, hsa-mir-708, hsa-mir-301b, hsa-mir-1246, hsa-mir-1277, hsa-mir-1307, hsa-mir-2115, mmu-mir-486b, mmu-mir-28c, mmu-mir-101c, mmu-mir-28b, hsa-mir-203b, hsa-mir-5680, hsa-mir-5681a, mmu-mir-145b, mmu-mir-21b, mmu-mir-21c, hsa-mir-486-2, mmu-mir-126b, mmu-mir-142b, mmu-mir-9b-2, mmu-mir-9b-1, mmu-mir-9b-3
This suggests that the relatively high expression of miR-148a found in the two libraries is a result of the testosterone supplementation of the animals. [score:3]
The most highly expressed miRNA (and isomiR) was the miR-148a with total counts of 270,801 and 763,877 reads per metastatic and non-metastatic libraries, respectively. [score:3]
The highest reads in the two RNA libraries were observed for miR-148a. [score:1]
When the isomiRs were grouped using the same starting position, the miR-148a remained the most abundant miRNA in the non-metastatic library with a total count of 846,468, whereas in the metastatic library miR-21 was most abundant with a total count of 310,102. [score:1]
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[+] score: 8
For example, miR-29, miR-181 and miR-148a can promote myoblast differentiation by inhibiting the expression of downstream target genes Akt3, Hox-A1 and ROCK1 at protein levels [10– 12]. [score:7]
MiR-148a, miR-206 and miR-214 have been shown to be similar to miR-322/424 and miR-503 [12, 33, 34]. [score:1]
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[+] score: 7
No expression differences were observed in the expression of miR-148a, miR-145 or miR-203 when compared to control vector grafts (Fig. S9). [score:4]
In HPV-infected CC or HNSCC, miR-145, miR-146a, miR-148a, miR-200a, miR-203 and miR-21 (among others) are deregulated, some of them in association with clinical variables [10], [68]– [71]. [score:2]
Figure S9 qRT-PCR for miR-148a, miR-145 and miR-203 miRNAs in E7-transplants. [score:1]
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47
[+] score: 7
Those miRNAs, we call them the epi-miRNAs, includes, for example, miR-148a, miR152, miR222 that targets mRNA of DNMTs and leads to re -expression of hyper-methylated tumor suppressors [32]. [score:7]
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[+] score: 7
Increased miR-21, miR-148a, and miR-126 in lupus CD4 [+] T cells reduced the expression of DNMT1 directly or indirectly, leading to DNA hypomethylation and overexpression of autoimmune -associated methylation-sensitive genes such as CD70, lymphocyte function -associated antigen 1 (LFA-1), and CD11a [24– 26]. [score:7]
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[+] score: 6
Interestingly, microarray analysis of NZB/W and NZW at 3–4 months of age, an age when overt lupus disease is not evident in NZB/W mice, revealed that only one miRNA, miR-148a, was significantly upregulated in NZB/W mice (data not shown). [score:6]
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[+] score: 6
Other miRNAs from this paper: hsa-let-7a-1, hsa-let-7a-2, hsa-let-7a-3, hsa-let-7b, hsa-let-7c, hsa-let-7d, hsa-let-7e, hsa-let-7f-1, hsa-let-7f-2, hsa-mir-21, hsa-mir-22, hsa-mir-24-1, hsa-mir-24-2, hsa-mir-25, hsa-mir-26a-1, hsa-mir-92a-1, hsa-mir-92a-2, hsa-mir-99a, mmu-let-7g, mmu-let-7i, mmu-mir-27b, mmu-mir-99a, mmu-mir-140, mmu-mir-10b, mmu-mir-181a-2, mmu-mir-24-1, mmu-mir-191, hsa-mir-192, hsa-mir-148a, hsa-mir-30d, mmu-mir-122, hsa-mir-10b, hsa-mir-181a-2, hsa-mir-181a-1, mmu-let-7d, hsa-let-7g, hsa-let-7i, hsa-mir-27b, hsa-mir-122, hsa-mir-140, hsa-mir-191, hsa-mir-320a, mmu-mir-30d, mmu-mir-192, mmu-let-7a-1, mmu-let-7a-2, mmu-let-7b, mmu-let-7c-1, mmu-let-7c-2, mmu-let-7e, mmu-let-7f-1, mmu-let-7f-2, mmu-mir-21a, mmu-mir-22, mmu-mir-24-2, mmu-mir-26a-1, mmu-mir-92a-2, mmu-mir-25, mmu-mir-181a-1, mmu-mir-26a-2, mmu-mir-92a-1, hsa-mir-26a-2, hsa-mir-423, hsa-mir-451a, mmu-mir-451a, hsa-mir-486-1, mmu-mir-486a, mmu-mir-423, bta-mir-26a-2, bta-let-7f-2, bta-mir-148a, bta-mir-21, bta-mir-30d, bta-mir-320a-2, bta-mir-99a, bta-mir-181a-2, bta-mir-27b, bta-mir-140, bta-mir-92a-2, bta-let-7d, bta-mir-191, bta-mir-192, bta-mir-22, bta-mir-423, bta-let-7g, bta-mir-10b, bta-mir-24-2, bta-let-7a-1, bta-let-7f-1, bta-mir-122, bta-let-7i, bta-mir-25, bta-let-7a-2, bta-let-7a-3, bta-let-7b, bta-let-7c, bta-let-7e, hsa-mir-1246, bta-mir-24-1, bta-mir-26a-1, bta-mir-451, bta-mir-486, bta-mir-92a-1, bta-mir-181a-1, bta-mir-320a-1, mmu-mir-486b, hsa-mir-451b, bta-mir-1246, mmu-mir-21b, mmu-let-7j, mmu-mir-21c, mmu-mir-451b, mmu-let-7k, hsa-mir-486-2
Several microRNAs had similar expression when comparing results from the present study with those of There were nine microRNAs (bta-miR-10b, bta-miR-423-3p, bta-miR-99a-5p, bta-miR-181a, bta-miR-423-5p, bta-miR-148a, bta-miR-26a, bta-miR-192, and bta-miR-486), that were upregulated in earlier stages of life in both studies. [score:6]
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[+] score: 6
Converse to the reported tumor suppressor role of ATF5 in HCC, Xu et al. report that ATF5 expression is regulated by miR-148a via decreased activation of the AKT/FOXO4/ATF5 pathway in HepG2 cells [76]. [score:6]
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[+] score: 6
In the presence of miR-148a or miR-1612 for DNMT1, neither the intensity nor percentage of GFP -expressing cells changed (data now shown). [score:3]
For the dual fluorescence reporter assay, the fusion contained the DsRed gene and either miR-148a or miR-1612 for DNMT1; miR-1596, miR-1687, miR-1741, or miR-1749 for DNMT3A; and miR-16c, miR-222, or miR-1632 for DNMT3B, and each was designed to be co-expressed under control of the CMV promoter (pcDNA-DsRed-miRNA). [score:2]
org/miRDB/) revealed putative binding sites for miR-148a and miR-1612 (for DNMT1) ; miR-1596, miR-1687, miR-1741, and miR-1749 (for DNMT3A) ; and miR-16c, miR-222, and miR-1632 (for DNMT3B). [score:1]
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[+] score: 6
Other miRNAs from this paper: mmu-mir-152
In the future, it may be possible to modulate HLA-G transcription with a miRNA, such as the hsa mir-148a and mir-152, which bind to the 3′ untranslated region of the HLA-G gene (3′UTR) [19], downregulating its mRNA levels. [score:6]
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[+] score: 6
Also, Robo2 was targeted by miR-153 in the Udown group and miR-148a/b, miR-338-3p, and miR-101a/b in the Uup group (Fig 6A). [score:3]
Specifically, miR-153in the Udown group microRNA and five microRNAs in the Uup group, miR-148a/b, miR-101a/b, and miR-338-3p, targeted the same mRNA, Robo2. [score:3]
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[+] score: 6
Other miRNAs from this paper: mmu-mir-199a-1, mmu-mir-199a-2, mmu-mir-503
Interestingly, IKKβ is the target of miR148a, miR503, and miR199a, 45, 46, 47 which are upregulated microRNAs in vascular calcification. [score:6]
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[+] score: 6
Qingjuan L demonstrated that miR-148a-3p overexpression contributes to glomerular cell proliferation by downregulating PTEN in lupus nephritis [52]. [score:6]
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[+] score: 6
Nine miRNAs (miR-148a-3p, miR-183a-5p, miR-214-3p, miR-27a-3p, miR-92a-3p, miR-378a-3p, miR-23a-3p, miR-21a-5p and miR-16-5p) were upregulated, and four (miR-155-5p, miR-199a-3p, miR-320-3p and miR-125a-5p) were downregulated in exosomes from RANKL -induced RAW 264.7 cells compared with RAW 264.7 cells (Figure 1f and Supplementary Figure S1d). [score:6]
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[+] score: 5
For example, miR-204 is primarily expressed in insulinomas and co-localizes mainly with insulin [43]; miR-127-3p and miR-184 are positively correlated with insulin biosynthesis and negatively correlated with glucose-stimulated insulin secretion (GSIS) [44]; miR-148 controls the insulin content in β-cells through regulation of the insulin repressor SOX6 [45] and miR-29 contributes to pancreatic β-cell dysfunction in prediabetic NOD Mice [46], and affects the release of insulin from β-cells by silencing of monocarboxylate transporter (MCT1) [47]. [score:4]
Indeed it has been reported that miR-24, miR-26 and miR-148 contribute to characterization of β-cell identity and maintenance of β-cell phenotype by suppressing two known insulin transcription repressors, Sox6 and Bhlhe22 [45]. [score:1]
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[+] score: 5
Besides the regulation of miR-103/107 and miR-143, we could also confirm the up-regulation of miR-422b, miR-148a, miR-30c, and miR30a-5p found in differentiating 3T3-L1 cells by Xie and colleagues [24]. [score:5]
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60
[+] score: 5
Joshi et al. [6] demonstrated that miR-148a acts as a tumor suppressor and inhibits the migration and invasion of the NSCLC cell line A549. [score:5]
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61
[+] score: 5
In addition to the 43 liver-specific miRNAs, five miRNAs (miR-148a, miR-192, miR-194, miR-122, and miR-21) were highly expressed in the liver but at low levels in the brain; four of them (miR-148a, miR-192, miR-194, miR-122) were expressed at levels at least 10-fold greater in the liver than in the brain. [score:5]
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[+] score: 5
Among these, several miRNAs including let-7/miR-98 family, miR-21, miR-34a/c, miR-142, miR148a, and miR-192 predominantly expressed in liver, exhibited elevated changes in plasma samples 20. [score:3]
Several additional miRNAs that have already been related to pathological conditions and neoplastic lesions were overrepresented among circulating molecules such as miR-155 (part of the miR-17-92 cluster) 22, miR-200 family 23, miR-148a 24 and miR-375 25. [score:1]
Interestingly, among the 16 miRNAs having >1000 normalized reads in at least one plasma sample (Table 2), several miRNAs (e. g. let-7/miR98 family members, miR-200b, miR-21a, miR-142, miR-192, miR-148a) have already been reported for their implication in liver carcinogenesis and other pathological conditions 13 20. [score:1]
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[+] score: 5
MiR-148a and miR-148b, which are found in UC blood MSC-derived exosomes, reportedly regulate the proliferation of UC blood MSCs by upregulating NF-κB or hedgehog signalling [38]. [score:5]
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64
[+] score: 4
Other miRNAs from this paper: hsa-let-7a-1, hsa-let-7a-2, hsa-let-7a-3, hsa-let-7b, hsa-let-7c, hsa-let-7d, hsa-let-7e, hsa-let-7f-1, hsa-let-7f-2, hsa-mir-17, hsa-mir-18a, hsa-mir-19a, hsa-mir-19b-1, hsa-mir-19b-2, hsa-mir-20a, hsa-mir-21, hsa-mir-24-1, hsa-mir-24-2, hsa-mir-27a, hsa-mir-29a, hsa-mir-30a, hsa-mir-92a-1, hsa-mir-92a-2, hsa-mir-93, hsa-mir-100, hsa-mir-29b-1, hsa-mir-29b-2, hsa-mir-103a-2, hsa-mir-103a-1, hsa-mir-107, mmu-let-7g, mmu-let-7i, mmu-mir-1a-1, mmu-mir-23b, mmu-mir-27b, mmu-mir-29b-1, mmu-mir-30a, mmu-mir-30b, mmu-mir-125a, mmu-mir-9-2, mmu-mir-133a-1, mmu-mir-136, mmu-mir-138-2, mmu-mir-181a-2, mmu-mir-24-1, mmu-mir-191, hsa-mir-196a-1, hsa-mir-148a, hsa-mir-30c-2, hsa-mir-30d, mmu-mir-122, mmu-mir-143, mmu-mir-30e, hsa-mir-34a, hsa-mir-181a-2, hsa-mir-196a-2, hsa-mir-181a-1, mmu-mir-296, mmu-mir-298, mmu-mir-34c, mmu-let-7d, mmu-mir-130b, hsa-let-7g, hsa-let-7i, hsa-mir-1-2, hsa-mir-23b, hsa-mir-27b, hsa-mir-30b, hsa-mir-122, hsa-mir-133a-1, hsa-mir-133a-2, hsa-mir-138-2, hsa-mir-143, hsa-mir-191, hsa-mir-9-1, hsa-mir-9-2, hsa-mir-9-3, hsa-mir-125a, hsa-mir-136, hsa-mir-138-1, mmu-mir-19b-2, mmu-mir-30c-1, mmu-mir-30c-2, mmu-mir-30d, mmu-mir-196a-1, mmu-mir-196a-2, mmu-let-7a-1, mmu-let-7a-2, mmu-let-7b, mmu-let-7c-1, mmu-let-7c-2, mmu-let-7e, mmu-let-7f-1, mmu-let-7f-2, mmu-mir-18a, mmu-mir-20a, mmu-mir-21a, mmu-mir-24-2, mmu-mir-29a, mmu-mir-29c, mmu-mir-27a, mmu-mir-92a-2, mmu-mir-93, mmu-mir-34a, mmu-mir-103-1, mmu-mir-103-2, mmu-mir-330, mmu-mir-346, hsa-mir-1-1, mmu-mir-1a-2, mmu-mir-107, mmu-mir-17, mmu-mir-19a, mmu-mir-100, mmu-mir-181a-1, mmu-mir-29b-2, mmu-mir-19b-1, mmu-mir-92a-1, mmu-mir-9-1, mmu-mir-9-3, mmu-mir-138-1, hsa-mir-29c, hsa-mir-30c-1, hsa-mir-34c, hsa-mir-296, hsa-mir-130b, hsa-mir-30e, hsa-mir-375, hsa-mir-381, mmu-mir-375, mmu-mir-381, hsa-mir-330, mmu-mir-133a-2, hsa-mir-346, hsa-mir-196b, mmu-mir-196b, hsa-mir-18b, hsa-mir-20b, hsa-mir-146b, hsa-mir-519d, hsa-mir-501, hsa-mir-503, mmu-mir-20b, mmu-mir-503, hsa-mir-92b, mmu-mir-146b, mmu-mir-669c, mmu-mir-501, mmu-mir-718, mmu-mir-18b, mmu-mir-92b, hsa-mir-298, mmu-mir-1b, hsa-mir-103b-1, hsa-mir-103b-2, hsa-mir-718, mmu-mir-21b, mmu-let-7j, mmu-mir-21c, mmu-mir-30f, mmu-let-7k, mmu-mir-9b-2, mmu-mir-9b-1, mmu-mir-9b-3
Xie et al. [27] identified miR-143, miR-148a, miR-30c, miR146b as being upregulated during in vitro differentiation of 3T3-L1 cells, which is identical to our findings. [score:4]
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65
[+] score: 4
Other miRNAs from this paper: hsa-mir-148a
Although ACVR1 can be regulated by miR-148a [25], the decreasing levels of ACVR1 R206H mRNA during mineralizing culture suggest that the 617 G > A mutation confers allele-specific regulation of RNA transcripts. [score:4]
[1 to 20 of 1 sentences]
66
[+] score: 4
Chen Y. Song Y. Wang Z. Yue Z. Xu H. Xing C. Liu Z. Altered expression of miR-148a and miR-152 in gastrointestinal cancers and its clinical significance J. Gastrointest. [score:3]
Of these microRNAs, fifteen constructs, including mmu-miR-487b [11, 12], mmu-miR-467e [13], mmu-miR-466d [14], mmu-miR-449a [15, 17, 18, 32, 33], mmu-miR-148a [20], mmu-miR-133a-1 [21], mmu-miR-1-2-as [22], mmu-miR24-2 [23], mmu-miR-1940, mmu-miR-1935, mmu-miR-1931 [24], mmu-miR-1902, mmu-miR-1895, mmu-miR-1894 [24], and mmu-miR-1193, were examined in this study. [score:1]
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67
[+] score: 4
Recently, deregulations of many miRs have been implicated in the growth and metastasis of HCC, such as miR-21 [11], miR-101 [12], miR-124 [13], miR-203 [13], and miR-148 [14], which may be used as potential therapeutic targets or candidates for HCC treatment. [score:4]
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68
[+] score: 4
Among the microRNAs downregulated by nCounter array in GFM aortas (Supplementary Fig. 2d), miR-204 and miR-148a were confirmed by quantitative PCR (qPCR), with a strong trend for miR-9 (Supplementary Fig. 2e). [score:4]
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69
[+] score: 3
Other miRNAs from this paper: mmu-mir-203, mmu-mir-30c-1, mmu-mir-30c-2, mmu-mir-29c, mmu-mir-34a
showed that the expression of several miRNAs including miR-203, miR-29c, miR-30c, miR-34a and miR-148a was substantially reduced in the HO samples (Supplementary Figure 1A). [score:3]
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70
[+] score: 3
Recent studies also indicate that some miRNAs contribute to gastric carcinoma, including activated miRNAs (such as miR-21, miR-107, miR-222, and miR-106b) and suppressed miRNAs (such as miR-143, miR145, miR-622, and miR-148a) [16]. [score:3]
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71
[+] score: 3
Other miRNAs from this paper: hsa-let-7a-2, hsa-let-7c, hsa-let-7e, hsa-mir-15a, hsa-mir-16-1, hsa-mir-21, hsa-mir-22, hsa-mir-23a, hsa-mir-24-2, hsa-mir-100, hsa-mir-29b-2, mmu-let-7i, mmu-mir-99b, mmu-mir-125a, mmu-mir-130a, mmu-mir-142a, mmu-mir-144, mmu-mir-155, mmu-mir-183, hsa-mir-196a-1, mmu-mir-199a-1, hsa-mir-199a-1, mmu-mir-200b, hsa-mir-148a, mmu-mir-143, hsa-mir-181c, hsa-mir-183, hsa-mir-199a-2, hsa-mir-199b, hsa-mir-181a-1, hsa-mir-200b, mmu-mir-298, mmu-mir-34b, hsa-let-7i, hsa-mir-124-1, hsa-mir-124-2, hsa-mir-130a, hsa-mir-142, hsa-mir-143, hsa-mir-144, hsa-mir-125a, mmu-mir-196a-1, mmu-let-7a-2, mmu-let-7c-1, mmu-let-7c-2, mmu-let-7e, mmu-mir-15a, mmu-mir-16-1, mmu-mir-21a, mmu-mir-22, mmu-mir-23a, mmu-mir-24-2, rno-mir-148b, mmu-mir-148b, hsa-mir-200c, hsa-mir-155, mmu-mir-100, mmu-mir-200c, mmu-mir-181a-1, mmu-mir-29b-2, mmu-mir-199a-2, mmu-mir-199b, mmu-mir-124-1, mmu-mir-124-2, mmu-mir-181c, hsa-mir-34b, hsa-mir-99b, hsa-mir-374a, hsa-mir-148b, rno-let-7a-2, rno-let-7c-1, rno-let-7c-2, rno-let-7e, rno-let-7i, rno-mir-21, rno-mir-22, rno-mir-23a, rno-mir-24-2, rno-mir-29b-2, rno-mir-34b, rno-mir-99b, rno-mir-100, rno-mir-124-1, rno-mir-124-2, rno-mir-125a, rno-mir-130a, rno-mir-142, rno-mir-143, rno-mir-144, rno-mir-181c, rno-mir-183, rno-mir-199a, rno-mir-200c, rno-mir-200b, rno-mir-181a-1, rno-mir-298, hsa-mir-193b, hsa-mir-497, hsa-mir-568, hsa-mir-572, hsa-mir-596, hsa-mir-612, rno-mir-664-1, rno-mir-664-2, rno-mir-497, mmu-mir-374b, mmu-mir-497a, mmu-mir-193b, mmu-mir-466b-1, mmu-mir-466b-2, mmu-mir-568, hsa-mir-298, hsa-mir-374b, rno-mir-466b-1, rno-mir-466b-2, hsa-mir-664a, mmu-mir-664, rno-mir-568, hsa-mir-664b, mmu-mir-21b, mmu-mir-21c, rno-mir-155, mmu-mir-142b, mmu-mir-497b, rno-mir-148a, rno-mir-15a, rno-mir-193b
Among them are two polycistronic transcripts (miR-15a~16-1 and miR-193b~365-1), and two expressing single miRNAs (miR-148a and miR-155). [score:3]
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72
[+] score: 3
Finally, PRMT5 loss did not consistently regulate MITF or p27 [Kip1] at the transcriptional level, or alter specific microRNAs that are key regulators of these proteins including miR-221, miR-222, miR-181b or miR-148a [36]– [39] (Table 4 and data not shown). [score:3]
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73
[+] score: 3
Other miRNAs from this paper: hsa-let-7a-1, hsa-let-7a-2, hsa-let-7a-3, hsa-let-7b, hsa-let-7c, hsa-let-7d, hsa-let-7e, hsa-let-7f-1, hsa-let-7f-2, hsa-mir-15a, hsa-mir-16-1, hsa-mir-17, hsa-mir-18a, hsa-mir-20a, hsa-mir-21, hsa-mir-29a, hsa-mir-33a, hsa-mir-29b-1, hsa-mir-29b-2, hsa-mir-107, hsa-mir-16-2, mmu-let-7g, mmu-let-7i, mmu-mir-1a-1, mmu-mir-29b-1, mmu-mir-124-3, mmu-mir-126a, mmu-mir-9-2, mmu-mir-132, mmu-mir-133a-1, mmu-mir-134, mmu-mir-138-2, mmu-mir-145a, mmu-mir-152, mmu-mir-10b, mmu-mir-181a-2, hsa-mir-192, mmu-mir-204, mmu-mir-206, hsa-mir-148a, mmu-mir-143, hsa-mir-7-1, hsa-mir-7-2, hsa-mir-7-3, hsa-mir-10b, hsa-mir-34a, hsa-mir-181a-2, hsa-mir-181b-1, hsa-mir-204, hsa-mir-211, hsa-mir-212, hsa-mir-181a-1, mmu-mir-34c, mmu-mir-34b, mmu-let-7d, mmu-mir-106b, hsa-let-7g, hsa-let-7i, hsa-mir-1-2, hsa-mir-124-1, hsa-mir-124-2, hsa-mir-124-3, hsa-mir-132, hsa-mir-133a-1, hsa-mir-133a-2, hsa-mir-138-2, hsa-mir-143, hsa-mir-145, hsa-mir-152, hsa-mir-9-1, hsa-mir-9-2, hsa-mir-9-3, hsa-mir-126, hsa-mir-134, hsa-mir-138-1, hsa-mir-206, mmu-mir-192, mmu-let-7a-1, mmu-let-7a-2, mmu-let-7b, mmu-let-7c-1, mmu-let-7c-2, mmu-let-7e, mmu-let-7f-1, mmu-let-7f-2, mmu-mir-15a, mmu-mir-16-1, mmu-mir-16-2, mmu-mir-18a, mmu-mir-20a, mmu-mir-21a, mmu-mir-29a, mmu-mir-29c, mmu-mir-34a, mmu-mir-330, hsa-mir-1-1, mmu-mir-1a-2, hsa-mir-181b-2, mmu-mir-107, mmu-mir-17, mmu-mir-212, mmu-mir-181a-1, mmu-mir-33, mmu-mir-211, mmu-mir-29b-2, mmu-mir-124-1, mmu-mir-124-2, mmu-mir-9-1, mmu-mir-9-3, mmu-mir-138-1, mmu-mir-181b-1, mmu-mir-7a-1, mmu-mir-7a-2, mmu-mir-7b, hsa-mir-106b, hsa-mir-29c, hsa-mir-34b, hsa-mir-34c, hsa-mir-330, mmu-mir-133a-2, mmu-mir-133b, hsa-mir-133b, mmu-mir-181b-2, hsa-mir-181d, hsa-mir-505, hsa-mir-590, hsa-mir-33b, hsa-mir-454, mmu-mir-505, mmu-mir-181d, mmu-mir-590, mmu-mir-1b, mmu-mir-145b, mmu-mir-21b, mmu-let-7j, mmu-mir-21c, mmu-let-7k, mmu-mir-126b, mmu-mir-9b-2, mmu-mir-124b, mmu-mir-9b-1, mmu-mir-9b-3
Altered expression of miR-152 and miR-148a in ovarian cancer is related to cell proliferation. [score:3]
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74
[+] score: 3
In addition to mir-34a, p53 protein promotes the expression of other miRNAs in lung cancer cells, including mir-184, mir-148, and mir-181. [score:3]
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75
[+] score: 3
Other miRNAs from this paper: hsa-mir-148a
2. Goedeke, L. et al. MicroRNA-148a regulates LDL receptor and ABCA1 expression to control circulating lipoprotein levels. [score:3]
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76
[+] score: 3
114.000598 25466411 91MiR-155 and miR-148a reduce cardiac injury by inhibiting NF-κB pathway during acute viral myocarditis [Internet]. [score:3]
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77
[+] score: 3
Among miRNAs preferentially expressed in the heart (Figure 4) mir-148a, mir-101, and mir-138 are particularly important. [score:3]
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78
[+] score: 3
Cancer Lett 30 Duursma AM Kedde M Schrier M le Sage C Agami R 2008 miR-148 targets human DNMT3b protein coding region. [score:3]
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79
[+] score: 2
In recent studies, miRNAs including miR-148a [8], miR-200c [9], miR-205 [2, 9], miR-21 [10], miR-31 [2], and miR-34 [11], have been reported to regulate drug resistance in PC. [score:2]
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80
[+] score: 2
sham rat) Peers' studies hsa-miR-34a-3p 2.63 upUp, Jess Morhayim[15] hsa-miR-433-3p 1.24 up This study hsa-miR-106b 2.24 up This study hsa-miR-23a 0.48 downDown, Sylvia Weilner[27] hsa-miR-328-3p 0.38 down Down, Sylvia Weilner hsa-miR-29b-3p 2.1 up Up, Jess Morhayim hsa-miR-146a-5p 2.68 up Up, Jess Morhayim hsa-miR-148a-3p 1.85 upUp, Cheng[28] We noted that DKK1 played important role in the development of osteoporosis. [score:2]
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81
[+] score: 2
Other miRNAs from this paper: mmu-mir-148b
MicroRNA-148/152 impair innate response and antigen presentation of TLR-triggered dendritic cells by targeting CaMKIIα. [score:2]
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82
[+] score: 2
Other miRNAs from this paper: mmu-mir-155, hsa-mir-148a, hsa-mir-155
Gonzalez-Martin A The microRNA miR-148a functions as a critical regulator of B cell tolerance and autoimmunityNat. [score:2]
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83
[+] score: 2
The results of our luciferase reporter assay showed that six candidates (mir-20a, mir-106a, mir-106b, mir-148a, mir-182 and mir-301a) could be Clock -targeting miRNAs (Additional file 3B and C). [score:2]
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84
[+] score: 1
Moreover, the quality-of-milk product indicators miR-148a and miR-200c were significantly lower in the extensively hydrolyzed formula than in the standard and follow-on formulas 51. [score:1]
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85
[+] score: 1
It further included miR-146b, miR-210 and multiple members of the miR-148 and miR-181 families. [score:1]
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86
[+] score: 1
Interestingly, the miRNA profile for different lactation days was similar, with the same seven miRNAs dominating each lactation day (miR-148a-3p, miR-181a-5p, miR-22-3p, miR-27b-3p, miR-30a-5p, miR-146b-5p, and miR-26a-5p) (Fig. 1, A–D). [score:1]
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87
[+] score: 1
MiR-122 was the most abundant miRNA in the FBS, followed by miR-1246, miR-423-5p, miR-148a-3p, and let-7 family (Fig. 1f). [score:1]
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88
[+] score: 1
01  hsa-let-7a-5p MIMAT0000062 0.010 −2.98  hsa-miR-4454 MIMAT0018976 0.021 −2.64  hsa-miR-148a-3p MIMAT0000243 0.030 −2.31  hsa-miR-146b-5p MIMAT0002809 0.009 −2.12  hsa-miR-342-3p MIMAT0000753 0.010 −2.11  hsa-let-7f-5p MIMAT0000067 0.021 −2.03  hsa-miR-26a-5p MIMAT0000082 0.034 −2.01  hsa-let-7d-5p MIMAT0000065 0.038 −2.01  hsa-miR-30b-5p MIMAT0000420 0.019 −1.96  hsa-miR-29b-3p MIMAT0000100 0.044 −1.94  hsa-miR-29a-3p MIMAT0000086 0.024 −1.70Significant deregulated microRNAs in JMML patients compared to Healthy Donors controls (P<0.05; see paragraph in Matherials and Methods section). [score:1]
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89
[+] score: 1
Serum miR-152, miR-148a, miR-148b, and miR-21 as novel biomarkers in non-small cell lung cancer screening. [score:1]
[1 to 20 of 1 sentences]
90
[+] score: 1
Previous studies have demonstrated that the myomiRs miR-1, miR-133a/b, miR-206, miR-486, miR-26a, miR-27b, miR-378, miR-148a and miR-181 are highly enriched in skeletal muscle and play a key role in skeletal muscle metabolism [28, 29, 30, 31]. [score:1]
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91
[+] score: 1
Other miRNAs from this paper: hsa-mir-148a
Hepatitis B virus X protein repressed miRNA-148a to enhance tumorigenesis through Akt and ERK mediating EMT of HCC [27]. [score:1]
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92
[+] score: 1
Hepatitis B virus X protein represses miRNA-148a to enhance tumourigenesis by mediating HCC EMT through the Akt and ERK signalling pathways 44. [score:1]
[1 to 20 of 1 sentences]
93
[+] score: 1
Other miRNAs from this paper: mmu-mir-26b
Shi C. Zhang M. Tong M. Yang L. Pang L. Chen L. Xu G. Chi X. Hong Q. Ni Y. miR-148a is Associated with Obesity and Modulates Adipocyte Differentiation of Mesenchymal Stem Cells through Wnt SignalingSci. [score:1]
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94
[+] score: 1
Furthermore, mmu-mir-101, mmu-mir-148a, mmu-mir-26a, and mmu-mir-30d were profuse in our sequencing libraries, as already reported in other animal gonads [1, 28, 37]. [score:1]
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95
[+] score: 1
Additionally, miR-23a [15], miR-24 [16], miR-26 [17], miR-27a [18, 19], miR-27b [20], miR-29 [21], miR-124 [22], miR-128a [23], miR-146b [24], miR-148a [25], miR-155 [26], miR-181 [27], miR-199 [28], miR-186 [29], miR-214 [30], miR-221/222 [31], miR-351 [32], miR-486 [33], miR-489 [34], miR-499 [35] and miR-3906 [36] are reported to be involved in skeletal myogenesis. [score:1]
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96
[+] score: 1
MiRs-141-3p and 200c-3p appeared to increase prior to amylase or lipase in the 3 μg/kg group and displayed increases similar to amylase in the 15 and 45 μg/kg groups while miR-148a-3p displayed increases similar to amylase. [score:1]
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