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290 publications mentioning hsa-mir-106b (showing top 100)

Open access articles that are associated with the species Homo sapiens and mention the gene name mir-106b. Click the [+] symbols to view sentences that include the gene name, or the word cloud on the right for a summary.

1
[+] score: 413
We further detected the expression of Bcl-2 and Bax in xenograft tumours by immunohistochemistry and found that miR-106b could upregulate the expression of Bcl-2, while it significantly downregulated the expression of Bax (Additional file 5: Figure S1F). [score:13]
Our studies found that the overexpression of miR-106b improves p-AKT1/2 expression, and miR-106b knockdown could inhibit the expression of p-AKT1/2 (Fig.   4a). [score:10]
The results suggested that the overexpression or knockdown of miR-106b could, respectively, enhance or reduce tumour radioresistance in vivo, as demonstrated by a lower or higher tumour inhibition ratio, respectively, compared with the control groups, while down-regulation resulted in an evidently higher ratio (**p<0.01; Fig.   1e and Additional file 5: Figure S1E). [score:8]
Overexpression of miR-106b reduced the expression of PTEN and p21 and increased the expression of p-AKT, which is a downstream of PTEN. [score:7]
The overexpression of p21 in miR-106b -overexpressing SW620 cells could reverse the miR-106b -mediated radioresistance, which suggested that p21 functioned as a DNA damage repair inhibitor. [score:7]
c The mRNA expression levels of PTEN after the inhibition of miR-106b in SW480 cells or the overexpression of the same miRNA in SW620 cells was detected using qRT-PCR. [score:7]
b The expression levels of PTEN and p21 after the inhibition of miR-106b via lentiviral transduction in SW480 cells or the overexpression of the same miRNA by oligonucleotide transfection or lentiviral transduction in SW620 cells were detected using western blot. [score:7]
We proved that miR-106b could positively regulate p-AKT expression by downregulating PTEN. [score:7]
miR-106b upregulation downregulates PTEN and p21 and subsequently enhances radioresistance. [score:7]
PTEN is one of the most frequent tumour suppressors in human cancers [26, 27], and miR-106b is upregulated in colorectal cancer tissues. [score:6]
The results showed that the expression of miR-106b inversely correlated with PTEN in colorectal cancer and normal colonic tissues, which further supported the finding that PTEN is a direct target of miR-106b in vivo. [score:6]
In addition, overexpression of miR-106b could enhance the tumour-initiating cell capacity without or with IR condition, such as the colony sphere formation capacity and the upregulation of stemness-related genes (CD133, Sox2). [score:6]
Comparison of G1/S fractions after miR-106b overexpression in SW620 cells or downregulation in SW480 cells by flow cytometry. [score:6]
a p-AKT1/2 levels were examined by western blot after miR-106b overexpression or downregulation. [score:6]
However, p21 knockdown in SW480- anti-miR-106b cells did not induce significant radiosensitivity changes, which indicated that p21 downregulation insufficiently reversed the radiosensitivity and did not ameliorate the DNA damage status, unless the PTEN/PI3K-AKT pathway was activated by miR-106b knockdown. [score:6]
However, we also found that p21 functioned as a DNA damage factor, not a repair factor, when the expression of miR-106b was up- or downregulated. [score:6]
However, only CD133 and Sox2 were up-regulated at the protein level after the overexpression of miR-106b in SW620 cells (Additional file 6: Figure S2). [score:6]
a The detection of cell sensitivity to irradiation by MTT after miR-106b overexpression or downregulation. [score:6]
Our research elucidated that miR-106b could enhance the cell self-renew capacity and upregulate the expression of stem cell markers under both normal and radiation conditions. [score:6]
Genes important for stem cell maintenance, i. e., CD133 and Sox2, were examined by western blot after miR-106b overexpression or downregulation. [score:6]
Our data indicated that HT29 and SW480 cells, which express higher levels of endogenous miR-106b and have been verified as radioresistant [42], expressed less PTEN than the more radiosensitive cell lines SW620 and LOVO cells. [score:5]
Finally, we treated miR-106b -overexpressing SW620 cells with LY294002, which is a highly selective inhibitor of Akt, and the cells were then irradiated (4 Gy). [score:5]
We observed that miR-106b treatment alone can decrease the expression of caspase-3, and this effect was much stronger when combined with radiation therapy (dose of X-ray 4 Gy); reducing miR-106b expression yielded the converse result (Fig.   1d). [score:5]
We focused on the targets of miR-106b and found via a bioinformatics search in Targetscan (http://www. [score:5]
A pcDNA3.1/PTEN vector that expressed the PTEN gene was constructed and successfully transfected into miR-106b -overexpressing SW620 cells, and the success of this transfection was verified with a western blot (Additional file 7: Figure 3B). [score:5]
staining suggested that the overexpression or down-regulation of miR-106b could decrease or increase the γ-H2AX foci numbers, respectively, compared to the control groups (*p<0.05; Fig.   1c). [score:5]
We further identified PTEN and p21 as novel direct targets of miR-106b by using target prediction algorithms and a luciferase assay. [score:5]
We found an inverse correlation between miR-106b RNA expression and PTEN protein expression in colorectal cancer cell lines of different differentiation degrees (Fig.   5a). [score:5]
The restoration of p21 and PTEN expression or treatment with a PI3K-AKT pathway inhibitor can reverse miR-106b -induced radioresistance. [score:5]
Restoring the expression of PTEN or p21 in stably miR-106b -overexpressed cells could rescue the effect of miR-106b on cell radioresistance. [score:5]
By integrating a bioinformatics search (Targetscan) and luciferase assay, we identified PTEN as another functional direct target of miR-106b. [score:5]
Increasing the endogenous miR-106b levels by either oligonucleotide transfection (*p<0.05; Additional file 7: Figure S3A) or lentiviral transduction could significantly decrease PTEN expression both at the RNA and protein levels, but the expression of P21 was only decreased at the protein level. [score:5]
The overexpression of miR-106b could inhibit cell apoptosis, promote proliferation and induce radioresistance in vitro and in vivo when cells were irradiated, which revealed that miR-106b may be an anti-apoptotic and DNA damage repair factor in the presence of radiation. [score:5]
Cell lines that stably overexpressed miR-106b or expressed reduced amounts of miR-106b were established via lentiviral transduction, and this procedure is shown in Additional file 5: Figure S1B (*p<0.05). [score:5]
Similarly, PTEN knockdown could restore the radioresistance of SW480, which may have been due to miR-106b downregulation. [score:5]
The data indicated that SW620 cells that overexpressed miR-106b more readily formed colony spheres, which was accompanied by increased CD133 and Sox2 protein levels, while the inhibition of miR-106b in SW480 cells yielded the opposite effect (**p<0.01; Fig.   2c, d). [score:5]
p21 functioned as a DNA damage repair promoter at “a relatively normal level” of miR-106b and PI3K/AKT, while it acted as a DNA damage repair inhibitor when altering miR-106b expression. [score:5]
The results further confirmed that PTEN and p21 are direct targets of miR-106b. [score:4]
The PI3K-AKT pathway can undoubtedly be activated by miR-106b via the direct targeting of PTEN. [score:4]
These observations illustrated that miR-106b could induce cell radioresistance by directly targeting PTEN and p21, this process was accompanied by tumour-initiating cell capacity enhancement, which is universally confirmed to be associated with radioresistance. [score:4]
We provide a direct link between the self-renewal capacity and radioresistance, which may partially explain why the overexpression of miR-106b could induce cell radioresistance. [score:4]
Additional file 3: miR-106b overexpression  or knockdown amounts of miR-106b were established via lentiviral transduction. [score:4]
Our findings indicated that p21 was also a direct target of miR-106b. [score:4]
To verify whether PTEN is a direct target of miR-106b, PTEN 3′-UTR, the sequence that contains the miR-106b binding sites, was cloned into the downstream luciferase open reading frame. [score:4]
We also showed a similar result in the HT29 cells (Additional file 5: Figure S1C); however, the up-regulation of miR-106b did not produce significant changes in LOVO cells (data not shown). [score:4]
Wang et al. previously demonstrated with a microarray that miR-106b was upregulated in colon cancer cases with lymph node metastasis [28]. [score:4]
In summary, p21 may play an important role in the miR-106b -mediated G1 to S transition and radioresistance, which may also explain why cells that express high levels of endogenous miR-106b are highly resistant to IR. [score:3]
The clinical specimens also revealed that elevated levels of miR-106b correlated with low PTEN expression, indicating miR-106b may be a causal factor for PTEN loss in CRC. [score:3]
We demonstrated that the induction of miR-106b expression could produce a radioresistant phenotype in the normally radiosensitive SW620 cells, while the restoration of PTEN could partially reverse this effect. [score:3]
Fig.  5PTEN expression is inversely related to that of miR-106b in colorectal cancer. [score:3]
When miR-106b increases the capacity of cells to initiate tumours, increased p21 expression promotes cell differentiation and limits self-renewal potential, which may partially explain why p21 minimally impacts the repair of DNA damage caused by miR-106b. [score:3]
The data indicated that the ability of cells to form colony spheres was dramatically enhanced, as indicated by more numerous and larger spheres in cells that expressed increased levels of miR-106b. [score:3]
d PTEN 3′UTRs are targets of miR-106b. [score:3]
In conclusion, cells that express high levels of miR-106b more strongly initiated tumours under both normal and IR conditions. [score:3]
We found that the expression of miR-106b was higher in the highly differentiated cells lines HT-29 and SW480 (Additional file 5: Figure S1A). [score:3]
Overall, our findings documented that cells that expressed more miR-106b were more likely to be radioresistant and repair DNA damage. [score:3]
Fig.  3PTEN and p21 are targets of miR-106b. [score:3]
This finding may explain why cells that express higher high levels of endogenous miR-106b exhibit greater proliferation potential and resistance to IR. [score:3]
The relative expression of miR-106b was normalized to the endogenous control U6. [score:3]
Conversely, decreasing the expression of miR-106b decreased the ability of cells to form colony spheres (**p<0.01; Fig.   2a). [score:3]
To further assess the relationship between PTEN and miR-106b, we screened the PTEN expression in CRC cell lines as well as clinical specimens. [score:3]
Next, we transfected siRNA/p21 into SW480-anti-miR-106b cells in order to determine whether reducing the expression of p21 in SW480-anti-miR-106b cells could restore the cell radioresistance potential. [score:3]
We found that the expression levels of miR-106b and PTEN significantly correlated in colorectal tissues (p = 0.006, Spearman’s r = −0.491) (Fig.   5b). [score:3]
First, we analysed the expression pattern of miR-106b in CRC cell lines with different degrees of differentiation, including LOVO (undifferentiated), HT-29 (highly differentiated), SW620 (poorly differentiated), and SW480 (highly differentiated) cells. [score:3]
In contrast, the transfection of miR-106b inhibitors into SW480 significantly increased the luciferase activity (**p<0.01; Fig.   3e). [score:3]
MicroRNA-106b mimics (sense 5′-UAAAGUGCUGACAGUACAGUGCAGAU-3′ and anti-sense 5′-AUUUCACGACUGUCACGACUA-3′), miR-106b inhibitor (5′-AUUUCACGACUGUCACGACUA-3′), the negative control (5′-CAGUACUUUGUGUAGUACAA-3′), PTEN-shRNA (sense 5′-GAGCGUGCAGAUAAUGACAdTdA-3′ and anti-sense 3′-dAdT CUCGCACGUCUAUUACUGU-5′) and p21-shRNA (sense 5′-GAAAUAAACGGGACUGAAA dTdT-3′ and anti-sense 3′-dTdTCUUUAUUUGCCCUGACUUU-5′) were purchased from GenePharma (Shanghai, China). [score:3]
In contrast, the transfection of miR-106b inhibitors into SW480 increased the luciferase activity. [score:3]
We sought to determine whether the restoration of PTEN in miR-106b -overexpressing SW620 cells could reduce the cell resistance to IR. [score:3]
We found overexpression of miR-106b could induce resistance to IR in vitro and in vivo in SW620 cells. [score:3]
We then transfected the pcDNA3.1/p21 vector into miR-106b -overexpressing SW620 cells (Additional file 7: Figure S3D the right). [score:3]
The expression of miR-106b and PTEN mRNA was detected by qRT-PCR in the 15 subjects from the tumour group and the 15 paired normal controls. [score:3]
e p21 3′UTRs are targets of miR-106b. [score:3]
We verified that p21 had little function in DNA damage repair at high levels of miR-106b and activated PI3K-AKT conditions; inversely, it induced growth arrest and senescence and functioned as a DNA damage repair inhibitor. [score:3]
The expression of this miR-106b is low in the SW620 cell line, which is poorly differentiated. [score:3]
We have verified that p21 is a direct target of miR-106b, as confirmed by a bioinformatics search and a luciferase assay. [score:3]
Moreover, this process was accompanied by an enhancement of the tumour-initiating cell capacity, suggesting that miR-106b may account for the resistance to radiotherapy and may be a potential clinical therapeutic target for patients who rarely benefit from radiation therapy in CRC (Fig.   6). [score:3]
The clonogenic assay results confirmed that cells that overexpressed miR-160b were more resistant to IR than their counterparts, while miR-106b knockdown could enhance cell radiosensitivity (*p<0.05; Fig.   1b). [score:3]
A series of in vitro and in vivo studies demonstrated that the ectopic expression of miR-106b could promote cell proliferation and tumour growth, enhance the tumour-initiating cell capacity and induce cell resistance to ionizing radiation in colorectal cancer. [score:3]
However, the transfection of mimics or inhibitors of miR-106b with the mutant 3′-UTR vector (pLuc-PTEN-mut 3′-UTR) did not affect the luciferase activity (Fig.   3d). [score:3]
In this study, we identified miR-106b could induce cell radioresistance by targeting p21, which induces G [1]/S transition and restrains apoptosis and activating the PTEN/PI3K-AKT pathway. [score:3]
The inhibition of miR-106b yielded the same effect (Fig.   3b, c). [score:3]
Additionally, the transfection of PTEN siRNA into miR-106b-knockdown SW40 cells (Additional file 7: Figure S3C) could induce cell resistance to IR, which was confirmed bys and immunofluorescence staining (*p<0.05, **p<0.01; Fig.   4b, c). [score:2]
Although miR-106b is clearly dysregulated in many human cancers, including CRC [29, 30], few studies are available on its roles on cancer radiosensitivity, especially in CRC. [score:2]
Correspondingly, knocking down miR-106b in SW480 yielded the opposite effect. [score:2]
MiR-106b, a member of the miR-106b-25 cluster, is frequently dysregulated in many human cancers, including CRC. [score:2]
MiR-106b is inversely correlated with PTEN expression in colorectal cancer. [score:2]
Our results determined that at a “relatively normal level” of miR-106b cells (such as that in wild type cells, like SW620), p21 knockdown could enhance cell sensitivity to IR, which indicated that p21 functioned as a DNA damage repair factor. [score:2]
Fig.  6 MiR-106b enhances radioresistance by targeting PTEN and p21. [score:2]
MiR-106b targets PTEN and p21 for repression. [score:2]
Brett et al. found that miR-106b~25 regulates neural stem/progenitor cells (NSPC) via the insulin/IGF-FoxO pathway, which may have important implications in the homeostasis of the neural stem cell (NSC) pool during aging [18]. [score:2]
The results were further confirmed by miR-106b knockdown in SW480 cells. [score:2]
The results revealed the novel roles of miR-106b in colorectal cancer and suggested that miR-106b may be a candidate for the treatment of patients with CRC. [score:1]
b Impact of miR-106b on cell survival foci formation when exposed to irradiation (2, 4, 6, 8 Gy). [score:1]
Taken together, these observations illustrated a synergistic effect between miR-106b restoration and IR. [score:1]
However, the relationship between miR-106b, stemness and radioresistance has not yet been elucidated. [score:1]
The data indicated that miR-106b could enhance the cell radioresistance (*p<0.05 **p<0.01; Fig.   1a). [score:1]
MiR-106b, as a member of the miR-106b-25 cluster, is known to promote cancer cell proliferation and survival in gastric cancer and hepatocellular carcinoma [15– 17]. [score:1]
e Effects of miR-106b on the xenograft radiosensitivity. [score:1]
HT-29 and SW480 are known as highly differentiated cell lines with high levels of endogenous miR-106b. [score:1]
c γ-H2AX was examined by immunofluorescence in the SW620 cells co -transfected with miR-106b and pcDNA3.1/PTEN or SW480 co -transfected with anti-miR-106b and siRNA/PTEN when exposed to radiation (4 Gy, 6 h). [score:1]
We also found that miR-106b could induce G1 to S transition (Additional file 9: Figure S5), which is a radioresistant cell cycle phase [34]. [score:1]
Thus, we sought to explore the effect of miR-106b on the colony survival of CRC cells in the presence of ionizing radiation. [score:1]
Thus, we sought to identify the role of p21 in cell radioresistance in the presence of miR-106b. [score:1]
d γ-H2AX was examined by immunofluorescence after co-transfection with mir-106b and pcDNA3.1/p21 in SW620 cells when exposed to radiation (4 Gy, 6 h). [score:1]
However, the function of miR-106b in radioresistance is currently poorly understood. [score:1]
To detect miR-106b, a stem-loop reverse transcription-polymerase chain reaction (RT-PCR) was performed using All-in-One TM miRNA quantitative RT-PCR (qRT-PCR). [score:1]
a miR-106b induces stem cell-like self-renewal properties. [score:1]
Our data suggested that miR-106b at least partly induces cell radioresistance in CRC. [score:1]
The Spearman correlation indicated an inverse relation between miR-106b and PTEN mRNA in the normal and tumour samples. [score:1]
org) that the 3′-UTRs of human PTEN and p21 contained regions that matched the seed sequences of miR-106b (Fig.   3a). [score:1]
Based on the above results, we concluded that miR-106b enhanced the cell resistance to IR via PTEN/PI3K/AKT pathway. [score:1]
Moreover, miR-106b may be one of the important factors that affect this role. [score:1]
We speculated that p21 is a point of internal contact and interaction between two genes and that the PTEN/PI3K-AKT pathway plays a dominant role during p21 function transformation and miR-106b -mediated cell radioresistance in CRC. [score:1]
b The detection of cell sensitivity to radiation (4 Gy) by MTT 4 days after co-transfection with mir-106b and pcDNA3.1/PTEN or anti-miR-106b and siRNA/PTEN. [score:1]
Based on these data, we concluded that the PTEN/PI3K/AKT pathway plays a dominant role in miR-106b mediated-radioresistance in CRC. [score:1]
Blocking the PI3K/AKT pathway by using LY294002 could reverse the miR-106b -mediated radioresistance. [score:1]
In the figure the alignment of the seed regions of miR-106b with PTEN and p21 3′UTRs is shown. [score:1]
c Effect of miR-106b on DNA damage detected by immunofluorescence when exposed to radiation (4 Gy, 6 h). [score:1]
a PTEN and p21 3′UTRs contain predicted miR-106b binding sites. [score:1]
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2
[+] score: 332
Other miRNAs from this paper: hsa-mir-17, hsa-mir-93, hsa-mir-106a
a HeLa cells were transfected with 100-nm miR-106b inhibitor (anti-miR-106b) or miR-106b control inhibitor (anti-NC) for 24 h, then migration was induced with or without TGF-β1 (5 ng/mL) for 24 h. b Quantification of A. ** P < 0.01, [$$] P < 0.01, [#] P < 0.05. c SiHa cells were transfected with 100-nm miR-106b inhibitor (anti-miR-106b) or miR-106b control inhibitor (anti-NC) for 24 h, then migration was induced with or without TGF-β1 (5 ng/mL) for 24 h. d Quantification of C. ** P < 0.01, [$$] P < 0.01, [#] P < 0.05 To understand how miR-106b was involved in TGF-β1 -induced cell migration in cervical carcinoma, we identified the target genes of miR-106b by using TargetScan. [score:13]
In gastric cancer, miR-106b activates PI3K/AKT signaling by inhibiting the expression of the tumor suppressor gene PTEN, which leads to the down-regulation of cell adhesion molecule E-cadherin, thereby promoting the migration of cancer cells [11, 19]. [score:10]
Studies showed that DAB2 protein as a tumor suppressor inhibits cell growth in lung cancer, and miR-93, which is homologous to miR-106b, can inhibit its function in regulating the DAB2 protein level [27]. [score:8]
The TGF-β1 downregulated expression of DAB2 protein was closely related to miR-106b expression (Fig.   6c, d). [score:8]
Another important finding from this study was that miR-106b directly targeted the 3′UTR of the DAB2 and inhibited DAB2 expression as seen on double luciferase reporter gene assay. [score:7]
The miR-106b mimic (50 nm) with increasing 30 times (Fig.   2b) or miR-106b inhibitor (100 nm) with knockdown efficiency at 90 % (Fig.   2c) was the optimal concentration to over -expression or knockdown of miR-106b. [score:7]
Data are mean ± SEM (n = 3)We overexpressed or knocked down miR-106b by transfecting the mimic 106b or inhibitor 106b, respectively, in HeLa cells and examined wound healing (Fig.   3a, b). [score:6]
The most appropriate concentration was obtained by using different concentrations of reagent to overexpress or knockdown miR-106b with mimics or inhibitors, respectively, in HeLa cells. [score:6]
Data are mean ± SEM (n = 3) We overexpressed or knocked down miR-106b by transfecting the mimic 106b or inhibitor 106b, respectively, in HeLa cells and examined wound healing (Fig.   3a, b). [score:6]
Overexpression of miR-106b promoted SiHa cell migration, and knockdown of miR-106b inhibited the cell migration (Fig.   4). [score:6]
This study showed that miR-106b was significantly upregulated in cervical cancer tissues as compared with control tissue, and miR-106b overexpression promoted the migration of HeLa and SiHa cells, which suggests that miR-106b may have a critical role in regulating infiltration and metastasis of cervical cancer. [score:6]
The characteristics of patients are in Table  1. The expression of miR-106b was significantly upregulated in cervical cancer tissues, with relative mean expression 6.21(P < 0.01) (Fig.   1a). [score:6]
TGF-β1 inhibits the expression of DAB2 protein by up -regulating miR-106 partly. [score:6]
Fig. 2Overexpression or knockdown of miR-106b with mimic or inhibitor in cervical cancer cells. [score:6]
Yang et al. showed that miR-106b is highly expressed in gastric cancer, and its expression is negatively correlated with the survival of patients; miR-106b significantly reinforced the invasion and migration ability of gastric cancer cells [11]. [score:5]
We further detected DAB2 expression with TGF-β1 treatment and miR-106b inhibition. [score:5]
The expression of DAB2 was low in cervical cancer tissues, and negatively correlated with miR-106b expression. [score:5]
The TargetScan predictive algorithm identified DAB2 as a potential target of miR-106b. [score:5]
Cells were transfected with miR-106b inhibitor(anti-miR-106b) and miR-106b control inhibitor (anti-NC). [score:5]
Fig. 8DAB2 had low expression in cervical cancer tissues, and which was negatively correlated with miR-106b expression. [score:5]
As well, DAB2 expression was negatively correlated with miR-106b expression in clinical tissue samples and cell experiments. [score:5]
b Western blot analysis of protein level of DAB2 in HeLa cells transfected with miR-106b inhibitor (anti-miR-106b) or miR-106b control inhibitor (anti-NC). [score:5]
miR-106b has been shown to participate in activation of the TGF-β/Smad signaling pathway by inhibiting Smad7 protein expression to intensify the epithelial mesenchymal transition (EMT) in breast cancer cells [13]. [score:5]
DAB2, a predicted target gene of miR-106b, was inhibited by TGF-β1 partly through miR-106b and was involved in TGF-β1 -induced cervical cancer cell migration. [score:5]
Fig. 6DAB2, a predicted target gene of miR-106b, was inhibited by TGF-β1 in part via miR-106b. [score:5]
miR-106b was frequently up-regulated in human cervical carcinoma specimens and cervical cancer cell lines. [score:4]
As well, DAB2 protein level was downregulated with TGF-β1 treatment for 24 h. miR-106b was confirmed to be involved in the effect of TGF-β1 by depleting DAB2 protein. [score:4]
c miR-106b inhibitor (anti-miR-106b) at four concentrations (50, 100, 150, 200 nm) was transfected into HeLa cells to knockdown miR-106b. [score:4]
6. Identification of DAB2 as a miR-106b-directed target gene. [score:4]
As well, the expression of DAB2 protein was increased with knockdown of miR-106b in HeLa cells, for an inverse relation (Fig.   6b). [score:4]
Fig. 9DAB2 was identified as a miR-106b-directed target gene. [score:4]
miR-106b is regulated by TGF-β1 and contributes to cell migration by targeting DAB2 in cervical carcinoma. [score:4]
Fig. 5Knockdown of miR-106b inhibited TGF-β1 -induced cell migration in cervical carcinoma. [score:4]
1. miR-106b was up-regulated in human cervical carcinoma. [score:4]
Wound healing area was significantly decreased with miR-106b knockdown for 24 h, by 27.8 % (18.6 ± 1.16 vs 25.5 ± 1.99 cm2, P < 0.05) (Fig.   3c) and was enhanced with miR-106b overexpression, by 1.66-fold (25.8 ± 1.02 vs 15.5 ± 0.59 cm2, P < 0.01) (Fig.   3d). [score:4]
was used to identify DAB2 as a miR-106b-directed target gene. [score:4]
3. Knockdown of miR-106b inhibited TGF-β1 -induced cell migration in cervical carcinoma. [score:4]
miR-106b inhibitor treatment decreased the TGF-β1-stimulated migration of HeLa and SiHa cells. [score:3]
Fig. 10 miR-106b is involved in TGF-β1 -induced cell migration by targeting DAB2 in cervical carcinoma. [score:3]
SiHa cells were transfected with a miR-106b inhibitor (anti-miR-106b) at 100 nm. [score:3]
Transwell migration assay with e miR-106b knockdown and f miR-106b overexpression. [score:3]
The high expression of miR-106b was also associated with lymph node metastasis in breast cancer. [score:3]
c Western blot analysis of DAB2 protein level in HeLa cells transfected with 100 nm miR-106b inhibitor (anti-miR-106b) for 24 h, then with or without TGF-β1 (5 ng/mL) for 24 h; GAPDH was an internal control. [score:3]
a analysis of mRNA expression of miR-106b in HeLa cells with TGF-β1 treatment for 24 h. Data are mean ± SEM (n = 3). [score:3]
We found that miR-106b had high expression in cervical cancer and promoted the migration of cervical cancer cells. [score:3]
b miR-106b mimic (miR-106b) at four concentrations (10, 50, 100, 200 nm) was transfected into HeLa cells to overexpress miR-106b. [score:3]
Finally, DAB2 was identified as a miR-106b-directed target gene by dual-luciferase reporter assay. [score:3]
b Spearman correlation analysis of DAB2 and miR-106b expression in 19 cervical cancer tissues. [score:3]
Scratch assay of cell migration with c miR-106b knockdown and d miR-106b overexpression. [score:3]
miR-106b was involved in TGF-β1 -induced cell migration by targeting DAB2 in cervical carcinoma. [score:3]
a analysis of the mRNA expression of miR-106b in 19 human cervical carcinoma tissues and 19 normal cervical samples. [score:3]
Likewise, inhibition of miR-106b decreased HeLa and SiHa cells migration. [score:3]
The expression of the miR-106b target gene DAB2 in human cervical tissues and cell lines were measured by qRT-PCR, western blot and immunohistochemistry. [score:3]
HeLa cells were transfected with a miR-106b inhibitor (anti-miR-106b) at 100 nm and b miR-106b mimic(miR-106b) at 50 nm. [score:3]
The TGF-β1/miR-106b/DAB2 axis could provide further insight into the pathogenesis of cervical carcinoma, and miR-106b could be a biomarker and potential therapeutic target in cervical cancer. [score:3]
a of the expression of miR-106b in 4 human cervical cancer cell lines. [score:3]
In general, miR-106b is involved in TGF-β1 -induced cell migration by targeting DAB2 in cervical carcinoma. [score:3]
c Quantification of   In situ hybridization staining of 19 normal cervical specimens and 19 cervical carcinoma tissues miR-106b was highly expressed in the cervical cancer cell lines HeLa, CaSki and SiHa(Fig.   2a). [score:3]
miR-106b inhibitor treatment decreased the TGF-β1-stimulated migration of cervical cancer cells. [score:3]
Transwell assay showed that cell migration was significantly reduced with miR-106b knockdown, by 26.5 % (67 ± 1 % vs 92 ± 4 %, P < 0.05) (Fig.   3e) and was elevated with miR-106b overexpression, by 1.46-fold (212 ± 9 vs 145 ± 7, P < 0.05) (Fig.   3f). [score:3]
The expression of miR-106b in C33A cells was a control. [score:3]
The expression of miR-106b was doubled with TGF-β1 treatment for 24 h (Fig.   6a). [score:3]
a The predicted interaction site of miR-106b and candidate target gene DAB2 3′UTR. [score:3]
Over -expression of miR-106b significantly promoted HeLa and SiHa cells migration. [score:3]
A number of reports have clarified that miR-106b is involved in the regulation of invasion and migration in various human cancers. [score:2]
The primer sequences were for miR-106b, 5′-AAGTGCTGACAGTG CAGATAA-3′, mature miR-106b mimic, 5′-CAAAGUGC UCAUAGUGCAGGUAG -3′ and miR-106b inhibitor, 5′-GUUUCACGAGUAUCACGUCCAUC-3′(Ribobio, Guangzhou, China). [score:2]
Our previous study first found that miR-106b was a key factor in cervical cancer development [10]. [score:2]
After inhibition of miR-106b, the number of cells migration was greatly reduced as compared with cells, treated with TGF-β1 alone (Fig.   5) (P < 0.05). [score:2]
4. DAB2 was regulated by TGF-β1 and miR-106b. [score:2]
In situ hybridization revealed positive expression of miR-106b in cervical cancer tissue and interstitial tissue as compared with controls (Fig.   1b, c). [score:2]
The expression of miR-106b in human cervical specimens was detected by real-time PCR analysis and in situ hybridization assay. [score:2]
We then found target genes of miR-106b according to the network map from our miRNA and mRNA microarray assays. [score:2]
We next identified the regulation of TGF-β1, miR-106b and DAB2. [score:2]
HEK-293A cells in 24-well plates were transfected with the wild-type and mutant DAB2 luciferase reporter vector and miR-106b mimics. [score:1]
We found out whether miR-106b was also involved in the progress of TGF-β1 -induced migration in cervical cancer cells. [score:1]
Moreover, we revealed the molecular mechanisms of miR-106b involved in TGF-β1 -induced cervical cancer cell migration. [score:1]
In situ hybridization In situ hybridization was performed by use of the miR-106b in situ hybridization labeling Kit. [score:1]
2. miR-106b promoted the migration of cervical cancer cells. [score:1]
MicroRNA-106b (miR-106b) was recently identified as an oncogene participating in cancer progression. [score:1]
Mature miR-106b was detected by using a miRNA miRcute fluorescent quantitative detection kit (FP401) (TIANGEN, Beijing). [score:1]
We evaluated the expression of miR-106b in 19 cervical cancer and 19 normal cervical samples by quantitative real-time PCR. [score:1]
Our data confirmed that miR-106b acts as a tumor promoter in cervical cancer progression. [score:1]
miR-106b promotes the activation of Wnt signal and induces β-catenin to enter the nucleus, thereby enhancing the ability of tumor cell invasion and migration [12]. [score:1]
Whether miR-106b is involved in TGF-β1 -induced migration of cervical cancer cells is unknown. [score:1]
The red rectangle represents miR-106b. [score:1]
However, the roles of miR-106b in cervical carcinoma progression and TGF-β1-involvement in the tumorigenesis of cervical cancer remain unknown. [score:1]
The DAB2 gene 3′UTR with 166 bp sequences including predicted miR-106b binding sites was amplified by PCR from human genomic DNA. [score:1]
The mutant DAB2 3′UTR vector was constructed in the dual luciferase reporter gene pmir-GLO vector with miR-106b matching nucleotides “GCACTTT” replaced with “TATAGGG” (Life Technologies, Shanghai). [score:1]
Our data suggest that the TGF-β1/miR-106b/DAB2 axis may be involved in the pathogenesis of cervical carcinoma. [score:1]
In situ hybridization was performed by use of the miR-106b in situ hybridization labeling Kit. [score:1]
b In situ hybridization of miR-106b in negative control and normal cervical specimens and cervical carcinoma tissue. [score:1]
miR-106b level was negatively correlated with DAB2 level (R [2] = −0.7744, P < 0.001) (Fig.   8b). [score:1]
The TGF-β1/miR-106b/DAB2 axis is involved in the migration of cervical cancer cells. [score:1]
We subsequently established effective cell mo dels, to explore gain-of-function and loss-of-function of miR-106b in human cervical cancer. [score:1]
After prehybridization for 4 h in a thermostat box at 38 °C, tissue was incubated with 5′digoxigenin-labeled oligonucleotide probe detecting miR-106b and hybridized overnight. [score:1]
and b miR-106b mimics (miR-106b) at 50 nm. [score:1]
Our previous study of miRNA and mRNA microarray first revealed miR-106b as a key node in the signal transduction pathway of cervical cancer [10]. [score:1]
The blue oval represents DAB2 protein We evaluated the expression of miR-106b in 19 cervical cancer and 19 normal cervical samples by quantitative real-time PCR. [score:1]
miR-106b was identified to be a tumor promoting factor in breast cancer, hepatocellular carcinoma and melanoma [16– 18]. [score:1]
Previous study found that miR-106b enhanced the migration in breast cancer cells by activating the TGF-β/Smad signaling pathway via degradation of Smad7 [13]. [score:1]
Furthermore, the relationship between DAB2 and miR-106b remains unknown. [score:1]
miR-106b is a member of the miR-106b ~ 25 cluster, which is homologous to the miR-17 ~ 92 cluster known as an oncogenic miRNA family. [score:1]
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3
[+] score: 300
Other miRNAs from this paper: mmu-mir-106b
This inhibitory effect of GSPs on tumor xenograft growth was associated with the downregulation of miR-106b expression as well as upregulation of p21/WAF1/Cip1 protein, which results in suppression of tumor cell proliferation in the xenograft tissues. [score:13]
We present evidence that GSPs inhibit melanoma cancer cell proliferation and in vivo tumor xenograft growth and that they do so through: (i) down-regulation of miRNA-106b expression, and (ii) blocking of melanoma cell division in the G1 phase of the cell cycle through reactivation of tumor suppressor protein p21/WAF1/Cip1. [score:10]
Downregulation of miR-106b resulted in suppression of melanoma cell viability, which suggests that the overexpression of miR-106b observed in the melanoma cells plays a key role in regulation of melanoma cell proliferation. [score:9]
Thus, it can be concluded that in melanoma cells overexpression of miR-106b may have a role in enhanced cell cycle progression while downregulation of miRNA-106b is associated with arrest of the G0/G1 phase and suppression of the levels of cyclins and CDKs proteins associated with the G0/G1 phase of the cell cycle. [score:8]
This is consistent with the report that miR-106b is overexpressed in the majority of gliomas and that downregulation of miR-106b suppresses the growth of human glioma cells(28). [score:8]
In addition, our study reveals for the first time that GSPs have the ability to inhibit the proliferation of melanoma cells and block their cell cycle regulation through their inhibitory effect on miR-106b expression. [score:8]
As treatment with GSPs downregulated miR-106b expression in melanoma cells and suppression of miRNA-106b reduced the viability of melanoma cells, we further determined the effect of GSPs on the viability of melanoma cells. [score:8]
Ivanovska et al. have shown that overexpression of miR-106b in cancer cells promotes cell cycle progression while downregulation inhibits it [16]. [score:8]
As we had found that treatment of melanoma cells with GSPs resulted in suppression of miR-106b (Fig. 3A ' 3B), we further determined whether treatment of GSPs upregulate or reactivate the expression of p21/WAF1/Cip1 in melanoma cells. [score:8]
As shown in Figure 2D, suppression of miR-106b in A375 and Hs294t human melanoma cells caused inhibition of cyclin D1, D2 and E, and reduction in the expression levels of CDK2, CDK4 and CDK6 proteins in both cell lines. [score:7]
These results suggest that the ability of the inhibitor of miR-106b to block the uncontrolled cell cycle progression typical of melanoma cells and to induce their G1-phase arrest is mediated through suppression of the levels of cyclins and CDKs and reactivation of the tumor suppressor protein, p21/WAF1/Cip1. [score:7]
The authors also demonstrated that p21/WAF1/Cip1 is a direct target of miR-106b and its downregulation plays an effective role in miR-106b -induced cell cycle progression. [score:7]
Our finding that downregulation of miR-106b restores the levels of p21/WAF1/Cip1 in vitro (Fig. 5B), suggested that p21/WAF1/Cip1 is a direct target of miR-106b. [score:7]
For this purpose, we used various human melanoma cancer cell lines as an in vitro mo del, and ascertained whether GSPs inhibit the growth of melanoma cancer cells through its inhibitory effect on miRNA-106b expression. [score:7]
Based on the above results, we determined whether inhibition of cell viability after the suppression of miRNA-106b in melanoma cells is associated with its reported effects on cell cycle regulation. [score:6]
Our cell cycle analysis showed that the treatment of melanoma cells (A375 and Hs294t) with anti-miR-106b (an inhibitor of miR-106b) markedly induces G1-phase arrest of both these cell lines indicating that the mechansim underlying the miR-106b -mediated upregulation of the proliferation potential of melanoma cells is associated with enhancement of cell cycle progression. [score:6]
Suppression of miR-106b leads to G0/G1 cell cycle arrest and inhibition of cell cycle regulatory proteins in melanoma cell lines. [score:6]
As we have found that inhibition of miRNA-106b in melanoma cells resulted in G1-phase arrest (Fig. 2C), we determined whether inhibition of melanoma cell viability by GSPs also results in G1-phase cell cycle arrest. [score:5]
For functional analysis, the expression of miR-106b in melanoma cells was silenced using a pre-designed anti-miR-106b inhibitor (Ambion, Austin, TX) following the manufacturer's instructions. [score:5]
To verify whether tumor suppressor protein (p21/WAF1/Cip1) is the direct target of miR-106b, we treated the cells with anti-miR-106b and scrambled miR-106b for 48 h. Treatment of cells with anti-miR-106b decreased the levels of miR-106b (Fig. 2A) while enhancing or reactivating the levels of p21/WAF1/Cip1 in both A375 and Hs294t cells as compared to the control cells that were not treated with anti-miR-106b or treated with scrambled miRNA, as shown in Figure 5A. [score:5]
In summary, we found that miR-106b is markedly upregulated in melanoma cells and acts as an oncogene by regulating the proliferation and cell cycle progression. [score:5]
We next tested whether GSPs have the ability to inhibit the over -expression of miRNA-106b in melanoma cells. [score:5]
Suppression of miR-106b inhibits cell proliferation. [score:5]
We found that downregulation of miR-106b in A375 and Hs294t cells resulted in significant inhibitory function on cell proliferation respectively by 40% and 53% (P<0.005) compared to untreated controls (Fig. 2B), which suggested a relationship between miRNA-106b and the cell proliferation capacity of melanoma cells. [score:5]
To verify whether overexpression of miR-106b in melanoma cells is associated with enhanced proliferation of cells, A375 and Hs294t cells were treated with an inhibitor of miRNA-106b and cell viability was determined. [score:5]
In efforts to develop an effective inhibitor of miR-106b for the treatment of melanoma, we tested the effect of GSPs on the expression level of miR-106b in melanoma cells. [score:5]
The G1 phase arrest in the melanoma cells after their treatment with anti-miR-106b was associated with marked suppression of the expression of both cyclins and CDKs (CDK2, CDK4 and CDK6) and concomitant reactivation of p21/WAF1/Cip1 protein. [score:5]
These data indicate two major observations: (i) GSPs act as an inhibitor of miR-106b in melanoma cells and (ii) that GSPs reactivate tumor suppressor protein p21/WAF1/Cip1 as does anti-miR-106b in melanoma cells. [score:5]
P21/WAF1/Cip1/p21 is a direct target of miR-106b. [score:4]
On RT-PCR analysis of miR-106b expression in the xenograft tumor tissues, we found that the expression level of miR-106b was markedly lower in the mice fed the GSPs-supplemented diet as compared with the control group (Fig. 7A). [score:4]
These cell cycle data suggest that the GSPs -induced reduction in cell proliferation and cell viability in melanoma cells may be associated with the induction of G1 arrest by the GSPs, and that these changes may also be associated with the downregulation of miR-106b levels in melanoma cells on GSPs treatment. [score:4]
Dietary GSPs down regulates miR-106b expression in tumor xenograft tissues. [score:4]
Recently, it has been reported that pRB/E2F and p21/WAF1/Cip1, which promote cell cycle progression, are direct targets of miR-106b [7, 16]. [score:4]
Downregulation of miR-106b in melanoma cells after treatment with GSPs leads to reduction in the viability of melanoma cells. [score:4]
To explore the expression levels of miR-106b in human melanoma cell lines and normal human epidermal melanocytes (NHEM), we examined several human melanoma cell lines (A375, Hs294t, SK-Mel 28, SK-Mel 119, Mel 1241, Mel 1011, and Mel 928) as well as NHEMs using RT-PCR. [score:3]
To further characterize the changes in miR-106b expression in the tumors, fluorescent in situ hybridization (FISH) was used to localize the expression pattern of miR-106b using Locked Nucleic Acid probe (Figure 7B). [score:3]
Effect of GSPs on miR-106b expression and cell viability in A375 and Hs294t melanoma cell lines in vitro. [score:3]
Figure 2(A) Melanoma cell lines (A375 and Hs294t) were transfected with siRNA (Anti-miR-106b, 70 nM) for 48 h. After transfection, miRNA was isolated by Trizol method and the expression levels of miR-106b analyzed using RT-PCR, as detailed in Materials and Methods. [score:3]
Inhibition of miR-106b reduced the levels of cell cycle regulatory proteins in both cell lines as compared to controls. [score:3]
The levels of miR-106b in A375 and Hs294t cell lines were suppressed through transfection with anti-miR-106b using lipofectamine as detailed in the Materials and Methods section. [score:3]
As shown in Figure 1C, overexpression of miR-106b in melanoma cell lines was associated with greater cell viability or proliferation potential, as is evident from the results shown in Figure 1B and Figure 1C. [score:3]
Comparison of the viability and expression of miR-106b in various melanoma cell lines with that of normal human epidermal melanocytes (NHEMs). [score:3]
Overexpression of miR-106b in melanoma cell lines and its association with cell proliferation. [score:3]
Our study indicates that the expression of miR-106b is multi-fold higher (3-6 fold) in melanoma cells than in NHEM. [score:3]
Figure 3Effect of GSPs on miR-106b expression and cell viability in A375 and Hs294t melanoma cell lines in vitro(A) A375 and Hs294t cells were treated with various concentrations of GSPs (0, 20, 40, and 60 μg/ml) for 48 h. miRNA was isolated and subjected to miR-106b analysis using RT-PCR. [score:3]
In the present study, we analyzed the expression profile of miR-106b in seven different melanoma cell lines and NHEM using RT-PCR. [score:3]
Figure 7(A) RT-PCR analysis of miR-106b expression in tumor samples from GSPs-fed and non-GSPs-fed control mice, n=4/group. [score:3]
Treatment of cells with GSPs reduced the expression levels of miR-106b. [score:3]
The expression level of miRNA-106b was significantly reduced (P<0.01) after the treatment of these melanoma cell lines with GSPs. [score:3]
Importantly, the levels of p21/WAF1/Cip1 also are overexpressed/reactivated in melanoma cells after treatment with anti-miR-106b. [score:3]
Suppression of miR-106b in melanoma cells leads to a reduction in cell viability and G1-phase arrest of cell cycle. [score:3]
As shown in Figure 1A, the melanoma cell lines express higher levels of miR-106b than NHEMs (amplicon size 58bp). [score:3]
Dietary administration of GSPs (0.5%, w/w) altered the expression of miR-106b, p21/WAF1/Cip1 and PCNA in A375 tumor xenograft tissues. [score:3]
As phytochemicals are emerging new options for the prevention and treatment of melanoma [19], the proanthocyanidins from grape seeds (GSPs) were tested for their efficacy against melanoma and in particularly as an inhibitor of miR-106b. [score:3]
In concurrence with our RT-PCR data, in situ signals for miR-106b expression (shown in green) were very low in tumor sections obtained from mice fed GSPs as compared to the mice fed the control diet. [score:2]
For the detection of expression levels of miR-106b in tumor sections, a FISH assay was performed using the following LNA/DNA oligos sequences: LNA-miR-106b 5′-ATCTGCACTGTCAGCACTTTA-3′, scramble 5′-GTGTAACACGTCT ATACG CCCA-3′ [34]. [score:2]
As shown in Figure 2A, this transfection strategy resulted in suppression of miR-106b levels in both cell lines as compared with those transfected with scrambled miR and others controls. [score:2]
Anti-miR-106b inhibitor, lipofectamine, primers specific for miRNA-106b and U6 were obtained from Invitrogen (Carlsband, CA). [score:2]
Our cell proliferation assay analysis indicates that the cell proliferation potential of melanoma cell lines (A375, Hs294t, SK Mel 28, SK Mel 119, Mel 1241, Mel 1011, and Mel 928) was several fold higher than that of NHEM and that this proliferation potential of melanoma cells is associated with the higher expression of miR-106b. [score:2]
We then determined the effect of suppression of miRNA-106b on the cell proliferation using an MTT assay. [score:2]
Our results suggested that treatment of melanoma cells with GSPs markedly lowered the levels of miR-106b in melanoma cells and that this resulted in a reduction in the viability and the colony forming ability of the cells. [score:1]
miR-106b is involved in multiple cancer/tumor types, such as gastric, hepatocellular, laryngeal, prostate, breast, endometrial, pancreas and gastric, and thyroid cancers, non-melanoma skin cancer and melanoma [7- 15]. [score:1]
In order to better understand the role of miR-106b in the proliferation of melanoma cells, we selected two melanoma cells lines, A375 and Hs294t. [score:1]
miR-106b -positive in situ hybridization signals appear green, and DAPI nuclear stain appears blue, magnification x40. [score:1]
Transient transfection of miR-106b. [score:1]
The levels of miRNA-106b varied among the cell lines, with the highest amounts being found in the Mel 1241, SK Mel 119, SK Mel 28, Hs294t and Mel 1011 lines. [score:1]
For this purpose, A375 and Hs294t cells were treated with anti-miR-106b for 48 h. The cells were then harvested and subjected to cell cycle analysis. [score:1]
The data for the two cell lines are summarized and presented in terms of the relative band intensity ratio of miRNA-106b vs. [score:1]
The role of miR-106b has been recognized in tumors of many organs [7, 8, 10- 14]; however, little is known about its role in melanoma progression. [score:1]
Thus, our study suggests that (i) miR-106b might be a useful potential therapeutic target for melanoma treatment, and (ii) GSPs should be further investigated as a pharmacological agent alone or in combination with other therapeutic drugs for better management of melanoma in humans. [score:1]
In this study, we first examined the role of miRNA-106b on the progression of melanoma cells. [score:1]
Significant difference between control vs Anti-miR-106b. [score:1]
In general, the expression levels of miRNA-106b in these cells lines is approximately 3- to 6-fold higher than in NHEMs, as estimated by densitometry quantification of the band intensity using imageJ software and calculation of the relative band intensity ratio of miR-106b vs. [score:1]
The A375 and Hs294t cells were treated with various concentrations of GSPs (0, 20, 40 and 60 μg/ml) for 48 h. The cells were then harvested and the levels of miRNA-106b were analyzed using RT-PCR. [score:1]
Fluorescence in situ hybridization detection of miR-106b in tumor sections. [score:1]
The RT-PCR analysis revealed that treatment of melanoma cells with GSPs decreased the levels of miR-106b in a dose -dependent manner (Fig. 3A). [score:1]
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4
[+] score: 299
Other miRNAs from this paper: hsa-mir-21, hsa-mir-125b-1, hsa-mir-143, hsa-mir-125b-2
miR-106b inhibits PTEN expression by directly targetting its 3′-UTRPrevious studies uncovered that miR-106b could post-transcriptionally inhibit PTEN expression in different cancer cells, such as pituitary adenoma, breast cancer, and colorectal cancer [23, 26–28], but whether PTEN was a direct target of miR-106b in human EEC cells remains to be further elucidated. [score:15]
In addition, our results demonstrated that knockdown of miR-106b up-regulated the pro-apoptotic proteins (cleaved-Caspase-3 and Bax) and down-regulated the anti-apoptotic protein (Bcl-2) compared with inhibitor NC group (Figure 3D,E). [score:9]
Previous studies identified that miR-106b inhibits PTEN expression through directly targetting its 3′-UTR in many cancer cells [23, 26, 27]. [score:8]
Previous studies uncovered that miR-106b could post-transcriptionally inhibit PTEN expression in different cancer cells, such as pituitary adenoma, breast cancer, and colorectal cancer [23, 26–28], but whether PTEN was a direct target of miR-106b in human EEC cells remains to be further elucidated. [score:8]
Moreover, we confirmed that miR-106b is up-regulated in EEC tissues and cells, and the suppressive effects of shikonin were abrogated by overexpression of miR-106b in EEC cells. [score:8]
Overexpression of miR-106b attenuates the suppressive effects of shikoninBased on the above results, our data demonstrated that miR-106b was down-regulated in Ishikawa cells after treatment with shikonin. [score:8]
These data indicated that miR-106b suppresses PTEN expression by directly targetting its 3′-UTR in human EEC cells. [score:8]
To investigate whether shikonin suppresses EEC cells’ growth via regulating miRNAs expression, we performed microarray analysis to determine miRNA levels in EEC cells after treatment with shikonin (5 μM) for 24 h. As shown in Figure 2A, compared with blank group, shikonin treatment resulted in aberrant expression of miRNAs, and miR-106b is one of the miRNAs being most significantly down-regulated in EEC cells. [score:8]
miR-106b inhibits PTEN expression by directly targetting its 3′-UTR. [score:8]
Then, we speculated that shikonin may exert suppressive effects on EEC cells via modulating PTEN/AKT/mTOR signaling pathway by suppressing miR-106b expression. [score:7]
Moreover, we further predicted the target genes of miR-106b using TargetScan, and identified PTEN as a potential target of miR-106b (Figure 5A). [score:7]
In the present study, we performed microarray analysis to identify miRNAs expression in EEC cells treated with shikonin, and found that shikonin alters a large set of miRNAs and miR-106b was one of the miRNAs being most significantly down-regulated. [score:6]
As shown in Figure 5B,C, up-regulation of miR-106b reduced the PTEN protein level compared with NC, conversely, knockdown of miR-106b increased the PTEN protein expression. [score:6]
These results indicated that the shikonin may exert suppressive effects on EEC cells via regulating miR-106b expression. [score:6]
As expected, shikonin treatment could inhibit the PTEN/AKT/mTOR signaling pathway in human EEC cells, but it was reactivated by miR-106b up-regulation. [score:6]
Figure 3Knockdown of miR-106b suppresses EEC cells apoptosis(A, B) The Ishikawa or HEC-1A cells were transfected with miR-106b inhibitor or inhibitor NC, and cell viability was measured using CCK-8 post treatment at 1, 2, 3 and 4 days, respectively. [score:6]
We found that shikonin treatment dramatically inhibits cell proliferation and promotes apoptosis in shikonin + mimic NC group compared with blank group, but these suppressive effects of shikonin on EEC cells were abolished by overexpression of miR-106b in shikonin + miR-106b mimic group (P<0.01; Figure 4A–D). [score:6]
Shikonin suppresses the PTEN/AKT/mTOR signaling pathway via down-regulation of miR-106b AKT/mTOR signaling which is negatively modulated by PTEN is a key pathway in cell survival, cellular proliferation, and tumor growth [29–31]. [score:6]
Shikonin suppresses the PTEN/AKT/mTOR signaling pathway via down-regulation of miR-106b. [score:6]
Overexpression of miR-106b attenuates the suppressive effects of shikonin. [score:5]
We observed that miR-106b mimic dramatically suppressed the luciferase activity compared with the mimic NC, but miR-106b inhibitor significantly increased the luciferase activity compared with the inhibitor NC (P<0.01; Figure 5D). [score:5]
These data suggested that shikonin may exert anticancer effects via suppressing the expression of oncogenic miR-106b in EEC cells. [score:5]
Taken together, these results suggested that shikonin blocks PTEN/AKT/mTOR signaling pathway via suppressing miR-106b expression in human EEC cells. [score:5]
Collectively, these data indicated that shikonin blocks PTEN/AKT/mTOR signaling pathway via inhibiting miR-106b expression in human EEC cells (Figure 8). [score:5]
Additionally, we first demonstrated that miR-106b acts as an oncogene by targetting the tumor suppressor gene PTEN in EEC cells. [score:5]
Microarray analyses uncovered that shikonin induces a large set of miRNAs dysregulation, and the miR-106b was one of the miRNAs being most significantly down-regulated. [score:5]
Knockdown of miR-106b suppresses EEC cells apoptosis. [score:4]
These data suggested that shikonin may exert the suppressive effects on EEC cells via down -regulating miR-106b. [score:4]
Inspired by these studies, we hypothesized whether shikonin -induced miR-106b down-regulation modulates PTEN/AKT/mTOR signaling pathway in EEC cells. [score:4]
Knockdown of miR-106b inhibits EEC cells apoptosis miR-106b has been demonstrated to function as an oncogene in many cancers [23–25], but its role in EEC has yet to be elucidated. [score:4]
Based on the above results, our data demonstrated that miR-106b was down-regulated in Ishikawa cells after treatment with shikonin. [score:4]
Our results showed that shikonin treatment markedly increased PTEN expression and decreased the p-AKT and p-mTOR levels compared with blank group in both Ishikawa and HEC-1A cells, but this shikonin-blocked PTEN/AKT/mTOR pathway was reactivated by overexpression of miR-106b (P<0.01; Figure 7A–D). [score:4]
Our results first demonstrated that miR-106b functions as an oncogene in EEC, and knockdown of miR-106b suppresses cell proliferation and apoptosis via modulating the intracellular apoptotic signaling pathway. [score:4]
Figure 8The schematic diagram illustrates that shikonin treatment induces the down-regulation of miR-106b in EEC cells, and then results in the up-regualtion of PTEN. [score:4]
The schematic diagram illustrates that shikonin treatment induces the down-regulation of miR-106b in EEC cells, and then results in the up-regualtion of PTEN. [score:4]
Additionally, miR-106b did not inhibit the luciferase activity of the reporter vector containing 3′-UTR of PTEN with mutations in the miR-106b -binding site (Figure 5D). [score:4]
Knockdown of miR-106b inhibits EEC cells apoptosis. [score:4]
To further validate that the PTEN level is regulated by miR-106b, the Ishikawa or HEC-1A cells were transfected with miR-106b mimic/inhibitor or NC and Western blot was used to detect PTEN level. [score:4]
More importantly, our results uncovered that shikonin possessed the suppressive effects on ECC cells via blocking miR-106b/PTEN/AKT/mTOR signaling pathway, suggesting shikonin could act as a promising anticancer agent for EEC treatment. [score:3]
To explore the role of miR-106b in the suppressive effects of shikonin on EEC cells, the Ishikawa cells were treated with various concentration of shikonin (0, 1, 2, 5, and 10 μM) for 24 h and miR-106b levels were quantitated by qRT-PCR. [score:3]
Figure 7Shikonin blocks the PTEN/AKT/mTOR signaling pathway via suppressing miR-106b(A and C) After transfection with or without miR-106b mimic, the Ishikawa or HEC-1A cells were treated with shikonin (5 μM) for 24 h, and then the expression levels of PTEN, AKT, p-AKT, mTOR, and p-mTOR were measured using. [score:3]
The miR-106b mimics/inhibitor and corresponding negative control (NC) were synthesized by RiboBio (Guangzhou, China). [score:3]
Shikonin blocks the PTEN/AKT/mTOR signaling pathway via suppressing miR-106b. [score:3]
As shown in Figure 3A–C, compared with inhibitor NC, knockdown of miR-106b markedly reduces cell viability and increases apoptotic cells (P<0.01). [score:3]
The wild-type (wt) PTEN-3′-UTR and mutant (mut) PTEN-3′-UTR containing the putative binding site of miR-106b were established (Figure 5A) and cloned in the firefly luciferase expressing vector pMIR-REPORT (Ambion, U. S. A. ). [score:3]
We observed that shikonin reduced the miR-106b expression in a dose -dependent manner in Ishikawa cells (Figure 2B). [score:3]
The potential binding site between PTEN and miR-106b was identified using TargetScan (http://www. [score:3]
Therefore, we speculated whether shikonin possesses the antiproliferation effects on EEC cells through modulating miR-106b expression. [score:3]
These data illustrated that shikonin is able to repress the PTEN/AKT/mTOR signaling pathway in human EEC cells, but it could be reactivated by miR-106b overexpression. [score:3]
PTEN is a target of miR-106b in EEC cells. [score:3]
In the present study, our results also verified that PTEN is a target of miR-106b in ECC cells. [score:3]
Taken together, these findings suggested that miR-106b is overexpressed in EEC tissues and cells, and function as an oncogene in EEC. [score:3]
Figure 5PTEN is a target of miR-106b in EEC cells(A) The PTEN 3′-UTR region containing the wt or mut binding site for miR-106b. [score:3]
Our results confirmed that the antiproliferative and pro-apoptotic effects of shikonin on EEC cell were abolished by miR-106b overexpression. [score:3]
To investigate the role of miR-106b in EEC, we performed the qRT-PCR to determine miR-106b expression in EEC tissues and found that miR-106b is dramatically up-regulated in cancer tissues compared with normal tissues (P<0.01; Figure 2C). [score:3]
It is well reported that miR-106b promotes the cell proliferation, invasion, and migration via regulating PTEN/PI3K/AKT signaling pathway in various cancers [23, 26, 27]. [score:2]
These results indicated that miR-106b may play an oncogenic role in the development of EEC. [score:2]
Site-directed mutagenesis of the PTEN 3′-UTR at the putative miR-106b binding site was performed by a QuikChange Kit (Qiagen). [score:2]
Moreover, our results further verified that miR-106b is also significantly overexpressed in EEC cell lines (Ishikawa, HEC-1A, KLE, and RL95-2) compared with ESC cell (P<0.01; Figure 2D). [score:2]
For the luciferase assay, Ishikawa cells at a density of 2 × 10 [5] per well were seeded into 24-well plates and co -transfected with 0.8 μg of pMIR-PTEN-3′-UTR or pMIR-PTEN-mut-3′-UTR, 50 nM miR-106b mimic/inhibitor or corresponding mimic NC using Lipofectamine 2000 reagent (Invitrogen). [score:2]
To further explore the effects of miR-106b on EEC cells, the Ishikawa and HEC-1A cells were transfected with miR-106b inhibitor or inhibitor NC, and then cell viability and apoptotic cells were measured by CCK-8 assay and cytometric analysis, respectively. [score:2]
Figure 4Overexpression of miR-106b attenuates the suppressive effects of shikonin(A and C) The Ishikawa or HEC-1A cells were transfected with miR-106b mimics or NC, and then treated with shikonin (5 μM) for 24, 48, and 72 h; the CCK-8 was assay used to measure cellular proliferation, respectively. [score:2]
Recent studies demonstrated that miR-106b promotes the cell proliferation, invasion, and migration in a variety of cancers via modulating PTEN/PI3K/AKT signaling pathway [23, 26, 27]. [score:1]
More importantly, our results indicated that shikonin represses proliferation and induces apoptosis in ECC cells via modulating miR-106b/PTEN/AKT/mTOR axis. [score:1]
To verify this hypothesis, after transfection with or without miR-106b mimics, the Ishikawa or HEC-1A cells were treated with shikonin (5 μM) for 24 h and PTEN, AKT and mTOR were identified using Western blot. [score:1]
Previous studies have demonstrated that miR-106b function as an oncogene in different cancers, such as breast cancer, osteosarcoma, and hepatocellular carcinoma [23–25]. [score:1]
Our results suggested that shikonin may possess anticancer effects on EEC via mediating miR-106b/phosphatase and tensin homolog (PTEN)/AKT/mTOR signaling pathway and act as a potential therapeutic agent for the treatment of EEC. [score:1]
Moreover, miR-106b was identified to act as an oncogene in EEC. [score:1]
miR-106b has been demonstrated to function as an oncogene in many cancers [23–25], but its role in EEC has yet to be elucidated. [score:1]
The wt or mut reporter plasmid was co -transfected into Ishikawa cells along with miR-106b mimics/inhibitor or NC, and measured the luciferase activity. [score:1]
It is well reported that miR-106b has been identified to act as an oncogene in various cancers including breast cancer, osteosarcoma, and hepatocellular carcinoma [23–25]. [score:1]
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5
[+] score: 271
Other miRNAs from this paper: hsa-mir-21, hsa-mir-373, hsa-mir-520c
miR-106b Over -expression Up-regulated RhoGTPases Expression. [score:8]
miR-106b knock-down cells decrease mesenchymal markers expression and increase epithelial marker expression indicating miR-106b expression can activate EMT process. [score:8]
When miR-106b expression was down-regulated, expression of epithelial marker, E-cadherin, increased while mesenchymal markers, N-cadherin, Vimentin, and TWIST1, decreased. [score:8]
Our result suggested that miR-106b over -expression can up-regulate RhoA and RhoC expression. [score:8]
We correlated clinicopathological parameters of the patients with miR-106b expression and observed that over -expression of miR-106b (>2-fold difference between tumor and non-tumor) correlated with higher tumor grade, which is associated with more aggressive disease and poor prognosis. [score:7]
Knock-down of miR-106b significantly down-regulate RhoA and RhoC expression, but not in the scramble control. [score:7]
This indicated that expression of miR-106b can indirectly regulate the expression of RhoGTPases. [score:7]
This observation can be confirmed by up-regulation of RhoGTPases in miR-106b over -expressing transfectant, PLC-PT/106b+, Huh7/106b+, and Hep3b/106b+. [score:6]
To investigate the functional role of miR-106b, we knocked down miR-106b in the lung metastasis cell line with high miR-106b expression and over-expressed miR-106b in the primary tumor cell lines with low miR-106b expression. [score:6]
0057882.g005 Figure 5 (A) High miR-106b expressing cells (PLC-LM, PLC-PT/106b+, PLC-PT/LNA-Scr, PLC-LM/LNA-Scr, Huh7/106b+, and Hep3B/106b+) show over -expression of RhoA and RhoC by western blotting. [score:5]
Our result suggested that increase of cell motility in vitro and metastasis development in vivo were affected by the indirect regulation of RhoA and RhoC through miR-106b regulation. [score:5]
Alteration of RhoGTPases and EMT markers expression attributed to miR-106b expression. [score:5]
Over -expression of RhoGTPases can be observed in miR-106b over -expressing cell lines, PLC-LM, PLC-PT/106b+, PLC-PT/LNA-Scr, PLC-LM/LNA-Scr, Huh7/106b+, and Hep3B/106b+, but not in the corresponding control. [score:5]
Our results demonstrated that miR-106b over -expressing cells, PLC-LM, have higher expression level for RhoA and RhoC than the PLC-PT. [score:5]
This is the first study reporting the role of miR-106b in HCC metastasis and implies a potential strategy to inhibit metastasis in HCC by targeting miR-106b. [score:5]
miRNA-106b LNA knock-down probe and the scramble control (Exiqon, Vedbaek, Denmark) were transfected into the miR-106b over-expressed cell line, PLC-LM, using Lipofectamine 2000 (Life Technologies, Carlsbad, CA) according to manufacturer's protocol. [score:4]
C. miR-106b was over-expressed in PLC-PT and knock-down in PLC-LM cells. [score:4]
miR-106b was over-expressed in PLC-PT and knock-down in PLC-LM cells. [score:4]
We postulated that miR-106b over -expression may regulate EMT process in cancer. [score:4]
A microarray study demonstrated that miR-106b was up-regulated in colon cancer with lymph node metastasis [8]. [score:4]
QPCR analysis showed successful miR-106b knock-down in PLC-LM cells by Locked Nucleic Acid (LNA) with >50% efficiency from Day 1 to Day 4 after transfection (Fig. S1E), while the lentiviral system stably over-expressed 9-fold higher miR-106b than the empty vector control in PLC-PT cells (Fig. S1F). [score:4]
This showed that miR-106b expression could promote formation of lung metastatic nodules in mice, further corroborating a critical role of miR-106b in development of HCC metastasis. [score:4]
Our results demonstrated that upon miR-106b knock-down, the expression of epithelial marker increased while the mesenchymal markers decreased (Fig. 5B). [score:4]
miR-106b can directly bind to p21 and regulate cell cycle progression [9]. [score:3]
Clinicopathological analysis for miR-21 and miR-106b expression in HCC clinical samples. [score:3]
The only significant correlation observed was higher tumor grade in tumors with miR-106b over -expression (T vs NT >2-fold) (p = 0.014). [score:3]
We demonstrated that over -expression of miR-106b can increase stress fiber formation, hence, enhancing migration ability in vitro. [score:3]
Higher miR-106b expressing cells, PLC-LM/Scr and PLC-PT/106b+, can promote cell migration in vitro. [score:3]
The results demonstrated that miR-106b expression can promote formation of stress fiber, hence, increase migration ability of the HCC cells. [score:3]
Lung metastatic nodules were observed in 4 out of 5 mice (80%) in the miR-106b over -expressing group, whereas in the empty vector control group, only 1 out of 5 mice (20%) developed lung metastasis. [score:3]
Meanwhile, cells transduced with lentivirus over -expressing miR-106b (PLC-PT/106b+, Huh7/106b+, Hep3B/106b+) also show activation of EMT compare to their corresponding vector control (PLC-PT/V. [score:3]
However, cell lines with higher miR-106b expression, PLC-LM/LNA-Scr and PLC-PT/106b+, had higher migration ability. [score:3]
Moreover, there was higher expression of miR-106b in more advanced tumor stage, although the difference was marginally not significant. [score:3]
More stress fiber (white arrow) was observed in miR-106b over -expression cells in Huh7/106b+ (C) and Hep3B/106b+ (D) cell lines compare to the vector control cell lines, Huh7/V. [score:3]
C. PLC-PT cells stably over -expressing miR-106b were implanted into liver of SCID mice. [score:3]
There was also a trend towards advanced TNM stage with miR-106b over -expression, but the difference was marginally not significant (p = 0.061). [score:3]
Other 2 HCC cell lines, Huh7 and Hep3B, with lentiviral transduction also show around 6-fold over -expression of miR-106b compare to the corresponding vector control (Fig. S1F). [score:3]
Previous studies have already demonstrated that miR-106b was involved in various important signaling pathways such as PTEN tumor-suppressive pathway [24], and TGF-beta signaling pathway [25]. [score:3]
This result suggested that miR-106b over -expression can activate EMT process and promote cell migration in vitro and metastasis in vivo. [score:3]
In addition, the phalloidin staining demonstrated that both cell lines process more stress fiber in the miR-106b over -expressing cells, but not in the vector control (Fig. 4C and 4D). [score:3]
To confirm this finding, we also over-expressed miR-106b in PLC-PT cell line. [score:3]
With higher miR-106b expression, the cells exhibited higher metastatic potential. [score:3]
Furthermore, two metastatic cell lines had higher miR-106b expression than the corresponding primary tumor cell lines (Fig. S1B). [score:3]
GFP+ cells were harvested and QPCR analysis was employed to confirm the over -expression of miR-106b. [score:3]
Although our focus in this study was miR-106b, the highest differentially expressed miRNA was miR-21, which is a well-known miRNA involved in various kinds of cancer including HCC [3], [16], [17] and has been proven to promote metastasis in breast and colorectal cancer [18], [19]. [score:3]
All HCC cell lines show higher expression of miR-106b than normal hepatocyte cell line, MIHA (Fig. S1A). [score:3]
In vitro Functional Studies of miR-106b Konck-down or Over-expressed Cell Lines. [score:3]
miR-106b over -expressing cells, Huh7/106b+ and Hep3B/106b+, show enhanced cell migration ability when compare to its corresponding vector control, Huh7/V. [score:3]
We observed lung metastatic nodules in 80% of mice inoculated with miR-106b over -expressing cells, whereas only 20% mice developed lung metastasis in the empty vector control group. [score:3]
We observed higher cell migration ability with increase in stress fiber formation upon miR-106b over -expression. [score:3]
miR-106b is transcripted from the miR-106b-25 cluster located on chromosome 7. This miRNA cluster is reported to be over-expressed in HCC clinical samples [7]. [score:3]
QPCR analysis for miR-21 and miR-106b expression in HCC and nontumorous liver was performed. [score:3]
Fig. 3A and 3B showed the effect on wound healing assay after miR-106b LNA knock-down in PLC-LM cell line and miR-106b over -expression in PLC-PT cell line respectively. [score:3]
EMT activation was also observed in miR-106b over -expressing cell lines, Huh7/106b+ and Hep3b/106b+, but not in its corresponding vector control. [score:3]
PLC-PT cell line with stable over -expression of miR-106b was orthotopically implanted into the mice to examine the in vivo metastatic potential. [score:3]
Migration ability was increased when we over-expressed miR-106b in the cells without affecting cell proliferation rate and invasion ability. [score:3]
miR-21 and miR-106b showed significant up-regulation in tumors compared with the non-tumor tissues (p = 0.0059 and 0.0005 respectively) (Fig. S1C and S1D). [score:3]
Our in vitro studies demonstrated miR-106b over -expression can increase cancer cell motility by inducing stress fiber formation. [score:3]
We also analyzed the clinical relevance of miR-106b expression. [score:3]
Orthotopic Metastasis Animal Mo del for PLC-PT with miR-106b Over -expression. [score:3]
Expression of miR-21 and miR-106b was significantly higher in HCC tumor tissue. [score:3]
miR-106b expression in other HCC cell lines was also compared. [score:2]
miR-106b were transiently knocked down by LNA in both PLC-PT and PLC-LM cell lines. [score:2]
Cell migration ability was compared in Huh7 (A) and Hep3B (B) cell lines with or without over -expression of miR-106b. [score:2]
Our results demonstrated that miR-106b was over-expressed in tumor tissue compared with the adjacent non-tumor tissue. [score:2]
Even we can observed miR-106b expression is higher in MHCC97H-LM, this does not make any differences in the in vitro functional characteristics of this two cell lines since some of the down-stream molecule are deregulated due to the aggressive nature in the parental cell line, MHCC97H. [score:2]
Our results suggested that migration ability decreased upon miR-106b knock-down without affecting cell proliferation rate and invasion ability, suggesting the main functional role of miR-106b in enhancing cell motility. [score:2]
The wound healing assay showed that miR-106b over -expression can enhance the cell migration ability in vitro in both cell lines (Fig. 4A and 4B). [score:2]
This study demonstrated the involvement of miR-106b in development of HCC metastasis by orthotopic animal HCC mo del. [score:2]
Regulation of Epithelial-mesenchymal Transition Process by miR-106b. [score:2]
However the role of miR-106b in cancer metastasis remains unclear. [score:1]
Taken together, our data suggest a role of miR-106b in metastasis of HCC via activation of EMT process and enhancement of cell motility. [score:1]
Pre-miR-106b was cloned into pCDH-CMV-MCS-EF1-copGFP vector (System Biosciences, Mountain View, CA). [score:1]
In vitro functional studies for miR-106b in Huh7 and Hep3B cell lines. [score:1]
MTT assay and trans-well invasion assay showed that miR-106b expression level affected neither the cell proliferation rate nor the invasion ability (Data not shown). [score:1]
In contrast, miR-106b is a new candidate miRNA with potential importance in HCC metastasis for further in vitro and in vivo studies. [score:1]
In vitro and in vivo studies for miR-106b. [score:1]
0057882.g003 Figure 3 In vitro and in vivo studies for miR-106b. [score:1]
Amount these miRNAs, miR-21 and miR-106b show clinical significance in this 20 HCC clinical sample cohort. [score:1]
This result demonstrated that miR-106b enhanced metastatic capacity of the PLC-PT cells. [score:1]
Since miR-106b could increase cell migration ability in PLC-PT cell lines, we visualized the stress fiber formation, which can promote cell migration, by phalloidin staining. [score:1]
0057882.g004 Figure 4 In vitro functional studies for miR-106b in Huh7 and Hep3B cell lines. [score:1]
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[+] score: 249
Other miRNAs from this paper: hsa-mir-20a, hsa-mir-23b, hsa-mir-142, hsa-mir-34b
Moreover, miR-106b-5p could directly target the SETD2 mRNA 3′UTR and down-regulate both mRNA and protein of SETD2, suggesting that miR-106b-5p may regulate SETD2 expression by inducing mRNA degradation and/or translational suppression. [score:14]
Given that SETD2 plays a tumor suppressor role and miR-106b-5p has been found responsible for post-transcriptional inhibition of SETD2 in our study, we further explored whether attenuation of miR-106b-5p could suppressed ccRCC cell biologic activity through up-regulation of SETD2. [score:10]
MiR-106b-5p antagomir induced cell cycle arrest and proliferation suppression through up-regulation of SETD2 expression in ccRCC cells. [score:8]
MiR-106b-5p antagomir induced up-regulation of SETD2 expression was reversed by knockdown of SETD2 in ccRCC cells. [score:7]
These results indicated that miR-106b-5p could down-regulate SETD2 expression in ccRCC cells. [score:6]
Inhibition of miR-106b-5p enhanced the binding of H3K36me3 to the promoter of p53, and upregulated p53 transcription through a SETD2 dependent way. [score:6]
Attenuation of miR-106b-5p promoted caspase-3 mediated apoptosis through up-regulation of SETD2 expression. [score:6]
miR-106b-5p downregulated the expression of SETD2 in ccRCC cells. [score:6]
miR-106b-5p down-regulated SETD2 expression in ccRCC cells. [score:6]
These observations revealed that attenuation of miR-106b-5p was able to suppress cell proliferation through up-regulation of SETD2 in ccRCC cells. [score:6]
In gastric cancer, miR-106b-5p could promote the cell cycle by down -regulating target gene expression of p21 and E2F5 [52]. [score:6]
Attenuation of miR-106b-5p suppressed ccRCC cells proliferation through up-regulation of SETD2. [score:6]
These results demonstrated that inhibition of miR-106b-5p could effectively enhance the binding of H3K36me3 to the promoter of p53, resulting in the up-regulation of its transcription through a SETD2 dependent way. [score:6]
Moreover, miR-106b-5p suppresses the expression of SETD2 via the binding site in the 3′-UTR in ccRCC cells, and plays an important role in regulating ccRCC cell proliferation and apoptosis through SETD2 -dependent way. [score:6]
Transfection of anti-miR-106b-5p inhibitor (100 nM) into 786-O (E) and SN12-PM6 (F) cells increased the luciferase activity when compared with those transfected with negative control inhibitor (anti-NC), whereas mutation of miR-106b-5p recognition site abolished these effects. [score:5]
The miRNA inhibitors (anti-miR-23b-5p, anti-miR-34b-3p, anti-miR-106b-5p, anti-miR-142–5p, anti-miR-20a-5p), miRNA inhibitor negative control, miR-106b-5p mimic and negative control mimic were designed and synthesized by RiboBio. [score:5]
In contrast, among the predicted miRNAs that might target SETD2, the expression of miR-23b-5p, miR-34b-3p, miR-106b-5p and miR-142–5p were significantly higher in ccRCC cell lines and tissues, while miR-20a-5p showed no significant difference (Figure 1G). [score:5]
The knockdown effects were further confirmed in 786-O and SN12-PM6 cells, and si-SETD2 could reverse the miR-106b-5p antagomir induced up-regulation of SETD2 mRNA and protein (Figure 4C–4F). [score:5]
To confirm whether miR-106b-5p could repress the expression of SETD2 through directly interacting with its binding sites in the mRNA 3′-UTR, we amplified and cloned the full-length 3′UTR of the SETD2 or the mutation of miR-106b-5p seed recognition sequence into the pmiR-RB-REPORT™ Luciferase reporter vector (Figure 3A). [score:5]
miR-106b-5p directly targeted the SETD2 mRNA 3′UTR. [score:4]
These results collectively demonstrate that SETD2 is indeed a direct target of miR-106b-5p. [score:4]
Moreover, we found that attenuation of miR-106b-5p suppressed cell proliferation and induced cell apoptosis in 786-O and SN12-PM6 ccRCC cells, suggesting it was critical in regulating ccRCC cell biologic activity. [score:4]
A microarray study demonstrated that miR-106b-5p was up-regulated in colon cancer with lymph node metastasis [50]. [score:4]
Furthermore, the inhibition of ccRCC cell proliferation and the induction of apoptotic cells by attenuation of miR-106b-5p were reversed upon knockdown of SETD2. [score:4]
These data indicated that attenuation of miR-106b-5p could promote processing of caspase-3 and induce ccRCC cells apoptosis through up-regulation of SETD2. [score:4]
Real-time RT-PCR and western blot analysis indicated that transfection of miR-106b-5p antagomir increased the p53 expression in both mRNA (E) and protein (F) levels, whereas knockdown of SETD2 reversed the effects. [score:4]
Attenuation of miR-106b-5p promoted processing of caspase-3 and induced ccRCC cells apoptosis through up-regulation of SETD2. [score:4]
In the present study, our data showed that miR-106b-5p was aberrantly up-regulated in both ccRCC samples and cell lines. [score:4]
As shown in Figure 2A, transfection of antagomir against miR-106b-5p significantly up-regulated SETD2 mRNA by 10.4- to 13.9-fold in 786-O cells, and 6.7- to 8.5-fold in SN12-PM6 cells, when compared with mock -transfected or negative control. [score:3]
Figure 7 (A) Western blot showed that transfection of miR-106b-5p antagomir up-regulated the level of H3K36me3 in 786-O and SN12-PM6 cells compared with negative control group, which was reversed by cotransfection of si-SETD2. [score:3]
Over -expression of miR-106b-5p was also demonstrated in breast cancer, and the miR-106b/MMP2/ERK pathway might play a pivotal role in bone metastasis of breast cancer [53]. [score:3]
Thus, p53 probably plays an important role in attenuation of miR-106b-5p to suppress cell biologic activity of ccRCC. [score:3]
Another study reported that miR-106b-5p played an oncogenic role in esophageal neoplasms, and p21 was identified as the target gene of miR-106b-5p [51]. [score:3]
In ccRCC, over -expression of miR-106b-5p was confirmed in renal cancer tissue and has been demonstrated to function as a potential marker for early metastasis after nephrectomy [54]. [score:3]
The renilla luciferase activities normalized to that of firefly were significantly reduced in HK-2, 786-O and SN12-PM6 cells transfected with miR-106B-5p mimic, and the effects were abolished by mutating the predicted miR-106b-5p binding site within the SETD2 mRNA 3′-UTR, indicating a specific suppressive effect of miR-106b-5p on SETD2 (Figure 3B, 3C, and 3D). [score:3]
Therefore, our data demonstrate that SETD2 is a novel target of miR-106b-5p, which has not been reported previously. [score:3]
This study extends the knowledge about the regulation of SETD2 at the posttranscriptional level by miRNA and regulatory mechanism downstream of SETD2, suggesting that miR-106b-5p may be of potential values as novel candidate for the therapeutics of ccRCC. [score:3]
In contrast, transfection of si-SETD2 decreased the apoptotic cells, and significantly inhibited miR-106b-5p antagomir induced cell apoptosis (Figure 6A). [score:3]
Moreover, knockdown of miR-106b-5p with miR-106b-5p antagomir increased the luciferase activity in 786-O and SN12-PM6 cells, whereas mutation of miR-106b-5p recognition site abolished these effects (Figure 3E and 3F). [score:3]
Here, the results revealed that miR-106b-5p was inversely correlated with the expression of SETD2 in ccRCC tissues. [score:3]
SETD2 was lowly expressed and inversely correlated with endogenous miR-23b-5p, miR-34b-3p and miR-106b-5p in ccRCC tissues and cell lines. [score:3]
Moreover, correlation analysis indicated that miR-23b-5p, miR-34b-3p and miR-106b-5p were inversely correlated with the expression of SETD2 in ccRCC (p < 0. 0001, Figure 1H). [score:3]
As shown in Figure 7A, transfection of miR-106b-5p antagomir significantly increased the total H3K36me3 levels in 786-O and SN12-PM6 cells, which was inhibited by cotransfection with si-SETD2. [score:3]
To further study the inhibitory effect of miR-106b-5p antagomir on ccRCC cells, we examined cell apoptosis by flow cytometry using Annexin V and PI staining method. [score:3]
These results indicated p53 probably plays a critical role in attenuation of miR-106b-5p to suppress cell biologic activity through SETD2. [score:3]
Figure 3 (A) Chematic representation of miR-106b-5p target binding site in the SETD2 mRNA 3′UTR identified by the microinspector prediction program. [score:3]
miR-106b-5p directly interacts with 3′UTR of SETD2 mRNA. [score:2]
Thus, our experimental evidences reveal that SETD2 plays an important role in regulating ccRCC cell proliferation and apoptosis, and loss of SETD2 affords for the miR-106b-5p -mediated oncogenic role. [score:2]
To investigate whether the predicted microRNAs could regulate the expression of SETD2, we respectively transfected 100 nM synthesized antagomirs against miR-23b-5p, miR-34b-3p, miR-106b-5p, miR-142–5p and miR-20a-5p into 786-O as well as SN12-PM6 cells. [score:2]
Moreover, the EdU assay showed that attenuation of miR-106b-5p inhibited proliferation of 786-O and SN12-PM6 cells, which was also reversed by transfection of si-SETD2 (Figure 5B and 5C). [score:2]
Therefore, we further investigated whether miR-106b-5p antagomir induced up-regulation of SETD2 could enhance the binding of H3K36me3 to the promoter of p53. [score:2]
More interestingly, the present findings reveal that the post-transcriptional regulation of SETD2 by miR-106b-5p accounts for its inactivation in ccRCC. [score:2]
These effects were abolished by the mutation in the putative miR-106b-5p binding site within the 3′-UTR of SETD2. [score:2]
In our study, the H3K36me3 level was indeed increased in ccRCC cells upon transfection of miR-106b-5p antagomir, which was reversed by cotransfection with si-SETD2. [score:1]
However, the function of miR-106b-5p in ccRCC cells is still unknown. [score:1]
miR-106b-5p is transcribed from the miR-106b-25 cluster, which is located on human chromosome 7q21, and there have been many pioneering studies based on its tumor-specificity [47, 48]. [score:1]
Transfection of miR-106b-5p antagomir produced processing of caspase-3 precursors to their active products, while transfection of si-SETD2 not only decreased the basal level but also reversed the miR-106b-5p antagomir induced high level of active caspase-3 (Figure 6C). [score:1]
Figure 2786-O and SN12-PM6 cells were transfected for 72 h with 100 nM anti-miR negative control, anti-miR-23b-5p, anti-miR-34b-3p, anti-miR-106b-5p, anti-miR-142–5p or anti-miR-20a-5p. [score:1]
Transfection of antagomir against miR-106b-5p resulted in the increased level of SETD2 mRNA in both 786-O (C) and SN12-PM6 (D) cells, which was blocked by co-transfection of si-SETD2. [score:1]
Low levels of SETD2 were inversely correlated with endogenous miR-23b-5p, miR-34b-3p and miR-106b-5p in ccRCC tissues and cell lines. [score:1]
The plasmids were co -transfected with miR-106B-5p mimic or negative control mimic, antagomir against miR-106b-5p or negative control antagomir, respectively. [score:1]
A mutation of the miR-106b-5p binding site in the 3 ‘UTR of SETD2 mRNA was generated using site-directed mutagenesis by the megaprimer PCR method with primers 5′-AATATGCGGCCGCCACATGCTACTGCTTAAAAT-3′ (forward) and 5′-GCCGAGCTCGTGTACGTACTTTATCCAA-3′ (reverse). [score:1]
The results indicated that the binding of H3K36me3 to the promoter of p53 were enhanced upon transfection of miR-106b-5p antagomir, resulting in the increased promoter activity, mRNA and protein levels of p53. [score:1]
EdU assay showed that transfection of miR-106b-5p antagomir inhibited proliferation of 786-O (B) and SN12-PM6 (C) cells compared with negative control ( p < 0.05), which was reversed by the transfection of si-SETD2. [score:1]
786-O and SN12-PM6 cells were transfected with the anti-miR negative control, anti-miR-106b-5p and SETD2 siRNA. [score:1]
In conclusion, we have demonstrated that miR-106b-5p is inversely correlated with SETD2 in ccRCC tissues. [score:1]
Furthermore, transfection of miR-106b-5p mimic resulted in the decreased mRNA and protein levels of SETD2 in 786-O and SN12-PM6 cells (Figure 2C and 2D). [score:1]
Thus, miR-106b-5p is probably a potential candidate for the therapeutics of ccRCC. [score:1]
Figure 6 (A) Annexin V and PI staining flow cytometry assay revealed that transfection of miR-106b-5p antagomir increased the rate of apoptosis in 786-O and SN12-PM6 cells compared with negative control group, while transfection of si-SETD2 decreased the apoptotic cells, and significantly inhibited miR-106b-5p antagomir induced cell apoptosis. [score:1]
Meanwhile, transfection of si-SETD2 both decreased the basal rate of cells in G0/G1 phase and effectively reverse the miR-106b-5p antagomir induced G0/G1 phase arrest (Figure 5A). [score:1]
Consistent with these findings, transfection of miR-106b-5p antagomir resulted in the increased promoter activity (Figure 7D), mRNA (Figure 7E) and protein (Figure 7F) levels of p53, and the effects were abolished by cotransfection with si-SETD2. [score:1]
The microRNAs including miR-23b-5p, miR-34b-3p, miR-106b-5p, miR-142–5p and miR-20a-5p were tested among HK-2,786-O and SN12-PM6 cell lines (F) as well as ccRCC tissues (G) by real-time RT-PCR, using U6 as an internal control. [score:1]
The protein level of SETD2 was also significantly increased upon tranfection of antagomir against miR-106b-5p (4.4- to 7.5-fold in 786-O cells, 3.4- to 5.9-fold in SN12-PM6 cells) (Figure 2B). [score:1]
786-O and SN12-PM6 cells were transfected for 72 h with 100 nM anti-miR negative control, anti-miR-23b-5p, anti-miR-34b-3p, anti-miR-106b-5p, anti-miR-142–5p or anti-miR-20a-5p. [score:1]
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[+] score: 228
Other miRNAs from this paper: hsa-mir-19a, hsa-mir-106a, mmu-mir-106a, mmu-mir-106b, mmu-mir-19a
LP of 400 mg/kg/day containing 112 mg/kg/day of GSE) via gavage, significantly down-regulated expressions of miR-106 and mRNA of its precursor gene MIR106B, and up-regulated mRNA expression of CDKN1A. [score:11]
Figure 1GSE significantly down-regulated oncomir miR-106b expression, and its precursor MIR106B mRNA expression in lung neoplastic cellsSpecific qPCR demonstrated down-regulation of (A) miR-106b, (B) MIR106B mRNA in A549 cells (n = 3). [score:11]
Oral LP treatment significantly down-regulated expressions of miR-106b, MIR106B mRNA, and up-regulated mRNA expression of CDKN1A (Figure 5). [score:11]
LP treatment significantly down-regulated MIR106B mRNA, miR-106b, and up-regulated CDKN1A mRNA expressions in human lung tumor xenograftsTo confirm that the in vitro effects of GSE do occur in vivo, we assessed and compared the expressions of precursor MIR106B mRNA, miR-106b, and CDKN1A mRNA in lung tumor xenografts with or without LP treatment. [score:10]
Figure 5LP treatment significantly down-regulated MIR106B mRNA, miR-106b, and upregulated CDKN1A mRNA expressions in human lung tumor xenograftsTo confirm that the in vitro effects of GSE do occur in vivo, we assessed and compared the expressions of MIR106B, miR-106b, and CDKN1A in lung tumor xenografts with or without LP treatment using qPCR. [score:10]
Reduction of miR-106b correlated with decreased human lung cancer cell proliferations, as well as up-regulations of CDKN1A mRNA expressions, and the respective protein product p21, a predicted target of miR-106b (TargetScanHuman, http://www. [score:10]
LP treatment significantly down-regulated MIR106B mRNA, miR-106b, and upregulated CDKN1A mRNA expressions in human lung tumor xenografts. [score:9]
In our study, we also show that GSE down-regulates miR-106b, which in turn up-regulates CDKN1A gene mRNA expression and its respective protein p21 production in our lung cancer mo dels. [score:9]
LP treatment significantly down-regulated MIR106B mRNA, miR-106b, and up-regulated CDKN1A mRNA expressions in human lung tumor xenografts. [score:9]
GSE significantly down-regulated oncomir miR-106b expression, and its precursor MIR106B mRNA expression in lung neoplastic cells. [score:8]
Oral gavage of LP to athymic nude mice bearing A549 NSCLC xenografts significantly down-regulated the expressions of miR-106b and its precursor MIR106B mRNA, and increased CDKN1A mRNA expression in tumor xenografts, correlating to markedly reduced tumor growth. [score:8]
GSE significantly down-regulated expressions of oncomir miR-106b, and mRNA of its precursor MIR106B gen e in lung neoplastic cellsSpecific qPCR demonstrated the dose -dependent, down-regulation of miR-106b (Figure 1A), its precursor MIR106B gene (Figure 1B) and further confirmation was obtained with miR-106b specific ISH assay in A549 cells (Figure 1C). [score:8]
In a recent report, the p53/p21 complex rather than p53 itself regulates cell invasion and death by targeting Bcl-2 proteins [24], suggesting that the GSE -induced down-regulation of miR-106b likely reduce lung cancer cell invasiveness, in part, though the increase in P21 production. [score:7]
In this study, we found that GSE significantly down-regulated the expression of oncomir miR-106b in a variety of human lung cancer cell lines, including A549 (adenocarcinoma), H1299 (metastatic NSCLC), DMS114 (Small cell lung cancer, SCLC), and H23 (adenocarcinoma). [score:6]
Down-regulation of miRNA-106b by GSE has been shown to inhibit growth of melanoma cells by promoting G1-phase cell cycle arrest and reactivation of p21 protein [21]. [score:6]
Furthermore, we demonstrate that GSE down-regulates the mRNA expression of MIR106B precursor gene. [score:6]
Transfection of miR-106b mimics partially abrogated the GSE -mediated up-regulation of CDKN1A mRNA expression (Figure 3B) and p21 production (Figure 3C). [score:6]
GSE significantly down-regulated expressions of oncomir miR-106b, and mRNA of its precursor MIR106B gen e in lung neoplastic cells. [score:6]
Figure 3GSE significantly increased (A) mRNA expressions of CDKN1A and p21 protein production, and miR-106 mimic abrogated such increases in (B) CDKN1A mRNA expression and (C) p21 protein production in A549 cells. [score:5]
Conceivably, the activation of caspase 3 is mediated, in part, through an increase in p21 production from the down-regulation of miR-106b. [score:4]
As the MIR106B gene is a paralogue of mir-17-92 cluster, it is conceivable that GSE down-regulates miR-106b via similar molecular mechanisms at the level of miRNA precursor gene transcription in lung tumors. [score:4]
Specific qPCR demonstrated down-regulation of (A) miR-106b, (B) MIR106B mRNA in A549 cells (n = 3). [score:4]
Transfection with miR-106b mimic significantly reversed the anti-proliferative effects of GSE in lung cancer cells, and abrogated the GSE -induced up-regulation of CDKN1A and p21. [score:4]
GSE also down-regulated both miR-106b and MIR106B precursor in H1299 (Figure 1D), DMS114 (Figure 1E), and H23 cells (Figure 1F). [score:4]
GSE, however, did not down-regulate miR-106b in H520 cells (data not shown). [score:4]
GSE induced anti-invasive effects in lung neoplastic cells via down-regulation of miR-106b, which was abrogated by transfection of miR-106b mimic. [score:4]
GSE increased CDKN1A/P21 in lung cancer cells via down-regulation of miR-106b. [score:4]
GSE induced anti-proliferative effects in lung neoplastic cells via down-regulation of miR-106b. [score:4]
GSE increased CDKN1A/P21 in lung cancer cells via down-regulation of miR-106bWe then evaluated the effects of GSE treatment on predicted targets of miR-106b that are known to play a role in cell proliferation, including CDKN1A or p21. [score:4]
Specific qPCR demonstrated the dose -dependent, down-regulation of miR-106b (Figure 1A), its precursor MIR106B gene (Figure 1B) and further confirmation was obtained with miR-106b specific ISH assay in A549 cells (Figure 1C). [score:3]
MiR-106b ISH assays further confirmed the down-regulation of these miRNA in A549 cells by GSE. [score:3]
However, it is noteworthy that GSE did not significantly decrease MIR106B nor miR-106b expression in H520, a squamous cell carcinoma cell line, in contrast to what was observed with miR-19a/b. [score:3]
The ability of GSE in modulating miR-106b and its downstream targets provides further evidence on its multi-faceted antineoplastic properties against lung cancer. [score:3]
In this study, we demonstrate novel GSE mediated anti-neoplastic mechanisms involving modulation of oncomir miR-106b, its molecular target p21, and correlated these findings to the in vivo efficacy of LP, against lung cancer. [score:3]
In this study, we report for the first time, the roles of miR-106b, and its downstream target CDKN1A or p21, in mediating the anti-neoplastic properties of GSE against NSCLC and SCLC. [score:3]
To confirm that the in vitro effects of GSE do occur in vivo, we assessed and compared the expressions of MIR106B, miR-106b, and CDKN1A in lung tumor xenografts with or without LP treatment using qPCR. [score:2]
To confirm that the in vitro effects of GSE do occur in vivo, we assessed and compared the expressions of precursor MIR106B mRNA, miR-106b, and CDKN1A mRNA in lung tumor xenografts with or without LP treatment. [score:2]
In addition to mediating the anti-proliferative effects of GSE, we found that miR-106b was involved in the anti-invasive effects of GSE in lung cancer, another important hallmark of the malignant phenotype. [score:1]
In addition, transfection with miR-106b mimic significantly reversed the anti-invasive effects of GSE in A549 cells. [score:1]
This is consistent with our findings that transfection of miR-106b mimics abrogated the antiproliferative effect of GSE in lung neoplastic cells. [score:1]
MiR-106b is one of these oncomirs that has been reported to play a role in tumors of many organs including lung [14– 20]. [score:1]
, which was abrogated by transfection of miR-106b mimic. [score:1]
GSE treatment significantly reduced the invasion of A549 cells through the 8 µM pore size co-culture inserts coated with matrigel as extracellular matrix (ECM), and transfection of miR-106b mimic significantly abrogated the GSE -mediated anti-invasive effects in A549 cells (A). [score:1]
Figure 4GSE treatment significantly reduced the invasion of A549 cells through the 8 µM pore size co-culture inserts coated with matrigel as extracellular matrix (ECM), and transfection of miR-106b mimic significantly abrogated the GSE -mediated anti-invasive effects in A549 cells (A). [score:1]
We then evaluated the effects of GSE treatment on predicted targets of miR-106b that are known to play a role in cell proliferation, including CDKN1A or p21. [score:1]
Transfections of miR-106b mimic into lung neoplastic cells were achieved using miRNA specific mimic, and transfecting reagents according to the manufacturer’s instructions (Qiagen Inc. [score:1]
The GSE -induced anti-proliferative effects in lung neoplastic cells was abrogated by transfection of miR-106b mimics. [score:1]
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8
[+] score: 221
While both miRs target CTSS, contrary to miR-106b-5p that we found upregulated during Mtb infection, miR-3619-5p was downregulated in BCG-infected THP1 derived Mø. [score:9]
A global transcriptomic analysis of Mø infected with M. smegmatis, revealed among the most differentially regulated miRNAs miR-142-3p;-5p; miR-32 (upregulated) and miR-106b-5p (downregulated). [score:8]
Then, they were incubated for 24 h with the transfection reagent and 100 nM of SMARTpool ON-TARGETplus human CTSS siRNA or with miRIDIAN miRNA human hsa-miR-106b-5p mimics or hairpin inhibitors and the respective siRNA or miRNA non -targeting controls (GE Dharmacon) in a ratio of 5 μl [reagent]:1 μg [siRNA] in antibiotic-free medium. [score:7]
Interestingly, miR-106b was described as the posttranscriptional target of the autophagy-related gene 16L1 (ATG16L1) regulating autophagy in the context of epithelial cells and Crohn’s disease (26). [score:6]
Our results indicate that Mtb actively manipulates miR-106b-5p by upregulating their gene expression during infection in opposition to what it is observed with the non-pathogen M. smegmatis. [score:6]
Using target prediction tools based on the miRanda (30), miRtaget2 (31), and miRmap (32) algorithms, we have identified several potential targets of miR-106b-5p, including CtsS mRNA (CTSS). [score:5]
When the inhibitors of miR-106b-5p were tested, significant effects were observed mostly later in the course of the infection, namely after 24 h p. i. In contrast to miR-106b-5p mimics, the transfection with inhibitors lead to an increase of CtsS levels in infected cells relatively to scramble-infected cells (Figure 3B, right panel). [score:5]
CtsS protein expression in human Mø transfected with miR-106b-5p mimics (A) or inhibitors (B) and subsequently infected with Mtb. [score:5]
Figure S2Original Western blots from Figure 3. Cathepsin S protein expression in human Mø transfected with miR-106b-5p mimics or inhibitors and subsequently infected with Mycobacterium tuberculosis (Mtb). [score:5]
These findings are correlated with our previous results showing that Mtb induces the downregulation of CtsS at 24 h, suggesting that miR-106b-5p might be implicated in this regulation. [score:5]
Next, we tested whether we were able to modulate CtsS protein levels in non-infected cells by overexpressing or inhibiting miR-106b-5p. [score:5]
For an accurate quantification of gene expression and in order to confirm that miR-106b-5p is being differentially regulated during infection with Mtb relatively to M. smegmatis, we independently validated the analysis. [score:4]
A recent study by Meng et al. (50) describes that miR-106b-5p is downregulated in samples from latently infected individuals, where Mtb is known to be not dividing and is enclosed within the phagosomes, avoiding the fusion with lysosomes containing cathepsins and other digestive enzymes. [score:4]
Our results showed an early Mtb -dependent upregulation of miR-106-5p and a specific interaction between this miRNA and CTSS. [score:4]
Here, we show miR-106b-5p isoform as another miRNA strongly upregulated during Mtb infection in contrast to challenge with non-pathogenic M. smegmatis. [score:4]
Notably, the results showed miR-106b-5p strongly upregulated during Mtb infection (Figure 1A). [score:4]
Altogether, our data suggest that manipulation of miR-106b-5p as a potential target for host-directed therapy (HDT) for Mtb infection. [score:4]
Thus, Mtb infection upregulates miR-106b-5p in primary human Mø (Figure 1). [score:4]
Our previous results indicated that miR-106b-5p was downregulated early upon M. smegmatis infection of the mouse Mø cell line J774 (23) while in the present study, using human cells, no effect was observed. [score:4]
The Modulation of miR-106b-5p Expression Regulates CtsS Protein Amounts in Mtb-Infected Mø. [score:4]
Given that Mtb manipulates miR-106b-5p expression resulting in reduced CtsS protein levels, we hypothesized that this regulation will affect the endolysosomal enzyme proteolytic activity and subsequently the ability of Mtb to survive inside host cells. [score:4]
In our experiments, we describe that miR-106b-5p is upregulated in macrophages infected with Mtb which are dividing and producing an infection that mimics active TB, with increasing numbers of CFU overtime (Figure 4A control samples). [score:4]
Our initial results portrayed an induction of miRNA-106b-5p in Mtb-infected Mø in agreement with our previous findings that CtsS is downregulated by Mtb infection (9). [score:4]
with anti-CtsS siRNA or with miR-106b-5p mimics and inhibitors was performed with Biontex K2 [®] System. [score:3]
Transfection with anti-CtsS siRNA or with miR-106b-5p mimics and inhibitors was performed with Biontex K2 [®] System. [score:3]
The results showed a significant reduction in luciferase expression (P < 0.05, paired t-test) during cotransfection with miR-106b-5p and 3′-UTR CTSS plasmid relative to the control (cells transfected with a nonsense miR and the 3′-UTR CTSS reporter plasmid) (Figure 2B). [score:3]
To further test this hypothesis, we performed similar experiments, as described above, using mimics and inhibitors of miR-106b-5p in the context of Mtb infection. [score:3]
The fact that miR-106b-5p, in addition to CtsS, also targets ATG16L1 may provide evidence for a double control of autophagy for bacteria survival and persistence. [score:3]
Mtb Induces the Expression of miR-106b-5p in Human Mø. [score:3]
From the 1,054 potential targets generated by the miRmap algorithm the top 30 with highest score are shown in Table 1 with miR-106b-5p at the 24th position with a score of 90.35. [score:3]
To test this, we performed miR-106b-5p gain- and loss-of-function experiments in Mtb-infected cells and analyzed changes in the surface expression of HLA-DR class II complexes using flow cytometry (Figure 5). [score:3]
For this, we transfected primary human Mø with miR-106b-5p mimics or inhibitors and analyzed protein levels by Western blotting (Figure 2C). [score:3]
miR-106b fine tunes ATG16L1 expression and autophagic activity in intestinal epithelial HCT116 cells. [score:3]
These results, combined with previous data from our group, establishing an important role of CtsS in Mtb infection (9), led us to generate the hypothesis of whether CtsS was a real target of miR-106b-5p, and if it has implications in bacterial survival, cell death as well as antigen presentation. [score:3]
Our data indicates that the consequence of miR-106b-5p manipulation by Mtb is a decrease of CtsS activity concomitant with an increase of the intracellular survival of the bacteria and decreased human leukocyte antigen (HLA)-DR class II surface expression in human macrophages, similar to what occurs during siRNA silencing of CtsS. [score:3]
Altogether, miR-106b-5p modulates CtsS expression in human Mø during infection with Mtb. [score:3]
This study revealed that miR-106b-5p targets CTSS for protein silencing with consequences in Mtb persistence in human Mø obtained from healthy (BCG vaccinated) donors. [score:3]
miR-106b-5p Targets CtsS mRNA. [score:3]
From the 1,054 targets generated by the miRmap algorithm, miRNA-106b-5p showed the 24th highest score (99.35) (Table 1). [score:3]
Here, we show that the manipulation of MHC-II expression through the axis miR-106b-5p/CtsS may overcome the blockade induced during Mtb infection. [score:3]
Here, we show that modulation of miR-106b-5p during infection indeed modulates the surface expression of the MHC Class II antigen presentation machinery (HLA-DR). [score:3]
miR-106b-5p Target Validation. [score:3]
Figure 4Intracellular survival of Mycobacterium tuberculosis (Mtb) in Mø transfected with miR-106b-5p mimics or inhibitors. [score:3]
In contrast, an exacerbated killing effect from day 3 p. i. was detected by using miR-106b-5p inhibitors in loss-of-function experiments (Figure 4A, right panel). [score:3]
We neither found an increase on necrosis upon miR-106b-5p mimics or inhibitors treatment that could account for Mtb survival. [score:3]
Surprisingly, there were no changes in LC3 puncta when comparing infected cells transfected with miR-106b-5p mimics or with inhibitors relatively to nonsense-scramble -transfected cells (Figure 4D). [score:3]
Figure S1Flow Cytometry generated dot-plots for necrosis and apoptosis effects of mimics and inhibitors of miR-106b-5p on Mycobacterium tuberculosis (Mtb)-infected cells and on non-infected cells. [score:3]
Our results confirm those performed by Exiqon, i. e., a distinct phenotype between the two species (Figure 1B), with M. smegmatis infection having no effect in miR-106b-5p expression while the challenge with Mtb led to a 2-fold increase in miR-106b-5p RNA at 4 h which was maintained for the 24 h assay. [score:2]
Altogether, these results indicate that a knock-down of CtsS in the context of Mtb manipulation of miR-106b-5p is relevant for pathogen intracellular survival by interfering with proteolysis in the endolysomal pathway and independently of autophagy and programed cell death activation. [score:2]
Curiously, one of the miRs we showed to be more differentially regulated during mycobacteria infection, in addition to miR-106-b was miR-142-3p (Figure 1A). [score:2]
The constructed plasmid, miR-106b-5p mimics and miRNA negative controls were transfected into HEK 293 T-cells using ScreenFect [®]A Reagent (ScreenFect GmbH), following the manufacturer’s instructions. [score:1]
This fragment included one putative sequence complementary to the “seed region” of miR-106b-5p. [score:1]
We then hypothesized that Mtb modulation of miR-106b-5p for CtsS silencing might be linked to poor antigen processing and presentation compromising adaptive immunity response to infection. [score:1]
Therefore, the work of Meng et al., combined with the present study might suggest that the miR-106b-5p is a good candidate to be used as a biomarker to distinguish between active and latent TB, although further experimental evidence would be required to formally validate this hypothesis. [score:1]
We concluded that the effect of miR-106b-5p was autophagy independent. [score:1]
Therefore, a modulation of mir-106b-5p to silence CtsS activity may be a pathogen strategy to survive along vesicles in this pathway. [score:1]
A 413 bp fragment of the 3′-untranslated region (3′-UTR) of the human CtsS gene (CTSS) containing a sequence complementary to the seed region of miR-106b-5p, was amplified by PCR using the Phusion [®] Hot Start II DNA Polymerase (New England BioLabs [®], MA, USA), following the manufacturer’s instructions (forward primer: 5′-GCGAGCTCCAAGAAATATGAAGCACTTTCTC-3′, reverse primer: 5′-CCCTCGAGTTTTTTGAAACAGAGTCTCCACT-3′). [score:1]
Altogether, this suggests that CtsS dependent Mtb intracellular survival via miR-106b-5p modulation resulted from a hydrolytic activity along the endocytic pathway upon phagocytosis. [score:1]
Importantly most members of the miR-17-92 cluster and all members of the miR-17 cluster are present in the list: hsa-miR-17-5p, hsa-miR-20a-5p, hsa-miR-20b-5p, hsa-miR-106a-5p, hsa-miR-106b-5p, and hsa-miR-93-5p which have been implicated all in innate and adaptive immune responses (36). [score:1]
Our results did not reveal significant changes in apoptosis after miR-106b-5p manipulation. [score:1]
Our data argue that the miR-106b-5p -dependent improved control of Mtb is independent of autophagy and more related to the process of phagosomal degradation. [score:1]
As shown in Figure 3A (right panel), transfecting cells with mimics of miR-106b-5p resulted in a decrease of CtsS protein levels in Mtb-infected cells, at all time points tested, relatively to scramble-infected cells (scramble: infected and transfected with control nonsense RNA). [score:1]
The present study reveals that Mtb blocks CtsS via miR-106b-5p for preventing innate and adaptive immune responses to persist in the host. [score:1]
miR-106b-5p Modulates the Intracellular Survival of Mtb. [score:1]
miRNA-106b-5p Interferes with the Antigen Presentation Machinery and T-Cell Activation. [score:1]
Using in silico prediction approach, we found that miR-106b-5p has a high probability of binding to CtsS mRNA. [score:1]
Our study opens the door for future manipulation of miR-106b-5p to enhance the antimicrobial activity of innate immune cells. [score:1]
We made use of gain or loss-of-function experiments to modulate miR-106-b-5p during Mtb infection. [score:1]
The results were in agreement with a decrease in protein levels and hydrolytic activity for CtsS using mimics (Figure 4B, left panels) and a significant increase in protein and enzyme activity using miR-106-b-5p inhibitors (Figure 4B, right panels) calculated 3 days p. i. A similar trend on Mtb survival using mimics experiments was confirmed by CTSS siRNA (Figure 4A, top right). [score:1]
Altogether, the data indicate the specificity of the interaction between CTSS 3′-UTR binding sites and miR-106b-5p leads to CtsS silencing. [score:1]
We further provide means how to revert this process by manipulation of miR-106-5p helping to control the infection. [score:1]
We tested whether a decrease on CtsS due to miR-106b-5p gain-of-function will augment apoptosis in infected cells by using Annexin V staining to monitor the event. [score:1]
As expected, the mimics for miR-106b-5p gain-of-function, we observed an increase in Mtb survival, relative to the control (scramble transfected and infected cells) at day 3 p. i. (Figure 4A, left panel). [score:1]
Interestingly, the function of miR-106b-5p on CtsS activity in the context of infection was independent of autophagy. [score:1]
To decipher whether the observed miR-106b-5p -dependent pathogen killing/survival was dependent on alternative activation pathways, we tested for the involvement of apoptosis, necrosis or autophagy, during gain- and loss-of-function experiments. [score:1]
Therefore, we envisage that miR-106b-5p is actively manipulated by Mtb to ensure its survival in innate phagocytic cells and escape to immune surveillance and activation. [score:1]
After screening the 3′-UTR of CTSS for potential miR-106b-5p interaction using RNAhybrid (33), we identified three different binding sites (Figure 2A). [score:1]
Figure 5Effects of miR-106b-5p on antigen presentation machinery and T-cell priming. [score:1]
Altogether, these results show that miR-106b-5p levels can impact intracellular survival of Mtb in human Mø. [score:1]
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9
[+] score: 195
Increased expression of miR-106b with prolactin treatment in T47D cells increased expression of fibronectin and vimentin, whereas increased expression of anti-miR-106b along with prolactin treatment decreased the expression of fibronectin, vimentin, twist2 and snail2, with the last reduced to undetectable levels, leaving us no ability to determine significance levels (Figure 3E–3H). [score:9]
Increased expression of miR-106b facilitates cell proliferation through a decrease in p21 and increases cell migration through upregulation of messenchymal gene expression. [score:8]
There are other reported targets for miR-106b, such as PTEN, SMAD7 and REST [72– 75] and downregulation of these targets by miR-106b also contributes to tumor progression. [score:8]
In PC3 cells, which grow more rapidly and are less epithelioid, increased expression of miR106b had no effect, while increased expression of anti-miR106b quadrupled the expression of p21 mRNA (Figure 2A and 2B). [score:7]
However, increased expression of anti-miR-106b significantly inhibited growth of cells in the presence of prolactin (Figure 3B). [score:5]
Inhibition of miR-106b by anti-miR106b shRNA blocked prolactin mediated effect on both the 3′UTR of p21 mRNA and p21 mRNA expression. [score:5]
Increased expression of miR-106b shRNA reduced p21 mRNA in T47D cells (A) while increased expression of anti-miR-106b shRNA resulted in more p21 mRNA in PC3 cells (B). [score:5]
Rather, we showed that prolactin induced miR106b, and miR-106b in turn increased expression of fibronectin and vimentin, while anti-miR-106b decreased expression of fibronectin, vimentin, twist2 and snail2. [score:5]
Using the artificial construct, the data presented show that prolactin stimulates the production of a miRNA that targets the 3′ UTR of p21 mRNA and that this is duplicated by increased expression of miR-106b and antagonized by anti-miR-106b. [score:5]
Figure 2Increased expression of miR-106b shRNA reduced p21 mRNA in T47D cells (A) while increased expression of anti-miR-106b shRNA resulted in more p21 mRNA in PC3 cells (B). [score:5]
To determine the outcome of upregulation of miR-106b in cancer, we first examined effects on relative cell number, as assessed by MTS assay, with increased expression of miR-106b or anti-miR106b in the absence or presence of prolactin. [score:5]
In addition to oncogenic miR-106b, prolactin also upregulated other oncomirs such as members of the miR-17/92 family. [score:4]
Therefore, the effect of prolactin to decrease p21 mRNA could be regulated by both miR-106b and miR-106a, but, based on relative expression levels, the contribution from miR-106a is less. [score:4]
Among these miRNAs, miR-106b has been shown to target to the 3′ UTR of p21 mRNA directly [47]. [score:4]
Using the luciferase assay to assess the effect of increased expression with and without prolactin, increased expression of miR-106b reduced luciferase activity and prolactin treatment did not augment this effect. [score:4]
In the current study, we have determined that upregulation of miR-106b by prolactin likely contributes to tumor malignancy. [score:4]
This is diagrammed in Figure 6. Thus, miR-106b or its regulated events might serve as therapeutic targets for both breast and prostate cancers. [score:4]
Once ERα is activated by one or both hormones, expression of miR-106b is increased. [score:3]
As would be predicted from these results, expression of anti-miR-106b decreased migration to about the level seen in the absence of prolactin and additional miR-106b, thereby confirming a role for miR-106b in the promotion of migration. [score:3]
In the PC3 cell line, which grows rapidly, increased expression of miR-106b or incubation with prolactin did not significantly increase cell number. [score:3]
Prolactin treatment induced miR-106b targeted to the 3′UTR of the p21 in cancers. [score:3]
How then does prolactin elevate expression of miR-106b? [score:3]
Cells expressing more miR-106b were more aggressive. [score:3]
However, cells with increased expression of miR-106b dispersed to a greater radius. [score:3]
To demonstrate that the effect of prolactin was mediated through miR-106b, we constructed shRNA plasmids to be used to increase expression of either miR-106b or anti-miR-106b. [score:3]
Alternatively, a greater effect of prolactin on cell number versus that produced by increased expression of miR-106b might be expected as a result of prolactin's ability to stimulate the cell cycle [59, 60]. [score:3]
Collectively, these results show that prolactin induced the production of miR-106b and that this then targeted the 3′ UTR of p21 mRNA. [score:3]
Rather, signaling from the prolactin receptor to increased expression of miR-106b is through MAPK/ERK and PI3K/Akt. [score:3]
As seen in Figure 3A, increased expression of miR-106b or anti-miR106b in T47D cells did not cause any effect on cell number in the absence of prolactin. [score:3]
We next examined whether increased expression of miR-106b affected cell migration. [score:3]
However, the luciferase-lowering effect of prolactin was blocked when there was increased expression of anti-miR-106b (Figure 2C and 2D). [score:3]
Further, that increased expression of miR-106b causes increased cell number and enhanced migratory capacity. [score:3]
The data also demonstrate that increased expression of miR-106b contributes to cell migration, which is consistent with previous studies by others. [score:3]
In T47D cells, increased expression of miR-106b essentially eliminated p21 mRNA, while anti-miR-106b had little effect. [score:3]
Increased expression of miR-106b essentially eliminated p21 mRNA in T47D cells, whereas anti-miR-106b increased p21 mRNA. [score:3]
Therefore, in response to prolactin, one might expect a greater reduction in p21 and a greater effect on cell number than that brought about only by increased expression of miR-106b. [score:3]
Additional expression of miR-106b in the presence of prolactin doubled the response. [score:3]
For example, Gong et al. [64] and Yau et al. [65] showed increased metastasis and migration in breast and hepatocellular carcinoma cells, respectively, with increased expression of miR-106b. [score:3]
Effect of miR-106b on cell number, cell migration and mesenchymal gene expression. [score:3]
However, combining increased expression of miR-106b with incubation in prolactin did not further increase the amount of migration. [score:3]
By contrast, increased expression of anti-miR-106b in the presence of prolactin decreased cell number below that without prolactin. [score:3]
miR-106b was the only predicted miRNA and had been shown to interact with p21 mRNA directly [47], although its role as a mediator of any of prolactin's functions had not been described. [score:2]
Prolactin also increases metastatic spread [55, 56], and the current experiments suggest that some of this may be through induction of miR-106b, although this was not directly addressed. [score:2]
Consistent with a p21-elevating effect of S179DPRL [46], S179DPRL also decreased expression of miR106b by 43% compared to the PBS control (Figure 1A). [score:2]
Furthermore, that the effects of miR-106b and anti-miR106b in the luciferase assay are translated to effects on levels of p21 mRNA. [score:2]
In addition to miR-106b, miR-106a was also induced by prolactin (1.5 fold), but to a level below the stringency of our microarray analysis. [score:1]
Cell movement was analyzed by comparing cell distribution between control shRNA- and shRNA-miR106 -treated cells. [score:1]
10,000 T47D (A) and PC3 (B) cells were transfected with control shRNA, miR-106b shRNA or anti-miR-106b shRNA plasmid and treated with vehicle (left panel) or 100 ng/mL prolactin (right panel) for 72 hours. [score:1]
Cells were seeded in a constrained area in the center of the well and then transfected with control shRNA or miR-106b shRNA plasmid. [score:1]
We therefore expected the Jak2/Stat5 signaling pathway to be involved in the production of miR-106b since both actions lead to reduced p21. [score:1]
miR-106b was not only increased by prolactin, but decreased by S179DPRL, suggesting in fact that at least part of the mechanism used by S179DPRL to elevate p21 is a reduction in miR-106b. [score:1]
We therefore examined the potential role for activated ERα in the production of miR-106b. [score:1]
Figure 310,000 T47D (A) and PC3 (B) cells were transfected with control shRNA, miR-106b shRNA or anti-miR-106b shRNA plasmid and treated with vehicle (left panel) or 100 ng/mL prolactin (right panel) for 72 hours. [score:1]
Furthermore, induction of miR-106b is found in multiple types of cancers, including breast, prostate and ovarian cancers [66– 69]. [score:1]
We therefore focused further analysis on miR-106b. [score:1]
T47D cells were transfected with control shRNA, miR-106b shRNA or anti-miR-106b shRNA plasmid in the presence of 100 ng/mL prolactin for 72 hours. [score:1]
Thus, prolactin has additional functions that affect cell number beyond those mediated by miR-106b. [score:1]
T47D cells were seeded in the constrained area and transfected with control shRNA or miR-106b shRNA plasmid in the absence (C) or presence (D) of prolactin. [score:1]
By contrast, increased levels of anti-miR-106b effectively block proliferation. [score:1]
One hundred thousand cancer cells, transfected with control shRNA or miR-106b shRNA were placed in a constrained area around the center of well. [score:1]
In the current study, we have determined the existence of an additional mechanism through which prolactin decreases the amount of p21, the induction of miR-106b, a mechanism duplicated by estradiol. [score:1]
Taken together, these results suggest a high impact of miR-106b on proliferative and metastatic aspects of tumor progression. [score:1]
Our focus was then on miR-106b. [score:1]
Incubation in prolactin (with control shRNA), had a similar effect to transfection with miR-106b shRNA (compare Figure 3C and 3D). [score:1]
Each transcript level from non -treated cells was set as 1. Both T47D (C) and PC3 (D) cells were co -transfected with luciferase-p21 3′UTR plasmid and control shRNA/ miR-106b shRNA/ anti-miR-106b shRNA and treated with 100 ng/mL prolactin or vehicle for 72 hours. [score:1]
These results suggest that increased levels of miR-106b alone are insufficient to cause an increase in cell number, but that by reducing p21 levels, any promotion of proliferation can be enhanced. [score:1]
Consistent with this suggestion, the cell lines with wild type p53, MCF-7 and TOV-21G cells, have lower induction of miR-106b by prolactin, while cell lines with mutant p53, TOV-112D, OV-90 and T47D, or with null p53, PC3, showed greater induction of miR-106b by prolactin. [score:1]
By contrast, miR-106b had little effect on p21 mRNA in PC3 cells, while anti-miR-106b quadrupled the amount of p21 mRNA. [score:1]
Given the ability of increased miR-106b to reduce p21 mRNA to essentially zero (albeit mRNA and not protein) and that this does not cause an increase in cell number, the most likely of these two explanations is that the additional effect of prolactin is pro-proliferative rather than anti-apoptotic. [score:1]
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[+] score: 187
We propose that the microbial product butyrate regulates the cell cycle through both epigenetic and translational regulation through its dual role as a HDAC inhibitor and inhibitor of miR-106b expression (Figure 5 ). [score:11]
The miR-106b family inhibits p21 translation, and therefore decreased expression of the miR-106b family leads to increased p21 translation. [score:9]
While treatment with miR-106b leads to decreased p21 protein expression, p21 mRNA levels do not change, which is consistent with prior reports that miR-106b regulates p21 through translational inhibition rather than mRNA stability [32]. [score:8]
Furthermore, mutations in both miR-106b target regions resulted in a 57% increase in luciferase activity, suggesting that both binding sites mediate miRNA inhibition of basal p21 expression in cancer cells. [score:8]
Butyrate regulates p21 expression via HDAC inhibition and decreased expression of the miR-106b family. [score:8]
This partial inhibition by miR-106b confirms previous reports that butyrate also regulates p21 expression via a miRNA independent mechanism, through its inhibition of HDAC [7], [13], [14]. [score:8]
Butyrate and miR-106b treatment of a p21 3′UTR luciferase reporter construct in HCT116 cells indicates that butyrate-stimulated p21 expression is translationally inhibited in part by miR-106b. [score:7]
As one example, butyrate induces expression of p21, a key regulatory molecule of cell cycle arrest, by suppressing members of the miR-106b family. [score:6]
miR-106b regulates p21 translation via two target sites in the 3′UTR. [score:6]
To investigate the effect of miR-106b on translational regulation of p21 expression, HCT-116 cells were transiently transfected with modified luciferase reporter vectors containing either the wild type p21 3′UTR or p21 3′UTRs containing mutations in either one or both of the miR-106b binding sites (Figure 3A ). [score:5]
miR-106b inhibits butyrate -induced p21 protein expression. [score:5]
Thus, butyrate might exert its effect on miR-106b expression via decreased E2F1 expression, though further studies in HCT-116 cells are needed to examine this possibility. [score:5]
In hepatocellular carcinoma (HCC), the expression of the miR-106b precursor strongly correlates with MCM7 expression, indicating that the miR-106b-25 polycistron is coordinately transcribed under the influence of the MCM7 promoter. [score:5]
Six of these miRNAs are in the same miRNA family (miR-17, miR-20a, miR-20b, miR-93, miR-106a, and miR-106b), share an identical seed sequence, and thus target the same binding sites in the 3′UTRs of target mRNAs. [score:5]
Butyrate -induced p21 protein expression is inhibited by miR-106b. [score:5]
High levels of expression of the transcription factor E2F1 in HCC also correlated with increased miR-106b expression [31]. [score:5]
An exogenous miR-106b mimic dampened butyrate -induced p21 protein expression as compared with cells treated with butyrate alone whereas control miRNA molecules had no effect on p21 expression. [score:4]
The 3′UTR of p21 mediates translational regulation by butyrate and miR-106b. [score:4]
Mutations were generated in these miR-106b target sites. [score:4]
Under basal conditions, mutations in the individual miR-106b target regions in the p21 3′UTR at nucleotides 468-474 and nucleotides 1148-1154 resulted in a 28% and 26% increase in luciferase activity respectively (Figure 3B ). [score:4]
Although miR-106b regulation of p21 expression has been described in many cell types, there is conflicting data on the mechanism of this interaction. [score:4]
For example, miRNAs regulate many key proteins in the signaling pathways of colorectal cancer, e. g. the miR-106b family reduces p21 expression and affects cell cycle progression [21]– [23]. [score:4]
The butyrate -induced inhibition of cell proliferation was reversed by the addition of miR-106b mimic molecules in a dose-dependant manner (Figure 4B ). [score:3]
are means ± SE, n = 4. Since p21 inhibits cell cycle progression, we examined the role of miR-106b on butyrate's anti-proliferative effects. [score:3]
The addition of a miR-106b mimic reversed the increased p21 expression and decreased cell proliferation induced by butyrate. [score:3]
analysis of sporadic-type human colon cancers found increased expression of the miR-106b family. [score:3]
In a human gastric carcinoma derived cell line, miR-106b repressed p21 protein expression, but did not cause a significant change in p21 mRNA levels [32]. [score:3]
Butyrate inhibition of miR-106b is also associated with a significant decrease in cancer cell proliferation rates. [score:3]
Since p21 inhibits cell cycle progression, we examined the role of miR-106b on butyrate's anti-proliferative effects. [score:3]
Butyrate's effect on cell proliferation is inhibited by miR-106b. [score:3]
Butyrate's effects on luciferase expression were reversed by the addition of exogenous miR-106b mimics, but not control miRNA molecules (miR-C). [score:3]
One of these miRNAs, miR-106b, was found to target p21. [score:3]
We performed studies on human colon cancer HCT-116 cells treated with butyrate and found significant alterations in miRNA profiles, including decreased expression of the miR-106b family. [score:3]
Furthermore, the luciferase activity of HCT-116 cells transfected with the chimeric vector containing both mutant miR-106b target sites was not altered with butyrate treatment or with butyrate in the presence of exogenous miR-106b. [score:3]
Butyrate also decreases the expression of miR-106b, and several other miRNAs with the same seed sequence region. [score:3]
Amongst the miR-106b predicted targets, silencing of p21 with siRNA most closely phenocopies miR-106b gain of function [22]. [score:3]
In contrast, the miR-106b mimic had no effect on p21 mRNA expression. [score:3]
Butyrate alters miRNA expression in human colon cancer HCT-116 cells, including members of the miR-106b family. [score:3]
A control miRNA (miR-C), with identical GC content but no sequence homology to miR-106b, was used as a control. [score:1]
Cells were also treated with butyrate (2 mM) or vehicle and miR-106b mimic or control miRNA molecules (miR-C). [score:1]
We, therefore, analyzed the effects of butyrate and a miR-106b mimic on p21 mRNA and protein levels in HCT-116 cells. [score:1]
HCT-116 cells were treated with butyrate (2 mM) or vehicle and were transfected with miR-106b mimic or control miRNA (miR-C) for 24 hours prior to harvest. [score:1]
Cells transfected with exogenous miR-106b or control for 24 hrs prior to 2 mM butyrate exposure were also analyzed (Figure 4B ). [score:1]
miR-106b reverses butyrate's anti-proliferative effects. [score:1]
In human mammary epithelial cells and normal lung fibroblasts, miR-106b decreased the p21 mRNA by about 40% [22]. [score:1]
The latter is reversed by the addition of miR-106b mimics. [score:1]
TransIT-LT1 (Mirus, WI) transfection reagent was used to transfect HCT-116 cells with an engineered miR-106b (Ambion's Pre-mir MiRNA Precursor Molecules) according to the manufacturer's protocol. [score:1]
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[+] score: 171
Furthermore, ectopic overexpression of miR-106b-5p downregulated C1orf24 expression, which induced apoptosis and suppressed invasion in thyroid cancer [43]. [score:10]
Knockdown of NEAT1_2 inhibited the ATAD2 expression by upregulating miR-106b-5p. [score:9]
Knockdown of NEAT1_2 inhibited ATAD2 expression by upregulating miR-106b-5p in PTC cells. [score:9]
Next, we overexpressed miR-106a-5p, miR-106b-5p, and miR-17-5p, separately, and detected whether the three miRNAs could downregulate the expression of ATAD2 in K1 and TPC1 cells. [score:8]
However, cumulative evidence indicates that the expression of miR-106b-5p is downregulated in thyroid cancer and breast cancer, where it might function as a tumor suppressor 43, 44. [score:8]
Knockdown of NEAT1_2 inhibited the cell growth, migration, and invasion, and promoted apoptosis by functioning as a ceRNA to regulate ATAD2 expression by sponging miR-106b-5p. [score:7]
NEAT1_2 functions as a competing endogenous RNA to regulate ATAD2 expression and promotes PTC progression by sponging miR-106b-5p The relative expression level of NEAT1_2 in 87 pairs of PTC and adjacent non-cancerous tissues was detected and analyzed by real-time reverse transcription polymerase chain reaction (qRT-PCR). [score:6]
We found that only miR-106b-5p could downregulate the expression of ATAD2 (Fig.   6b). [score:6]
Taken together, these results demonstrated that NEAT1_2 could upregulate ATAD2 expression by sponging miR-106b-5p. [score:6]
Ni X Downregulation of miR-106b induced breast cancer cell invasion and motility in association with overexpression of matrix metalloproteinase 2Cancer Sci. [score:6]
NEAT1_2 functions as a competing endogenous RNA to regulate ATAD2 expression and promotes PTC progression by sponging miR-106b-5p a Relative expression levels of miR-106a-5p, miR-106b-5p, and miR-17-5p were detected by qRT-PCR in PTC cells transfected with si-NEAT1_2 or NC. [score:6]
We found that ectopic overexpression of miR-106b-5p significantly suppressed the luciferase activity of the wild-type ATAD2-3′UTR (ATAD2-3′ UTR-Wt), but failed to affect that from mutated-type ATAD2-3′UTR (ATAD2-3′ UTR-Mt) in HEK 293T cells (Fig.   6f). [score:5]
Thus, we hypothesized that NEAT1_2 may function as a competing endogenous RNA to regulate ATAD2 expression by sponging miR-106b-5p in an AGO2 -dependent manner. [score:4]
The results suggested that miR-106b-5p was the crucial miRNA that binds to both NEAT1_2 and the 3′ UTR of ATAD2, and that NEAT1_2 could regulate the expression of ATAD2 through sponging miR-106b-5p, which suggested the mechanism by which how NEAT1_2 promotes malignant biological behavior via modulation of ATAD2. [score:4]
Consistently, we found that miR-106b-5p was significantly downregulated in 87 pairs of PTC tissues and matched normal tissues. [score:4]
Similarly, a dual-luciferase reporter system was carried out to determine whether ATAD2 was a direct target of miR-106b-5p. [score:4]
NEAT1_2 functions as a competing endogenous RNA to regulate ATAD2 expression and promotes PTC progression by sponging miR-106b-5p In the human genome, only 1–2% of the entire genome encodes proteins, with evidence of at least 80% of the remaining genome being actively transcribed 24, 25. [score:4]
However, further western blotting results indicated that only miR-106b-5p could downregulate the level of ATAD2 in PTC cells. [score:4]
HEK 293T cells were seeded into 96-well plates the day before transfection, and transfected with the pMIR-REPORT-NEAT1_2-lncRNA-Wt, pMIR-REPORT-NEAT1_2-lncRNA-Mt1, and pMIR-REPORT-NEAT1_2-lncRNA-Mt2 reporter vector, together with the Renilla luciferase -expressing vector pRL-TK (Promega, Madison, WI, USA) and miR-106b-5p mimic or NC using Lipofectamine 2000 (Invitrogen). [score:3]
b Protein expression of ATAD2 was detected by western blotting in PTC cells transfected with miR-106b-5p mimic or NC. [score:3]
Among these 28 miRNAs, qRT-PCR indicated that miR-106a-5p, miR-106b-5p, and miR-17-5p were upregulated in PTC cells transfected with si-NEAT1_2 compared with the NC group. [score:3]
The Wilcoxon signed-rank test was used to analyze the different relative expressions of NEAT1_2, ATAD2, and miR-106b-5p in PTC tissues and adjacent non-cancerous tissues. [score:3]
HEK 293T cells were seeded into 96-well plates the day before transfection, and transfected with either the pMIR-REPORT- ATAD2-3′UTR-Wt or the pMIR-REPORT- ATAD2-3′UTR-Mt reporter vector, together with the Renilla luciferase expression vector pRL-TK (Promega) and miR-106b-5p mimic or NC using Lipofectamine 2000 (Invitrogen). [score:3]
Moreover, we detected the relative expression of miR-106b-5p in 87 pairs of PTC and adjacent non-cancerous tissues. [score:3]
Fig. 6 a Relative expression levels of miR-106a-5p, miR-106b-5p, and miR-17-5p were detected by qRT-PCR in PTC cells transfected with si-NEAT1_2 or NC. [score:3]
In addition, dual-luciferase reporter assays were used to confirm whether miR-106b-5p could directly target ATAD2 and bind to NEAT1_2. [score:3]
We found that miR-106a-5p, miR-106b-5p, and miR-17-5p were significantly highly expressed in the NEAT1_2 knockdown group compared with their levels in the NC group (Fig.   6a). [score:3]
The expression level of miR-106b-5p and NEAT1_2 were negatively correlated in 87 matched PTC tissues (Fig.   6d). [score:3]
The fragment from NEAT1_2 containing the putative binding sites for miR-106b-5p was amplified by PCR and cloned in the firefly luciferase expression vector pMIR-REPORT (Obio Technology, China) and named as NEAT1_2-Wt. [score:3]
Similarly, the ATAD2-3′UTR-Wt and ATAD2-3′UTR-Mt containing the putative binding site of miR-106b-5p were established and cloned into the Firefly luciferase expression vector pMIR-REPORT (Obio Technology, China). [score:3]
Thus, we found that miR-106b-5p targeted ATAD2 and has two binding sites that interact with NEAT1_2. [score:3]
Yang TS MicroRNA-106b in cancer -associated fibroblasts from gastric cancer promotes cell migration and invasion by targeting PTENFEBS Lett. [score:2]
In addition, we found that NEAT1_2 may act as a ceRNA that regulates ATAD2 by modulating miR-106b-5p. [score:2]
In our study, miR-106b-5p was confirmed to bind directly to NEAT1_2. [score:2]
To further confirm that NEAT1_2 could regulate ATAD2 through interacting with miR-106b-5p, we constructed a pcDNA3.1-NEAT1_2 Wt containing both binding sites for miR-106b-5p and the pcDNA3.1-NEAT1_2 Mt containing mutated binding sites for miR-106b-5p. [score:2]
We found that miR-106b-5p showed significantly lower expression in PTC compared with that in adjacent non-cancerous tissues (Fig.   6c). [score:2]
After confirming that miR-106b-5p could directly bind to both NEAT1_2 and the 3′ UTR of ATAD2, another dual-luciferase reporter assay was applied to further confirm whether NEAT1_2 could regulate ATAD2 by interacting with miR-106b-5p. [score:2]
To further confirm that miR-106b-5p could bind directly to NEAT1_2 and the 3′ UTR of ATAD2, three dual-luciferase reporter assays were performed. [score:1]
We found that co-transfection of miR-106b-5p mimic and NEAT1_2 wild type (NEAT1_2-Wt) significantly reduced the luciferase activity, while miR-106b-5p mimic and NEAT1_2-mutated-type 1 (NEAT1_2-Mt1) or NEAT1_2-mutated-type 2 (NEAT1_2-Mt2) co-transfection failed to change the luciferase activity (Fig.   6e). [score:1]
The sequence was si-NEAT1_2 (sense): 5′-GGA GGA GUC AGG AGG AAU AUU-3′, si-ATAD2 (sense): 5′-GGA CCA AGA AGU CCU UAC UTT-3′, miR-106b mimic (sense) 5′-UAA AGU GCU GAC AGU GCA GAU-3′, miR-106a mimic (sense) 5′-AAA AGU GCU UAC AGU GCA GGU AG-3′, miR-17-5p mimic (sense) 5′-CAA AGU GCU UAC AGU GCA GGU AG-3′. [score:1]
To mutate the putative binding sites for miR-106b-5p in NEAT1_2, the sequence of putative binding site was replaced as indicated and was named as NEAT1_2-Mt1 and NEAT1_2-Mt2. [score:1]
e The predicted miR-106b-5p binding sites in NEAT1_2 (NEAT1_2-Wt) and the designed mutant sequence (NEAT1_2-Mt1, NEAT1_2-Mt2) are indicated. [score:1]
Thus, miR-106-5p was speculated to be the miRNA that binds to both NEAT1_2 and the 3′ UTR of ATAD2. [score:1]
The correlation analysis showed that the levels of miR-106b-5p and NEAT1_2 were negatively correlated. [score:1]
f The predicted miR-106b-5p binding sites in the 3′-UTR region of ATAD2 (ATAD2-3′UTR-Wt) and the designed mutant sequence (ATAD2-3′UTR-Mt) are indicated. [score:1]
Thus, we speculated that NEAT1_2 may also interact with miR-106b-5p in a paraspeckle protein -dependent manner. [score:1]
MiR-106b-5p, as a member of the miR-106b-25 cluster, has been confirmed to promote cancer cell proliferation and metastasis in prostate cancer, esophageal squamous cell carcinoma, and gastric cancer 41, 42. [score:1]
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[+] score: 164
Reduction of miR-106b regulated RB expression via targeting 3'UTR of RB, and expression of RB largely abrogated miR-106b -induced cell proliferation in laryngeal carcinoma cells. [score:8]
Of note, upregulation of miR-106b, miR-423, miR-20a, and miR-16 as well as downregulation of miR-10a were newly observed. [score:7]
Further, As-miR-106b regulated RB expression via targeting 3'UTR of RB. [score:6]
In the pathogenesis of Alzheimer's diseases, miR-106b regulated TβR II expression via binding 3' UTR of the TβR II mRNA, thereby leads to impairment in TGF-β signaling [12]. [score:6]
To further explore the molecular mechanism of As-miR-106b induced cell cycle in laryngeal carcinoma cells, bioinformatics analysis of miR-106b potential target genes was performed through the databases TargetScan http://www. [score:5]
These results raise the possibility that there exists a threshold value for miR-106b up-regulation. [score:4]
RB is a direct target of miR-106b. [score:4]
Having demonstrated RB as a direct target of miR-106b, we next examined the importance of RB in miR-106b -mediated cell proliferation. [score:4]
MiR-106b inhibition suppresses cell proliferation and induces G0/G1 arrest. [score:4]
showed that a notable induction of RB expression was detected after knockdown of miR-106b in Hep-2 and TU212 cells (Figure 3B). [score:4]
Here, we evidenced that RB was a novel direct and functional target of miR-106b involved in cell proliferation of laryngeal carcinoma cells. [score:4]
And p21/CDKN1A is a direct target of miR-106b and that its silencing plays a key role in miR-106b -induced cell cycle phenotypes [11]. [score:4]
Western blot assay showed that transfection with RB without 3'UTR overrided RB expression targeted by miR-106b (Figure 4B). [score:4]
The cell cycle distribution analysis showed that upregulation of miR-106b significantly reduced cell cycle G0/G1 phase arrest induced by serum starvation (Figure 4A). [score:4]
Moreover, RB was a direct target of miR-106b by luciferase reporter assay. [score:3]
Figure 2 Reduction of miR-106b suppressed laryngeal carcinoma cell proliferation. [score:3]
Figure 1 Expression of miR-106b in laryngeal carcinoma. [score:3]
Finally, there was an inverse correlation of expression of miR-106b and RB in laryngeal carcinoma tissues. [score:3]
Finally, expression of RB abolished cell proliferation of miR-106b. [score:3]
In this study, repression of miR-106b resulted in cell proliferation inhibition and cell cycle G0/G1 arrest in laryngeal carcinoma cells. [score:3]
And we also found high miR-106b expression in Hep-2 and TU212 laryngeal carcinoma cells (Figure 1). [score:3]
To determine whether RB is directly regulated by miR-106b, and were employed. [score:3]
However, when we transfected with RB without 3'UTR and miR-106b, expression of RB largely abrogated the effect of miR-106b on cell cycle distribution. [score:3]
To explore miR-106b expression in laryngeal carcinomas, we examined 20 human laryngeal carcinoma specimens with different clinical stages using. [score:3]
Further, Pearson correlation showed that a significant negative correlation existed between miR-106b and RB expression in laryngeal carcinoma tissues (R = 0.673, P < 0.005) (Figure 5B). [score:3]
These findings suggest that RB is a major target of miR-106b involved in laryngeal carcinoma cell proliferation. [score:3]
In both two cells, miR-106b expression significantly decreased in As-miR-106b group and increased in miR-106b group 48 h after transfection (Figure 2A). [score:3]
edu, We found that tumor suppressor RB associated with cell cycle contained the highly conserved putative miR-106b binding sites (Figure 3A). [score:3]
In conclusion, we have showed that miR-106b is one of oncogenic miRNAs in laryngeal carcinomas and RB is a novel and critical target of miR-106b. [score:3]
We further explored the correlation of between miR-106b and RB expression in laryngeal carcinomas. [score:3]
These results suggest that miR-106b might be useful as a potential therapeutic target for laryngeal carcinoma and more in depth analysis is required. [score:3]
Inverse correlation of expression of miR-106b and RB in laryngeal carcinoma tissues. [score:3]
However, we did not observe a significant difference in the rate of growth inhibition between miR-106b group and blank control group; although a slightly increasing trend of cell survival rate and G0/G1 phase was seen in Hep-2 and TU212 cells. [score:3]
Taken together, reduction of miR-106b can induce cells arrest at G0/G1 phases, thereby inhibiting cell proliferation in laryngeal carcinoma cells. [score:3]
Figure 3 RB was identified as target genes of miR-106b. [score:3]
Reduction of miR-106b by antisense oligonucleotides inhibited cell proliferation and induced cell cycle G0/G1 arrest in laryngeal carcinoma cells. [score:3]
Several genes have been evidenced to be the targets of miR-106b, such as p21/CDKN1A and TGF-β type II receptor (TβR II). [score:3]
Figure 4 Expression of RB abrogates miR-106b -induced cell proliferation. [score:3]
And miR-106b increased with the increasing stages of laryngeal carcinoma tissues, and inversely correlated with RB expression. [score:3]
Reporter assay revealed that inhibition of miR-106b triggered a marked increase of luciferase activity of pGL3-WT-RB-3'UTR plasmid both in Hep-2 and TU212 cells, without change in luciferase activity of pGL3-MUT-RB-3'UTR (Figure 3C). [score:2]
Recent evidences indicate that miR-106b has participated in development and progression of human tumors, such as hepatocellular cancer, prostate cancer, gastric cancers and renal cell carcinoma [7- 10]. [score:2]
MiR-106b expression in laryngeal carcinomas. [score:2]
data showed that a statistically significant cell proliferation inhibition was found in As-miR-106b group of Hep-2 cells, compared with control groups respectively. [score:2]
Figure 5 MiR-106b inversely correlates with RB expression in laryngeal carcinoma tissues. [score:2]
Introduction of RB cDNA without 3'UTR abrogated miR-106b -induced cell proliferation. [score:1]
MiR-106b, located at Chr 7, is one member of miR-106b-25 cluster. [score:1]
As-miR-106b and miR-106b mimic oligonucleotides were employed to change miR-106b expression in Hep-2 and TU212 cells to evaluate the significance of miR-106b in laryngeal carcinoma. [score:1]
Core role of RB in miR-106b -mediated cell proliferation. [score:1]
As-miR-106b treated cells represented significant ascends in G0/G1 phase in comparison to untreated Hep-2 and TU212 cells (Figure 2C). [score:1]
pGL3-MUT-RB-3'UTR plasmids were generated from pGL3-WT-RB-3'UTR by deleting the binding site (bases 883-889) for miR-106b "GCACUUU". [score:1]
Expression levels of miR-106b in laryngeal carcinoma tissues and cell lines (21: Hep-2 cells, 22: TU212 cells) were measured by and quantified as described in methods. [score:1]
In present work, we determined the function of miR-106b involved in laryngeal carcinoma. [score:1]
Ivanovska et al reported that miR-106b gain of function promotes cell cycle progression, whereas loss of function reverses this phenotype. [score:1]
Sequences as follows: miR-106b, 5'- UAAAGUGCUGACAGUGCAGAU-3'; anti-miR-106b (As-miR-106b), 5'-AUCUGCACUGUCAGCACUUUA-3'; scrambled miRNA (negative control), 5'-UUGUACUACACAAAAGUACUG-3'. [score:1]
As shown in Figure 1, the levels of miR-106b increased markedly in laryngeal carcinomas with stage III and IV in comparison to those with stage I and II (P < 0.01). [score:1]
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[+] score: 162
Other miRNAs from this paper: hsa-mir-25, hsa-mir-93
In summary, our data indicated that miR-106b expression was significantly upregulated and associated with poor prognosis in HCC. [score:6]
Our data indicated that miR-106b expression was significantly upregulated in HCC and could serve as a potential unfavorable prognostic biomarker. [score:6]
Kaplan-Meier analysis showed that patients with high miR-106b expression had a worse overall survival than patients with low miR-106b expression (log-rank P = 0.004). [score:5]
The median fold change of miR-106b was used as a cutoff value to divide all 104 patients into two groups: the low expression group (n = 52) and the high expression group (n = 52). [score:5]
It has been demonstrated that ectopic expression of miR-106b can enhance the proliferation and anchorage-independent growth of HCC cells, whereas inhibition of miR-106b had the opposite effect [20, 22]. [score:5]
As shown in Figure  4, HCC patients with high miR-106b expression had shorter overall survival than those with low miR-106b expression. [score:5]
Our qRT-PCR data confirmed that miR-106b expression was upregulated in tumor tissues compared with the adjacent non-tumor tissues, which validated our previous microarray high-throughput profiling results [23]. [score:5]
Overall survival rate in patients with high miR-106b expression was significantly lower than that in patients with low miR-106b expression (log-rank P = 0.004). [score:5]
Kaplan-Meier analysis showed that patients with high miR-106b expression level had a significantly shorter overall survival than those with low miR-106b expression level. [score:5]
It has been reported that miR-106b acts as an oncogene and is upregulated in many human cancers. [score:4]
In our previous study, using miRNA array, we also found miR-106b is one of the upregulated miRNAs in HCC [23]. [score:4]
Hence, by regulating its target genes, miR-106b could promote HCC cell cycle progression, cell proliferation, and cell migration and invasion. [score:4]
MiR-106b expression was significantly upregulated in as high as 76.0% of HCC tissues, compared with their non-tumor counterparts (P < 0.001). [score:4]
It has also been shown that miR-106b contributed to metastasis by activating the EMT process and promoting cell migration in vitro and metastasis in vivo in HCC, indicating that upregulation of miR-106b may correlate with HCC progression [21]. [score:4]
Figure 2 Upregulation of miR-106b was observed in 79/104 (76.0%) HCCs. [score:4]
The multivariate Cox regression analysis indicated that miR-106b expression was an independent prognostic factor for overall survival (HR, 2.002; 95% CI, 1.130-6.977; P = 0.027). [score:3]
MiR-106b was upregulated in 79 of 104 patients (76.0%) totally (Figure  2). [score:3]
Further studies are needed to validate the prognostic value of miR-106b expression in other cohorts. [score:3]
As summarized in Table  1, miR-106b expression was significantly higher in HCC patients with large tumor than those with small tumor (P = 0.019). [score:3]
We performed quantitative real-time RT-PCR to examine the miR-106b expression level in 104 pairs of HCC and adjacent non-tumor tissues. [score:3]
More importantly, we demonstrated that miR-106b expression was significantly associated with overall survival of patients with HCC. [score:3]
High miR-106b expression was significantly associated with large tumor size (P = 0.019) and vascular invasion (P = 0.016). [score:3]
In addition, we correlated clinicopathological characteristics of the patients with miR-106b expression and observed that overexpression of miR-106b correlated with large tumor size and vascular invasion, which strongly indicated that this miRNA plays oncogenic roles in HCC, including promoting cell growth, cell invasion and tumor metastasis. [score:3]
These observations could be attributed to the miR-106b target genes, which include p21/CDKN1A, adenomatous polyposis coli (APC), transforming growth factor-β type II receptor (TGF-βRII), and RhoA and RhoC [16, 21, 22, 29]. [score:3]
We determined the expression level of miR-106b in 104 cases of paired HCC and adjacent non-tumor tissues by quantitative real-time PCR (qRT-PCR). [score:3]
Therefore, although our study is based on frozen tissue samples, it offers a significant opportunity for using archived samples to detect changes in miR-106b expression levels by using in situ hybridization methodology with miRNA localization in routine clinical setting [32]. [score:3]
As shown in Figure  1, the expression level of miR-106b in HCC tissues was significantly higher than that in adjacent non-tumor tissues after normalization (median fold change of T/NT = 2.27, P < 0.001). [score:3]
Multivariate analysis using the Cox proportional hazards mo del for variables that were significant in the univariate analysis showed that tumor size (P = 0.022), vascular invasion (P = 0.028) and miR-106b expression (P = 0.027) were independent prognostic factors for patients with HCC (Table  2). [score:3]
Analysis using the Student’s t-test showed that the relative expression levels of miR-106b in the HCC tissues were significantly higher than those in adjacent non-tumor tissues (P < 0.001). [score:3]
In the present study, we analyzed the clinical relevance of miR-106b expression in HCC patients. [score:3]
The relative miR-106b expression levels in paired tissues that were collected from the same patients were analyzed by the 2 [-ΔΔCt] method, represented by the -ΔΔCt value [−(ΔCt of tumor tissues - ΔCt of non-tumor tissues)]. [score:3]
Moreover, miR-106b was expressed at significantly higher levels in patients with vascular invasion than in patients without vascular invasion (P = 0.016). [score:3]
The correlation between miR-106b expression and prognosis of HCC was studied by univariate and multivariate analysis. [score:3]
Figure 1 Comparison of miR-106b expression levels between HCC tissues and adjacent non-tumor tissues. [score:3]
Univariate analysis demonstrated that Serum AFP level (P = 0.041), tumor size (P < 0.001), vascular invasion (P = 0.001), histological grade (P = 0.048) and TNM stage (P = 0.004), and miR-106b expression (P = 0.004) were significantly associated with overall survival of HCC patients (Table  2). [score:3]
MiR-106b has been reported as an oncogene and upregulated in many human cancers, including stomach, prostate and kidney [17- 19]. [score:3]
Prognostic analysis of miR-106b expression and clinicopathological factors. [score:3]
MiR-106b expression in HCC. [score:2]
Figure 3 MiR-106b expression correlated with tumor size. [score:2]
MiR-106b is a member of the miR-106b ~ 25 cluster, which consists of miR-106b, miR-93 and miR-25, that is encoded within intron 13 of the minichromosome maintenance complex component 7 (MCM7) gene on chromosome 7q22.1 [16]. [score:1]
We also analyzed the association of miR-106b expression with clinicopathological characteristics and overall survival of the patients and determined whether miR-106b is potentially predictive of prognosis in HCC. [score:1]
However, the clinical significance and prognostic value of miR-106b in HCC remain unclear. [score:1]
The expression level of miR-106b for each sample was calculated, represented by the ΔCt value (Ct of miR-106b - Ct of U6). [score:1]
Additionally, a Pearson correlation analysis also showed that the miR-106b level and tumor size were positively correlated (r = 0.2894, P = 0.0029; Figure  3). [score:1]
We next analyzed the correlation between miR-106b expression and the clinicopathological characteristics of HCC, including patients’ age, gender, HBsAg, Child-Pugh classification, serum AFP level, tumor size, tumor number, vascular invasion, histological grade (Edmondson-Steiner) and TNM stage. [score:1]
eu/vs/13000_2014_226 Hepatocellular carcinoma miR-106b Prognosis Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide with poor prognosis [1]. [score:1]
In the present study, we investigated the expression levels of miR-106b in resected HCC specimens and adjacent non-tumor tissues. [score:1]
The aim of this study was to investigate the clinical significance of miR-106b expression in HCC. [score:1]
However, no significant correlation was observed between miR-106b expression and other clinicopathological characteristics. [score:1]
Furthermore, multivariate Cox analysis proved that miR-106b was a prognostic factor independent of adjusted well-known prognostic variables for HCC including serum AFP level, tumor size, vascular invasion, histological grade, and TNM stage. [score:1]
Previous studies suggest that miR-106b also plays an important role in hepatocarcinogenesis [20- 22]. [score:1]
However, the prognostic value of miR-106b in hepatocellular carcinoma (HCC) remains unclear. [score:1]
qRT-PCR of miR-106b was performed using Bulge-Loop™ miRNA qRT-PCR kits (Ribobio, Guangzhou, China) according to the manufacturer’s instructions. [score:1]
Correlation of miR-106b expression with clinicopathological characteristics of HCC patients. [score:1]
MicroRNA-106b (miR-106b) is a member of the miR-106b ~ 25 cluster. [score:1]
Thus, miR-106b could be used as a potential prognostic biomarker in addition to other known prognostic indicator, in order to identify a subgroup of patients who have higher risk of death, thus, should receive monitoring more frequently and effective adjuvant treatment. [score:1]
MiR-106b is a member of the oncogenic miR-106b-25 cluster [16]. [score:1]
The association between miR-106b expression and prognosis of HCC patients was investigated by Kaplan-Meier analysis and log-rank test. [score:1]
A Pearson correlation analysis showed that the miR-106b level and tumor size were positively correlated (r = 0.2894, P = 0.0029). [score:1]
However, the prognostic value of miR-106b in HCC has not been fully clarified yet. [score:1]
[1 to 20 of 60 sentences]
14
[+] score: 110
Other miRNAs from this paper: hsa-mir-17, hsa-mir-20a, hsa-mir-25, hsa-mir-93, hsa-mir-375
We identified miRNAs targeting CIC from the miRNAs known to be overexpressed in prostate cancer tissues, and proposed that miR-93, miR-106b, and miR-375 could potentially contribute to the down-regulation of CIC levels in the process of prostate cancer progression. [score:8]
Moreover, disruption of the putative miRNA binding sites in the 3′UTR of CIC abrogated suppression of luciferase activity by the three miRNAs (Figure 6E), demonstrating that miR-93, miR-106b, and miR-375 directly target the 3′UTR of CIC to regulate CIC levels. [score:7]
The miRNAs -mediated increases in cell proliferation and invasion were partially abolished by recovery of CIC levels in PC-3 cells (Figures 7B and 7C and Supplementary Figure 16), suggesting that miR-93, miR-106b, and miR-375 promote prostate cancer progression in part by down-regulation of CIC expression. [score:6]
Overexpression of miR-93, miR-106b, and miR-375 increased cell proliferation and invasion (Figures 7B and 7C and Supplementary Figure 16), accompanied with down-regulation of CIC levels (Figure 7A), suggesting the cancer promoting property of these three miRNAs in prostate cancer cells. [score:6]
We also measured CRABP1 levels in the same set of cells, and found that co -expression of miR-93, miR-106b, and miR-375 resulted in up-regulation of CRABP1, which was restored by overexpression of CIC in PC-3 cells (Figure 7D). [score:6]
However, co-transfection with all three miRNA duplexes markedly down-regulated CIC levels in PC-3 cells (Figures 6B and 6C), indicating that miR-93, miR-106b, and miR-375 cooperatively regulate CIC levels. [score:5]
In fact, among the two putative miR-17 family miRNA binding sites in the CIC 3′UTR, the first site is predicted to be more preferentially targeted by miR-93, whereas the second one by miR-106b, according to the miRNA target prediction databases (Supplementary Figure 15B). [score:5]
Comparative analysis on the selected miRNAs identified five miRNAs, miR-20a, miR-25, miR-93, miR-106b, and miR-375, which not only potentially target CIC, but are also known to be frequently overexpressed in prostate cancer cells (Supplementary Figure 15A). [score:5]
miR-93, miR-106b, and miR-375 cooperatively down-regulate CIC levels. [score:4]
Inhibition of miR-375, but not miR-93 and miR-106b, significantly increased CIC levels (Figure 6D), suggesting that, among the three miRNAs, miR-375 is the most critical endogenous miRNA for regulation of CIC levels in PC-3 cells. [score:4]
miR-93, miR-106b, and miR-375 cooperatively down-regulate CIC levels in PC-3 cells. [score:4]
We also examined whether CIC expression is regulated by endogenous miR-93, miR-106b, and miR-375 in PC-3 cells. [score:4]
Of the five miRNAs, we initially chose to evaluate miR-93, miR-106b, and miR-375, considering the number of putative binding sites for each miRNA in the 3′UTR of CIC and their frequency of overexpression in prostate cancer patients, and tested whether these miRNAs can down-regulate CIC levels. [score:4]
Co-transfection with three miRNAs decreased luciferase activity in PC-3 cells (Figure 6E), suggesting that miR-93, miR-106b, and miR-375 down-regulate CIC levels through the 3′UTR of CIC. [score:4]
For clonogenic assay of PC-3 cells treated with miRNA duplexes and CIC-S expressing lentivirus, 5 × 10 [3] PC-3 cells were seeded in six well plates a day before transfection, and then co -transfected with miR-93, miR-106b, and miR-375 duplexes using Dhamafect 2. After 24 h, the cells were infected with lentivirus expressing CIC-S for 3 sequential days. [score:4]
All error bars show s. e. m. To determine the impact of the miRNAs -mediated down-regulation of CIC on prostate cancer progression, we assessed cell proliferation and invasion in PC-3 cells transfected with either control, miR-93/miR-106b/miR-375 or siCIC duplexes. [score:4]
To verify that miR-93, miR-106b, and miR-375 directly target the 3′UTR of CIC, we constructed luciferase reporter gene linked to the CIC 3′UTR (pGL3-CIC 3′UTR WT), and carried out dual luciferase assays. [score:3]
On the other hand, the three miRNAs still slightly repressed luciferase activity derived from the pGL3-CIC 3′UTR Mut compared with control vector (Figure 6E), implying that there might be other binding sites for miR-93, miR-106b, and miR-375 in the 3′UTR of CIC, or that the three miRNAs might also be able to repress CIC expression indirectly. [score:3]
B. analysis for changes in CIC levels by overexpression of miR-93, miR-106b, and miR-375 in PC-3 cells. [score:3]
All error bars show s. e. m. D. analysis for changes in CIC levels by inhibition of endogenous miR-93, miR-106b or miR-375 in PC-3 cells and its quantification. [score:3]
In sum, our findings suggest that miR-93/miR-106b/miR-375-CIC-CRABP1 is a novel regulatory axis in prostate cancer progression (Figure 7E). [score:2]
miR-93, miR-106b, and miR-375 cooperatively regulate CIC-CRABP1 axis to promote prostate cancer progression. [score:2]
We did not observe such effect when different combinations of two miRNA duplexes were co -transfected (Figure 6B), suggesting that miR-93 and miR-106b may not function redundantly to regulate CIC levels, although they share the same seed sequences. [score:2]
For cell growth assay of PC-3 cells treated with miRNA duplexes and CIC-S expressing lentivirus, 1 × 10 [3] PC-3 cells were seeded in 24 well plates a day before transfection, and then co -transfected with miR-93, miR-106b, and miR-375 duplexes using Dhamafect 2 and set as day “0”. [score:2]
miR-93, miR-106b, and miR-375 co-regulate CIC-CRABP1 axis to promote cancer progression in PC-3 cells. [score:2]
Taken together, these data demonstrate that miR-93, miR-106b, and miR-375 function cooperatively to regulate the CIC-CRABP1 axis in promoting prostate cancer progression. [score:2]
Figure 6 in PC-3 cells A. analysis for CIC levels in PC-3 cells transfected with control, miR-93, miR-106b, or miR-375 duplexes. [score:1]
miR-106b sense; 5′-UAAAGUGCUGACAGUGCAGAU-3′, and antisense; 5′-CUGCACUGUCAGCACUUUGUU-3′. [score:1]
Comparative miRNA profiling of prostate carcinomas with increasing tumor stages has revealed that levels of miR-375 and miR-106b gradually increase from normal to lymph node metastasizing tumors, whereas miR-93 increases from normal to extracapsular growing tumors [36], suggesting that these miRNAs are likely to participate in the gradual decrease in CIC levels during prostate cancer progression. [score:1]
Since the seed sequences of miR-20a, miR-93, and miR-106b are identical, they are classified as the same miRNA family (miR-17 family). [score:1]
There are two putative binding sites for miR-20a/miR-93/miR-106b, one for miR-25 and another for miR-375 in the 3′UTR of CIC (Supplementary Figure 15B). [score:1]
All error bars show s. e. m. A. analysis for CIC levels in PC-3 cells transfected with control, miR-93, miR-106b, or miR-375 duplexes. [score:1]
[1 to 20 of 32 sentences]
15
[+] score: 104
Interestingly, when testing each 3 pmol of the individual inhibitors alone, only the miR-106b -inhibitor was able to strongly downregulate E2F-activity, whereas the miR-20a -inhibitor showed only moderate effects and the miR-17 -inhibitor did not affect E2F activity. [score:12]
These microRNAs are also found downregulated in XXL-USSC, as well as miR-137 and miR-214 (Fig. S2), which both target CDK6 [61], [62] In addition to miR-17 [37], miR-20a, and miR-106b (this study), miR-214 also downregulates PTEN [63]. [score:9]
In contrast to the neuronal lineage differentiations, expression of miR-17, miR-20a, and miR-106b remained unchanged or was slightly upregulated after 7 days of osteogenic differentiation. [score:6]
Stains from time points 24 h and 48 h after transfection are shown from untransfected SA5/03, and from SA5/03 transfected with negative control mimic and the inhibitor batch, as well as with the miR-17, miR-20a, and miR-106b inhibitors alone (48 h only). [score:5]
Cell-cycle related proteins predicted as targets for miR-17, miR-20a, and miR-106b and chosen for experimental target gene validation. [score:5]
The inhibitor batch strongly reduced E2F-activity, whereas only miR-20a-, and miR-106b -inhibitor alone gave significant effects on E2F-activity. [score:5]
Proliferation-inhibiting effects of microRNA inhibitors to miR-17, miR-20a, and miR-106b in USSC. [score:5]
MicroRNAs miR-17, miR-20a, and miR-106b were found consistently downregulated in all USSC lines differentiated into cells of neuronal lineage. [score:4]
MiR-17 and miR-20a belong to the medium abundant microRNAs in native USSC and they are found among the most strongly downregulated microRNAs in XXL-USSC, together with miR-106b. [score:4]
Despite their cell cycle relevant target proteins, miR-17, miR-20a, and miR-106b also impact neuronal lineage differentiation of USSC, since certain genes relevant for neuronal differentiation and function like NBEA, EPHA4, NTN4 and NEUROG1 are also affected by these microRNAs [55]. [score:3]
Validation of putative cell cycle relevant target genes for microRNAs miR-17 (A), miR-20a (B), and miR-106b (C) in HEK293T-cells. [score:3]
Fold expression changes (2 [−ddCt]-values) are given for microRNAs miR-17, miR-20a, and miR-106b. [score:3]
0016138.g002 Figure 2Validation of putative cell cycle relevant target genes for microRNAs miR-17 (A), miR-20a (B), and miR-106b (C) in HEK293T-cells. [score:3]
Figure S3 List of cell-cycle related genes predicted as targets for miR-17, miR-20a, and miR-106b. [score:3]
MiR-17, miR-20a, and miR-106b have common target proteins. [score:3]
Differential expression of miR-17, miR-20a, and miR-106b in USSC differentiating in neuronal and osteogenic lineages. [score:3]
Expression data of microRNAs miR-17, miR-20a, and miR-106b and additional cell-cycle-related microRNAs are shown from native USSC as well as from days 14 and 28 (SA8/25) of differentiations. [score:3]
On the other hand, miR-106b, which shares high sequence homology with miR-17 and miR-20a, was shown to promote cell cycle progression by targeting CDKN1A (also termed p21, [39]). [score:3]
Mir-17, miR-20a, and miR-106b inhibit E2F transcription factor activity. [score:3]
Firefly activities were normalized to effects caused by (i) endogenous HEK293T microRNAs on the 3′UTRs cloned (miR-17, miR-20a, and miR-106b and homologs are highly expressed in HEK293T cells [52]), (ii) unspecific effects of certain microRNA -mimics on Firefly and Renilla activity per se, and (iii) transfection efficiency variations. [score:3]
Different regulation patterns of microRNAs miR-17, miR-20a, and miR-106b during neuronal lineage and osteogenic differentiation of USSC. [score:2]
” gives the TaqMan qPCR-assay data from osteogenic differentiations of USSC SA5/73 and SA8/25 at days 0 (native) and 7. “Deep sequencing” gives deep sequencing expression data of microRNAs miR-17, miR-20a, and miR-106b aquired from native USSC lines SA5/73, SA8/25, SA8/77, and SA4/101. [score:2]
As seen in Figs. 2B and 2C, miR-20a and miR-106b showed highly similar behavior compared to miR-17 regarding significant Firefly activity reductions and relative influences between the analyzed target genes. [score:2]
Normalized Firefly-activities were compared to those of pairwise co-transfections of these vectors with the microRNA mimic of interest (miR-17, miR-20a, miR-106b, also including an unspecific mimic negative control) to test for (i) unspecific effects of the given microRNA -mimic on Firefly/Renilla per se, (ii) effects of endogenous HEK293T microRNAs (iii) for validation of the particular target prediction. [score:2]
Functional effect of miR-17, miR-20a, and miR-106b on cell cycle arrest in XXL-differentiating USSC. [score:1]
Including paralogs, this family consists of miR-17, -18, -19a, -19b, -20a, and -92 (located within a region of 1 kb on chromosome 13), of miR-106a, -19b, -363, and -92 (X-chromosomal) and of miR-106b, -93, and -25 (on chromosome 7) [32]. [score:1]
Proliferation-activating effect of microRNA mimics to miR-17, miR-20a, and miR-106b in USSC. [score:1]
Figure S1 Sequence Aligning between miR-17, miR-20a, and miR-106b. [score:1]
This mo del can now be extended to miR-20a and miR-106b. [score:1]
0016138.g006 Figure 6Relationships between pro-proliferative and anti-proliferative proteins involved in G [1]/S transition and miR-17, miR-20a, and miR-106b. [score:1]
A batch of miR-17, miR-20a, and miR-106b increases E2F transcription factor activity in HEK293T cells. [score:1]
Relationships between pro-proliferative and anti-proliferative proteins involved in G [1]/S transition and miR-17, miR-20a, and miR-106b. [score:1]
[1 to 20 of 32 sentences]
16
[+] score: 92
Other miRNAs from this paper: hsa-mir-25, hsa-mir-93
The mRNA and protein levels of p21 were upregulated significantly when treated with TSA alone, but the magnitudes of the increases were attenuated significantly in the cells overexpressing miR-106b (Fig. 4D), indicating that the induction of p21 by TSA was regulated, at least in part, by downregulation of the miR-106b-93-25 cluster. [score:10]
Consistent with this, our data showed that the upregulation of p21 and BIM by depletion of MYC could be partially reversed by miR-106b and miR-25, suggesting that miRNA involvement is one of the reasons for the upregulation of p21 and BIM by MYC-siRNA. [score:7]
In order to verify the alteration in expression level of this cluster, we used quantitative real-time PCR (qRT-PCR) to detect these three miRNAs in total RNA isolated from cultured ECC-1 and HEC-1A cells with or without TSA (100 ng/mL) for 24 h. The expressions of miR-106b, miR-93, and miR-25 were shown to be downregulated significantly in cells treated with TSA compared to control (Fig. 1D & C), consistent with our microarray results (Fig. 1C). [score:7]
According to previous reports, p21 and BIM are the direct targets and inhibited by miR-106b and miR-25, respectively [18]. [score:6]
To certify the role of the miR-106b-93-25 cluster in the upregulation of p21 and BIM by TSA, the ECC-1 cells transfected with miR-106b or miR-25 mimics were cultured with or without TSA for 24 h, and then the mRNA and protein expression of p21 and BIM were analyzed by qRT-PCR ands, respectively. [score:6]
To corroborate these findings in EMC cells, a dual-luciferase reporter system was used to detect inhibition of p21 and BIM expression by miR-106b and miR-25 in ECC-1 cells, respectively. [score:5]
The expression of miR-106b, miR-93, miR-25 and their host gene MCM7 were upregulated in EMC tissues compared to the normal adjacent tissues. [score:5]
Thus, p21 was directly regulated by miR-106b through the 3′UTR, while BIM was directly regulated by miR-25. [score:5]
The miR-106b-93-25 cluster consists of three miRNAs, miR-106b, miR-93 and miR-25, and is located in the 13th intron of the minichromosome maintenance protein 7 (MCM7) gene of human chromosome 7. This miRNA cluster is upregulated in many human cancers, such as gastric, prostate, and pancreatic neuroendocrine tumors, The miRNAs of the miR-106b-93-25 cluster are co-transcribed in the context of the MCM7 primary transcript. [score:4]
This result suggested that TSA may regulate the expressions of miR-106b, miR-93, and miR-25. [score:4]
0045133.g003 Figure 3(a) pGL3 luciferase reporter constructs containing either the wild-type or mutant 3′UTR target sequence of miR-106b or miR-25 in the P21 or BIM gene were co -transfected into ECC-1 cells with either miRNA -negative control, miRNA mimics or empty pGL3 control vector (each n = 3). [score:3]
miR-106b and miR-93 gain of function led to an increase in cells in S-phase, while the G1-phase population was increased in the cells transfected with their inhibitors. [score:3]
p21 and BIM are target genes of miR-106b and miR-25 respectively [18]. [score:3]
miR-106b, miR-93, miR-25 promoted the growth of ECC-1 cells, while their inhibitors significantly decreased proliferation in ECC-1 cells. [score:3]
Luciferase activity was determined in the cell extracts after 24 h. In the presence of the wild-type P21 3′UTR, the miR-106b mimics significantly inhibited the luciferase activity compared with vector control. [score:2]
Transcriptional inhibition of the luciferase reporter gene by either miR-106b or miR-25 was assayed in ECC-1 cells. [score:2]
Co-transfection of either miR-106b with the reporter construct containing the wild-type 3′UTR of p21 or miR-25 with the reporter construct containing the wild-type 3′UTR of BIM resulted in a significant inhibition of the luciferase reporters when compared with the miRNA negative control. [score:2]
We found the expressions of miR-106b, miR-93 and miR-25 were decreased in the group treated with TAM and TSA, while they were unchanged in the group treated with TAM only, compared with the control (Fig. 1C). [score:2]
The mutant 3′UTRs contained a point mutation in the miR-106b and miR-25 seed region complementary sites. [score:2]
The miR-106b, miR-93 and miR-25 duplexes promoted cell proliferation compared with a control duplex, whereas their inhibitors significantly decreased proliferation of ECC-1 cells (Fig. 2A). [score:2]
P21 mRNA was significantly decreased by miR-106b mimics while BIM mRNA was not significantly changed by miR-25 mimics. [score:1]
Cell numbers in G1 phase were reproducibly increased by anti- miR-106b and anti- miR-93 but were unchanged by anti- miR-25 (Fig. 2B). [score:1]
The p21 mRNA level was reduced by the miR-106b duplex, and the same change was detected at the protein level (Fig. 3B). [score:1]
The proportion of cells transfected with miR-106b, or miR-93 in the G1 phase fell, while that of cells transfected with miR-25 remained unchanged (Fig. 2B). [score:1]
The miR-106b-93-25 cluster is composed of the highly conserved miR-106b, miR-93, and miR-25 that have been shown to accumulate in different types of cancer, including gastric cancer [37], prostate cancer [38], and esophageal adenocarcinoma [39], hepatocellular carcinoma [40], and multiple myeloma [41]. [score:1]
We also constructed plasmids containing the p21-3′UTR with mutated seed regions for the predicted miR-106b/miR-93 binding sites (p21-mut-3′UTR), along with plasmids containing the BIM-3′UTR with mutated seed regions for the predicted miR-25 binding sites (BIM-mut-3′UTR). [score:1]
We also measured the mRNA and protein levels of p21 and BIM after miR-106b and miR-25 overexpression. [score:1]
miR-106b and miR-93 had no effect on the apoptosis levels of the cells. [score:1]
However, miR-106b and miR-93 had no appreciable apoptotic effects on the cells (Fig. 2C), suggesting that these miRNAs from the cluster had more subtle effects. [score:1]
[1 to 20 of 29 sentences]
17
[+] score: 75
In this study, inhibition of miR-106B increased ADAMTS7, DPP3, MST1 and PRSSS12 gene expression, but subtly reduced CPE gene expression, an effect that resulted in reduced influenza virus replication, implying the effect of miR-106B inhibition on CPE may be dominant. [score:9]
In contrast, inhibition of miR-106B and miR-124* resulted in a >20-fold and >40-fold increase of DPP3 gene expression, respectively (Figure 5C), while miR-1254, miR-1272, and miR-17-3p inhibition caused a decrease of DPP3 expression. [score:9]
For example, inhibition of miR-106B and miR-124* resulted in 20-fold and 40-fold increased ADAMTS7 gene expression levels, respectively, while CPE gene expression was slightly reduced by miRNA inhibitors. [score:9]
For example, inhibition of miR-106B had little effect on CPE gene expression, but dramatically increased DPP3 gene expression. [score:7]
Finally, PRSS12 expression levels were significantly (p<0.05) increased in response to miR-106B inhibition, but a slight decrease was detected by inhibition of miR-1254 (Figure 5E). [score:7]
Of the 8 miRNA inhibitors tested, inhibition of miR-106B was associated with a decrease in influenza virus replication, while inhibition of miR-124 resulted in an increase in virus replication with respect to the negative control. [score:7]
At 24 h post-treatment, ADAMTS7 gene expression levels increased 20-fold when miR-106B was inhibited, and 40-fold when miR-124* was inhibited (Figure 5A). [score:7]
The decrease of virus replication associated with inhibition of miR-106B is likely associated with a decrease of CPE gene expression as RNAi silencing of CPE was associated with low levels of virus replication (Figures 1 and 2). [score:5]
For example, inhibition of miR-106B, a miRNA known to cause cell cycle arrest when inhibited in a laryngeal cancer mo del [65], resulted in substantially decreased virus replication. [score:5]
Given the evidence that miR-1254, miR-1272, miR-17-5p, miR-17-3p, miR-106B, miR-106B*, miR-124-a, and miR-124* are involved in governing aspects of ADAMTS7, CPE, DPP3, MST1, and PRSS12 gene expression (Figure 5), the role of these miRNAs in the regulation of influenza virus replication was determined (Figure 6). [score:4]
A library of miRNA antagonists was used to confirm miRNA regulation, and several miRNAs were identified to affect virus replication and host gene regulation, notably miR-1254, miR-106B, miR-106B*, miR-124-a, and miR-124*. [score:3]
Human papillomavirus oncoproteins E6 and E7 have also been reported to dysregulate miR-106B [66]. [score:2]
Pathway analysis of the five validated host genes revealed potential miRNA interaction (Figure S4) with eight miRNAs (miR-1254, miR-1272, miR-17-5p, miR-17-3p, miR-106B, miR-106B*, miR-124-a, and miR-124*). [score:1]
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[+] score: 61
As shown in Figure 3A and 3B, miR-106b was highly expressed in CRC tissue samples (P<0.01), and its expression was positively correlated with hsa_circ_000984 expression in CRC samples (R [2]=0.488, P<0.01), suggesting the co -expression of miR-106b and hsa_circ_000984 in CRC. [score:9]
Hsa_circ_000984 can bind to miR-106b as a miRNA sponge, exerting its function via regulating the downstream target CDK6, and knockdown of hsa_circ_000984 could inhibit CRC cell proliferation, migration, invasion in vitro and tumor formation in vivo, respectively. [score:7]
Next, we utilized the miRNA bioinformatics database TargetScan and miRanda, and identified 6 target miRNAs (miR-17, miR-20a, miR-93, miR-106a, miR-106b, miR-20b) for hsa_circ_000984. [score:5]
miR-106b expression levels in SW480 cells (E) and SW620 cells (F) co -transfected with miR-106b mimic or inhibitor. [score:5]
MiR-106b level was determined by using qPCR after SW480 and SW620 cells were transfected with the miR-106b mimics and miR-106 inhibitors (Figure 3E and 3F). [score:3]
Next, we performed luciferase reporter assay to determine whether miR-106b directly target the CDK6 3’UTR by co-transfecting psiCHECK2- CDK6-3’UTR with miR-106b mimics. [score:3]
The full-length of CDK6 3’-UTR containing miR-106b target site was inserted downstream of the firefly luciferase gene in psiCHECK2 to create the psiCHECK2-CDK 3’UTR-WT plasmid (Wt). [score:3]
To examine whether the miR-106b influences both mRNA and protein levels of CDK6, based on bioinformatics analysis, we found CDK6 might be a target of miR-106b with the complementary binding sites with the CDK6 3’UTR (Figure 3D). [score:3]
Further experiments and analysis discovered that hsa_circ_000984 can bind to miR-106b as a miRNA sponge, contributing to the increase of downstream target CDK6 (Figure 4E). [score:3]
The correlation between CDK6 expression and miR-106b in CRC cells. [score:3]
We found that only miR-106b expression differed between the CRC tissues and those matched colorectal nontumorous tissues with statistical significance. [score:3]
The full-length of CDK6 3’-UTR containing miR-106b target site and the full-length of CDK6 3’-UTR deleted miR-106b -binding sequence were inserted downstream of the firefly luciferase gene in psiCHECK2 to create the psiCHECK2- CDK6 3’UTR-WT plasmid (WT) and psiCHECK2- CDK6 3’UTR-MU plasmid (MU), respectively. [score:3]
Next, we assumed whether hsa_circ_000984 could act as miR-106b sponge to regulate its circRNA-miRNA-mRNA network. [score:2]
Figure 3 (A) MiR-106b expression in CRC tissue samples and those matched colorectal nontumorous tissues were detected by qRT-PCR. [score:2]
Hsa_circ_000984 may serve as miR-106b sponge to regulate its circRNA-miRNA-mRNA network. [score:2]
Moreover, hsa_circ_000984 affected CRC cell growth, migration and invasion by competing with cell cycle -associated proteins for binding by miR-106b, indicating an essential role of hsa_circ_000984 in tumor and progression. [score:1]
Additionally, miR-106b levels were also higher in CRC cell lines than in control cells (Figure 3C). [score:1]
The full-length of CDK6 3’-UTR deleted miR-106b -binding sequence was inserted downstream of the firefly luciferase gene in psiCHECK2 to create the psiCHECK2-CDK6 3’UTR-MU plasmid (MU). [score:1]
Hence, with the application of bioinformatics, we first found that hsa_circ_000984 may interact with miR-106b. [score:1]
The luciferase activity was decreased observed about >72% in both SW480 cells and SW620 cells with the co-transfection of CDK6-3’UTR and miR-106b mimics, whereas mutant of nucleotides in the miR-106b -binding site of CDK6 3’UTR elicited no changes of the reporters to the introduction of miR-106b (Figure 3G and 3H). [score:1]
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[+] score: 57
This suggestion corresponds to the results of our study showing that over -expression of the miR-106b∼25 cluster in NASH-derived HCC, especially miR-93-5p, is accompanied by substantial decrease in the levels of E2F1, PTEN, and CDKN1A proteins, direct targets of miR-93 [19, 42, 43]. [score:6]
We also demonstrated that over -expression of miR-25-3p, miR-93-5p, miR-106b-5p, miR-221-3p, and miR-222-3p was accompanied by the reduced protein levels of their targets, including E2F1, PTEN, and CDKN1A. [score:5]
Among the miRNAs distinctively over-expressed in NASH-derived HCC, miR-221-3p and miR-222-3p, which exhibited a carcinogenesis stage -dependent increase in expression, and miR-25-3p, miR-93-5p, and miR-106b-5p, which are members of the oncogenic miR-106b∼25 cluster, are of special interest. [score:5]
In particular, we identified 10 over-expressed miRNAs (miR-17-5p, miR-221-3p, miR-93-5p, miR-25-3p, miR-181b-5p, miR-106b-5p, miR-186-5p, miR-222-3p, miR-15b-5p, and miR-223-3p; Figure 2A) that are involved in the activation of major liver carcinogenesis-related gene expression networks, especially the TGF-β- and Wnt/β-catenin signaling pathways, the roles of which are well-established in hepatocarcinogenesis [14]. [score:5]
Mechanistically, the over -expression of miR-25-3p, miR-93-5p, and miR-106b-5p in NASH-derived HCC may be attributed to an increased expression of the Mcm7 gene, which harbors the miR-106b∼25 cluster [16– 18]. [score:5]
This suggestion is based on the results of the present study showing a concomitant up-regulation of the Mcm7 gene and the miR-106b∼25 cluster in NASH-derived HCC, and a positive correlation between the level of miR-93-5p and the Mcm7 transcript during mouse liver carcinogenesis and in human HCC. [score:4]
Expression of the Mcm7 gene and miR-106b∼25 cluster during NASH -associated hepatocarcinogenesis. [score:3]
Mechanistically, the over -expression of the miR-106b∼25 cluster during NASH -associated liver carcinogenesis may be attributed to a markedly increased level of yes -associated protein 1 (YAP1) and TEA domain transcription factor 4 (TEAD4) proteins (Figure 4G), members of YAP and TAZ transcriptional effectors of the Mcm7 gene [16]. [score:3]
Among these miRNAs, the over -expression of ten miRNAs (miR-15b-5p, miR-17-5p, miR-25-3p, miR-93-5p, miR-106b-5p, miR-181b-5p, miR-186-5p, miR-221-3p, miR-222-3p, and miR-223-3p) was associated with the activation of major hepatocarcinogenesis-related pathways, including the TGF-β, Wnt/β-catenin, ERK1/2, mTOR, and EGF signaling. [score:3]
Expression of the minichromosome maintenance protein 7 (MCM7) gene and its miR-106b∼25 intragenic cluster in the livers of STAM mice. [score:3]
Figure 4Expression of the Mcm7 gene and miR-106b∼25 cluster during NASH -associated hepatocarcinogenesis (A) Diagram of the mouse Mcm7 gene and its intragenic miR-106b∼25 cluster. [score:3]
Among the differentially expressed miRNAs in NASH-derived HCC, three miRNAs, miR-106b, miR-93, and miR-25, are members of the oncogenic miR-106b∼25 intragenic cluster [15, 16]. [score:3]
This cluster is highly conserved in vertebrates and is located in the 13 [th] intron of the Mcm7 gene on mouse chromosome 5 (Figure 4A) and human chromosome 7. The miR-106b∼25 cluster is actively co-transcribed with the MCM7 primary RNA transcript [17, 18]; hence, the expression of Mcm7 was examined at different stages of NASH -associated liver carcinogenesis. [score:3]
In general, the tumorigenic effect of MCM7 has been associated with its direct role in compromising genome integrity and, to a much greater extent, with oncogenic activity of the gene-embedded miR-106b∼25 cluster. [score:2]
Importantly, five of these miRNAs (miR-34a-5p, miR-93-5p, miR-106b-5p, miR-221-3p, and miR-222-3p) were in common with those in the 10-miRNA set in our study. [score:1]
For example, miR-17-5p, located in the miR-17∼92 cluster, and miR-93-5p and miR-106b-5p, located in the miR-106b∼25 cluster, belong to the same miR-17 family [33]. [score:1]
To investigate the functional consequences of the miR-106b∼25 cluster over -expression with respect to the hepatocarcinogenic process, the levels of E2F1, PTEN, and CDKN1A proteins, experimentally confirmed targets of miR-106b, miR-93-5p, and miR-25, were evaluated. [score:1]
The miR-106b∼25 cluster is one of two paralogs of the miR-17∼92 cluster [33]. [score:1]
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[+] score: 49
Our results showed that IRAK1 (P = 1.04 × 10 [−7]), the targets of miR-146a, MAPKBP1 (P = 10.44 × 10 [−7]) and CASP6 (P = 0.001), targets of miR-106b, were down-regulated, whereas MAP2K6 (P = 5.30 × 10 [−5]), target of miR-194-5p, was up-regulated in epilepsy patients compared with normal controls. [score:12]
According to these criteria, we found that 6 miRNAs (miR-144-5p, -15a-5p, -181c-5p, -194-5p, -889-3p and novel-mir-96) were down-regulated and 4 (let-7d-5p, miR-106b-5p, -130a-3p, and -146a-5p) were up-regulated in epilepsy patients compared to controls (Supplementary Table S1). [score:6]
The results revealed that let-7d-5p, miR-106b-5p, -130a-3p and -146a-5p were up-regulated, whereas miR-15a-5p and -194-5p were down-regulated in epilepsy patients compared to controls (Fig. 3). [score:6]
The results showed that that let-7d-5p, miR-106b-5p, -130a-3p, -15a-5p and -194-5p were significantly up-regulated in patients with idiopathic generalized epilepsy compared with normal controls (P < 0.0001, = 0.035, 0.001, 0.006, 0.008, respectively); while the expression of miR-146a-5p showed no significant difference in two groups (P > 0.05). [score:5]
For miR-106b-5p and miR-130a-3p, contrary to our findings, previous studies have reported that they were down-regulated in epilepsy patients and animal mo dels 12 13. [score:4]
The odds ratio for cases with expression level of miR-106b-5p more than 1.7239 being associated with epilepsy was 17.710 (95%CI: 9.171–34.199). [score:3]
We got 361, 48, 8, 19, 87 and 26 intersected targets for let-7d-5p, miR-106b-5p, miR130a-3p, miR-146a-5p, miR-15a-5p and miR-194-5p, respectively (Supplementary Table S3). [score:3]
To further confirm the expression differences of the 7 miRNAs (let-7d-5p, miR-106b-5p, -130a-3p, -146a-5p, -15a-5p, -194-5p and novel-mir-96) selected in the training phase, the expression levels of these miRNAs were measured on additional 117 epilepsy patients and 112 healthy controls (Supplementary Table S2). [score:3]
The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed many predicted target genes that were involved in inflammation and neuronal apoptosis, including IRAK1 19 of miR-146a-5p, CASP6 20 and MAPKBP1 21 of miR-106b-5p, MAP2K6 22 of miR-194-5p, etc. [score:3]
At the cutoff value of 1.7239 for miR-106b-5p, the optimal sensitivity and specificity were 80.3% and 81.2% respectively. [score:1]
Multivariate logistic regression analyses on variables including age, gender and BMI revealed that miR-106b-5p was a potential biomarker for epilepsy diagnosis (P = 2.11 × 10-11). [score:1]
Among these miRNAs, miR-106b-5p showed the highest diagnostic accuracy with an area under the ROC curve (AUC) of 0.882 (95%CI: 0.839–0.926). [score:1]
Among these miRNAs, miR-106b-5p showed the best diagnostic value for epilepsy with 80.3% sensitivity and 81.2% specificity. [score:1]
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[+] score: 47
In order to further understand the role of aberrant miRNAs in physiological functions and biologic processes in arsenite -induced neoplastic transformation cells, 11 downregulated miRNAs (miR-197-3p, miR-192-5p, miR-127-3p, miR-139-5p, miR-490-3p, miR-196b-5p, miR-125a-3p, miR-298, miR-542-3p, miR-15b-5p, and miR-33b-5p) and six upregulated miRNAs (miR-200b-3p, miR-106b-5p, miR-574-5p, miR-320d, miR-200c-3p, and miR-141-3p) (Table S2) were selected, and their target genes were predicted with the TargetMiner, miRDB, and TarBase databases. [score:11]
Among the 191 dysregulated miRNAs, seventeen miRNAs (downregulation miRNAs: miR-197-3p, miR-192-5p, miR-127-3p, miR-139-5p, miR-490-3p, miR-196b-5p, miR-125a-3p, miR-298, miR-542-3p, miR-15b-5p, miR-33b-5p; upregulation miRNAs: miR-200b-3p, miR-106b-5p, miR-574-5p, miR-320d, miR-200c-3p, miR-141-3p, Table S2) were selected for bioinformatics analysis. [score:8]
Three of downregulated miRNAs (miR-192b-5p, miR-15b-5p, and miR-33b-5p) and three upregulated miRNAs (miR-141-3p, miR-106b-5p, and miR-200b-3p) (Table S2) were selected for validating the reliability of analysis results from miRNA Array. [score:7]
As indicated in Figure 4, the target genes were mainly regulated by miR-15b-5p (338 genes), miR-106b-5p (316 genes), and miR-320d (177 genes), and these three miRNAs were the key node in the regulatory network. [score:5]
The miRNA-gene network illustrated that miR-15b-5p (338 regulated genes), as well as miR-106b-5p (316 regulated genes) and miR-320d (177 regulated genes), may play key roles in arsenite -induced carcinogenesis. [score:4]
The interactions of miRNAs and their target genes were shown in miRNA-gene regulatory network, in which miR-15b-5p, miR-106b-5p, and miR-320d were the core hubs. [score:4]
Also, miR-141-3p, miR-106b-5p, and miR-200b-3p expression levels of HBE-T cells were 2.29-, 10.51-, and 14.47-fold of that in HBE cells. [score:3]
Also, studies have shown over -expression of miR-106b promotes cell migration and metastasis in hepatocellular carcinoma by activating epithelial-mesenchymal transition process [41]. [score:3]
We determined the level of six miRNAs (miR-33b-5p, miR-15b-5p, miR-192-5p, miR-141-3p, miR-200b-3p, and miR-106b-5p) to validate the reliability of the miRNA Array detection. [score:1]
MiR-106b was one of the significant difference miRNAs between recurrent lung adenocarcinomas and non-recurrent lung adenocarcinomas [26]. [score:1]
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[+] score: 47
Altered levels of miR-17∼92 and miR-106b∼25 are known to play crucial roles in mammalian cell regulation and have been implicated in numerous hyperproliferative diseases although the mechanisms driving their altered expression are unknown. [score:6]
Indeed, the miR-17∼92 and miR-106b∼25 clusters appear to attenuate apoptotic responsiveness by targeting several mRNAs encoding pro-apoptotic effectors and favor progression from G1 to S-phase by targeting mRNAs that encode negative regulators of the cell cycle [19], [20]. [score:6]
We show that both the primary transcripts for miR-17∼92 and miR-106b∼25 and the pivotal miRNAs that are derived from miR-17∼92 display increased abundance in Toxoplasma-infected primary human cells; a Toxoplasma -dependent up-regulation of the miR-17∼92 promoter is at least partly responsible for this increase. [score:4]
The transcription of pri-miR-17∼92 has been shown to be positively regulated by E2F3 [38] and c-Myc [37] transcription factors, and pri-miR-106b∼25 is positively regulated by E2F1 [40]. [score:3]
Whether this or one of the other injected Toxoplasma effectors is responsible for the alterations in host miR-17∼92 and miR-106b∼25 expression, and what role these changes play on the host-pathogen interaction in vivo are the focus of on-going work. [score:3]
In adult animals, miR-17∼92 and miR-106b∼25 have been shown to influence the functionally intertwined pathways of apoptosis and G1/S cell cycle progression by targeting multiple components of each pathway [20]. [score:3]
The ultimate, downstream target of these changes in miRNAs, in terms of benefit to the parasite, is not clear; in the set of HFF mRNAs that decrease in abundance upon Toxoplasma infection [5], there is no significant enrichment for mRNAs containing predicted miR-17∼92 or miR-106b∼25 binding sites (data not shown). [score:3]
Ultimately, a conditional knockout of miR-17∼92 in a miR-106b∼25 -null background will be necessary to score the full biological role(s) of these miRNAs in Toxoplasma-infected animals. [score:2]
Second, concurrent analyses using locked nucleic acid -mediated knockdown of miR-17∼92- and miR-106b∼25-derived miRNAs was performed using a wide range of conditions in mouse fibroblasts and HFFs. [score:2]
Examples relevant to the present work are four families of miRNAs (miR-17, miR-18, miR-19 and miR-25) that are encoded by three paralogous loci; these related loci, which are miR-17∼92, miR-106b∼25 and miR-106a∼363 (see Figure 1B), produce primary transcripts that are post-transcriptionally processed to yield mature miR-17, miR-18, miR-19 and miR-25 family members. [score:1]
There are no previous reports of pri-miR-106b∼25 northern blots and so, while we cannot be certain that this band corresponds to pri-miR-106b∼25 or to a splice variant of MCM7, it was consistently seen in multiple experiments and is within the size range expected for this molecule. [score:1]
It is, therefore, probable that the Toxoplasma -dependent increase in the levels of pri-miR-17∼92 and pri-miR-106b∼25 are at least in part due to such changes in host transcription factors. [score:1]
To understand the role of increased miR-106b∼25 and/or miR-17∼92 in Toxoplasma infection we took several approaches. [score:1]
These results suggest that the mature miR-18 and miR-19 family members that increase upon infection with Toxoplasma are derived from miR-17∼92; although pri-miR-106b∼25 is also increased in Toxoplasma-infected cells, miR-106b∼25 does not encode miR-18 and miR-19 family members and, consistent with previous reports [32], [37], no pri-miR-106a∼363 was detectable. [score:1]
The mature miRNAs encoded by miR-17∼92 and its paralog miR-106b∼25 play important roles in mammalian biology. [score:1]
To our knowledge this represents the first report of a pathogen that specifically increases the levels of miR-17∼92 and/or miR-106b∼25. [score:1]
miR-17∼92 and miR-106b∼25 are encoded in the 3rd intron of C13ORF25 and the 13 [th] intron of MCM7, respectively; for these genes, exons are indicated as boxes, and introns are lines. [score:1]
From top to bottom panels, probes are: miR-17∼92, miR-106b∼25 and RPS29. [score:1]
The rows are the averaged data from all probes that are predicted to hybridize to members of the indicated miRNA families; these families represent all miRNAs encoded by the miR-17∼92, miR-106a∼363 and miR-106b∼25 clusters. [score:1]
As miR-17 family members are co-transcribed with members of the miR-18 (Figure S1, blue box), miR-19 and miR-25 families, and are encoded in three separate paralogous loci (miR-17∼92, miR-106a∼363 and miR-106b∼25; Figure 1B), we assembled a heat-map from our microarray data that contains the averaged fold-change values for all probes that hybridized to members of the miR-17, miR-18, miR-19 or miR-25 families (18, 4, 4, and 4 probes, respectively; Figure 1C). [score:1]
We focused our attention on 18 microarray spots (9 closely related human and mouse probe sequences that were spotted in duplicate) that displayed comparable increases in hybridization intensities on arrays hybridized with RNA derived from infected HFFs (Figure S1, red boxes); these 18 spots contained probes that hybridized to members of the miR-17 family (the miR-17 family is composed of miR-17, miR-106a, miR-106b, miR-20a, miR-20b and miR-93; see Figure 1A for a sequence alignment of the miR-17 family). [score:1]
The situation is further complicated by the fact that both pri-miR-17∼92 and pri-miR-106b∼25 are increased upon Toxoplasma infection and these two clusters are believed to be partially functionally redundant. [score:1]
When the membrane was stripped and hybridized with a pri-miR-106b∼25 probe, infection with either Toxoplasma or Neospora showed a major band at ∼850nt, and this band demonstrated an increase of ∼2.5-fold and ∼2.6-fold, respectively, relative to uninfected HFFs (Figure 4). [score:1]
Toxoplasma-infected HFFs have elevated levels of pri-miR-17∼92 and pri-miR-106b∼25. [score:1]
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[+] score: 45
Other miRNAs from this paper: hsa-mir-151a, hsa-mir-1229, hsa-mir-3613
Therefore, the downregulation of hsa-miR-106b-3p and hsa-miR-151a-3p expression by BIX01294 treatment may exert a tumor suppressive effect, presumably through the derepression of their target gene expression at the post-transcriptional level. [score:12]
The extent of derepression of the individual target genes may determine the overall cellular response to the downregulation of hsa-miR-106b-3p and hsa-miR-151a-3p. [score:6]
The target genes of hsa-miR-106b-3p and hsa-miR-151a-3p were searched for, and their biological activities and associated human diseases were identified. [score:5]
The normalized and averaged expression levels of the remaining eight miRNAs are shown in Fig. 1. Two of the miRNAs, hsa-miR-106b-3p and hsa-miR-151a-3p, exhibited a significant reduction (40 and 33%, respectively) in expression level that is consistent with the result that was obtained from the microarray analysis. [score:5]
Coupled with qPCR analysis, the two miRNAs that were identified, hsa-miR-106b-3p and hsa-miR-151a-3p, were downregulated in H1299 cells following BIX01294 treatment. [score:4]
The small number of genes identified for hsa-miR-106b-3p precluded the performance of a robust prediction of their associated biological functions or human diseases. [score:3]
In addition, the genes exhibiting a similar function (TFAP2C, PCDHB13 and MNT) (46, 47) are also target genes of hsa-miR-106b-3p. [score:3]
A total of 14 and 182 genes were predicted to be the targets of hsa-miR-106b-3p and hsa-miR-151a-3p, respectively (Table II). [score:3]
Further studies are required to establish the functional role, and prognostic and diagnostic potential of hsa-miR-106b-3p and hsa-miR-151a-3p in lung cancer development. [score:2]
The small number of genes identified for hsa-miR-106b-3p precluded the performance of a robust prediction of the associated biological functions or disorders. [score:1]
Based on their genomic location, hsa-miR-106b-3p and hsa-miR-151a-3p are known to reside in chromosome 7q22.1 and 8q24.3, respectively. [score:1]
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[+] score: 41
The results showed that miR-378 was downregulated in GC tissues, whereas the other five miRNAs (miR-21, miR-106b, miR-17, miR-18a and miR-20a) were upregulated in GC (Figure 2). [score:7]
In conclusion, our systemic review identified five upregulated miRNAs (miR-21, miR-106b, miR-17, miR-18a and miR-20a) and one downregulated miRNA (miR-378) that are potential novel biomarkers for GC. [score:7]
Kim et al. [27] found that miR-106b may exert its oncogenic activity by suppressing p21 expression in GC. [score:5]
0073683.g002 Figure 2 Using U6 as a normalization control, the expression of miR-21, miR-106b, miR-17, miR-18a and miR-20a was significantly higher in GC tissues, while the expression of miR-378 was significantly lower. [score:5]
MiR-106b was also consistently reported as an upregulated miRNA in GC tissue by this and previous studies [14], [25]. [score:4]
MiR-106b, miR-17 and miR-18a levels were significantly higher in poorly differentiated GC, cases with lymph node involvement, or late stage disease, while miR-20a levels were significantly higher in cases of GC with lymph node involvement. [score:3]
Expression levels of miR-21, miR-106b, miR-17, miR-18a, miR-20a and miR-378 in GC and adjacent noncancerous tissue samples. [score:3]
The high expression of miR-106b has been previously associated with lymph node metastasis [25], [26], and this was validated in our study. [score:3]
MiR-106b could induce epithelial-to-mesenchymal transition (EMT) and a tumor initiating cell phenotype in breast cancer by targeting Smad7 and Six1 and activating TGF-β signaling [28]. [score:2]
For example, serum miR-21 was significantly elevated in perioperative serum from adenomas and colorectal cancer (CRC), and was an independent prognostic marker for CRC [50], [51]; Plasma miR-106b, together with miR-20a and miR-221 have the potential as novel biomarkers for early detection of gastric cancer [40]; Circulating miR-17 may used as a novel noninvasive biomarker for nasopharyngeal carcinoma [52], gastric cancer [53] and CRC [54]; Serum miR-18a may be used as a novel biomarker in breast cancer [55], colorectal cancer [56], hepatocellular carcinoma [57], and pancreatic cancer [58]; Circulating miR-378 may be used as a biomarker in renal cell carcinoma [59] and gastric cancer [60]. [score:1]
Three of these miRNAs were reported in five microarray studies (miR-21, miR-106b and miR-378), four were reported in four studies (miR-17, miR-18a, miR-20a and miR-638), and seven were reported in three studies (miR-19a, miR-20b, miR-25, miR-30d, miR-923, miR-375, and miR-148a). [score:1]
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25
[+] score: 41
MiR-151a-3p, miR-181b-5p, miR-320a, miR-328, miR-433, miR-489, miR-572 and miR-663a were downregulated, while miR-101-3p, miR-106b-5p, miR-19b-3p, miR-195-5p, miR-130a-3p and miR-27a-3p were upregulated. [score:7]
miR-151a-3p (ΔΔCt = -2.01, P = 8.29E-06), MiR-181b-5p (ΔΔCt = -3.39, P = 1.04E-10), miR-320a (ΔΔCt = -2.47, P = 5.02E-12), miR-328 (ΔΔCt = -2.28, P = 4.33E-06), miR-433 (ΔΔCt = -2.33, P = 0.0001), miR-489 (ΔΔCt = -2.10, P = 1.25E-06), miR-572 (ΔΔCt = -2.47, P = 2.66E-08) and miR-663a (ΔΔCt = -2.06, P = 0.00002) were downregulated, while miR-101-3p (ΔΔCt = 1.43, P = 0.003), miR-106b-5p (ΔΔCt = 1.30, P = 0.008), miR-130a-3p (ΔΔCt = 2.35, P = 1.89E-09), miR-195-5p (ΔΔCt = 1.43, P = 0.0016) and miR-19b-3p (ΔΔCt = 1.87, P = 6.88E-09) were upregulated in the ASD individuals. [score:7]
miR-151a-3p, miR-181b-5p, miR-320a, miR-328, miR-433, miR-489, miR-572 and miR-663a were downregulated while miR-101-3p, miR-106b-5p, miR-19b-3p, miR-195-5p, miR-130a-3p and miR-27a-3p were upregulated. [score:7]
MiR-151a-3p, miR-181b-5p, miR-320a, miR-328, miR-433, miR-489, miR-572, and miR-663a were downregulated, while miR-101-3p, miR-106b-5p, miR-130a-3p, miR-195-5p, and miR-19b-3p were upregulated. [score:7]
The differentially expressed miRNAs in this study, which included miR-101, miR-106b, miR-130a, miR-151a, miR181b, miR-328, miR-433, miR-489 and miR-572, were previously reported to have altered expression in schizophrenia [31- 35], supporting the contention that ASD and schizophrenia share common neurobiological features [36]. [score:5]
The fact that the direction of alteration in the expression of hsa-miR-106b-5p in this study was the opposite of that reported in the previous postmortem study [13] suggests that the serum level of certain miRNAs may not reflect that in the brain, and thus that our findings should be treated with caution. [score:4]
The results of the present and previous studies are summarized in Table  2, in which hsa-miR-181b-5p, hsa-miR-195-5p, hsa-miR-320a and hsa-miR-328 showed the same direction of regulation as in the brain [13] and lymphoblasts [14- 16], while hsa-miR-106b-5p, hsa-miR-19b-30 and hsa-miR-663a did not. [score:3]
The Ct values of nine miRNAs (miR-101-3p, miR-106b-5p, miR-151a-3p, miR-195-5p, miR-19b-3p, miR-27a-3p, miR-320a, miR-328, and miR-489) were in the range of 25–30, while the remaining five miRNAs (miR-130a-3p, miR-181b-5p, miR-433, miR-572, and miR-663a) had Ct values in the range of 30 to 35. [score:1]
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[+] score: 39
Of note are the upregulated HRMs predicted to target Bone morphogenetic protein 2 or BMP2; miR-106b-5p,-106a-5p and miR-20a-5p, whose repression has recently been associated with enhanced hMSC yields in hypoxic conditions and inhibition of chondrogenesis [8, 53]. [score:8]
Similarly, in embryoid bodies, hypoxia downregulated miRNA clusters- miR-17/92 or its paralogs miR-106a/363 or miR-106b/25 have been shown to be upregulated [33]. [score:7]
Further evidence of the distinct hESC and hMSC HRM profiles emerged via miRNA clusters- miR-379/656, mir-532/502, miR-17/92 and its paralog miR-106b/25 being downregulated by hypoxia in hESCs while conversely up-regulated in hMSCs. [score:7]
For instance miR-17/92 cluster members were upregulated in hMSC (miR-106b-5p and miR-25-3p) but downregulated (miR-93-3p and miR-25-5p) in hESCs (Fig 3c). [score:7]
The miR-512/519a cluster was highly represented containing 14 upregulated miRNA while 2 members of the miR-17/92 cluster and its paralogs miR-106a/363 and miR-106b/25 showed down-regulation in hypoxic hESCs. [score:7]
A role for HRMs in cytokine expression modulation has also been demonstrated for BMP2 (miR-106b, -20a, and miR-106a), Zinc finger and BTB domain containing 16 or ZBTB16 (miR-1271, miR-342), and Chemokine (C-X-C motif) ligand or CXCL3,6, and 8 (miR-106a/b, -20a, -493 and miR-425) via the HRMs indicated [49, 67, 68]. [score:3]
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[+] score: 37
miR-106b over -expression can silence two important effectors of the TGF-β signaling pathway: the cell cycle inhibitor CDKN1A and the pro-apoptotic gene BCL2L11 [39], and miR-590-5p and miR-17 have been reported to target TGFBRII, which also affects TGF-β signaling [38, 40]. [score:7]
Three of the up-regulated miRNA species (miR-106, miR-590-5p and miR-17) in the current study are also reported to be overexpressed in CD4 [+] T cells in multiple sclerosis (MS) patients [38– 41]. [score:6]
a miR-155, b miR-21, c miR-146a, d miR-210, e miR-17, f miR-590-5p, g miR-106b, h miR-301a miR-155 was consistently overexpressed following both antibody treatments: OKT3 seemed to induce stronger expression than FvFcR (Fig.   2a). [score:5]
a miR-155, b miR-21, c miR-146a, d miR-210, e miR-17, f miR-590-5p, g miR-106b, h miR-301a miR-155 was consistently overexpressed following both antibody treatments: OKT3 seemed to induce stronger expression than FvFcR (Fig.   2a). [score:5]
Eight of the tested miRNAs (miR-155, miR-21, miR-146a, miR-210, miR-17, miR-590-5p, miR-106b and miR-301a) were statistically significantly up- or down-regulated relative to untreated cells. [score:4]
All treatments induced up-regulation of miR-106b (Fig.   2g). [score:4]
Conversely, the miR-17, miR-106, and miR-590-5p expression data suggest the disrupture of the TGF-β signaling. [score:3]
Moreover, miR-106b and miR-590-5p exhibit higher expression in Tregs from MS patients compared to healthy controls [38]. [score:2]
As they were the least variable, the CD3 [+] T cell expression profiles of eight distinct miRNAs, miR-155, miR-21, miR-146a, miR-210, miR-17, miR-590-5p, miR-106b and miR-301a, were further investigated (Fig.   2 and Additional file 1: Table S5). [score:1]
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[+] score: 35
Here, we took a closer look at members of the tumorigenic miR-17~92 cluster, since (i) miR-17–5p was among the top ten hits of abundant miRNAs of which the expression was maintained by the E6/E7 oncogenes, (ii) all other members of this cluster, as well as of the paralog cluster miR-106b~25, were also downregulated by E6/E7 silencing when applying less stringent selection criteria (S3 Table), (iii) several members of the miR-17~92 cluster are well-decumented to be overexpressed in cervical cancer tissues, including the tested miR-17–5p [27– 30, 34, 37] and miR-20a-5p [23, 30, 31, 34, 35] (also see S2 Dataset), and (iv) four of these miRNAs (miR-17–5p, miR-20a-5p, miR-93–5p, and miR-106b-5p) possess the same seed sequence and can bind to the 3’ UTR of the p21 mRNA [18]. [score:8]
HPV E6/E7 increase intracellular levels of members of the oncogenic miR-17~92 cluster that reduce p21 expression in HPV -positive cancer cellsThe 52 most abundant cellular miRNAs that were downregulated > 1.5-fold upon E6/E7 silencing in both deep sequencing and qRT-PCR analyses encompassed miR-17–5p and miR-19b-3p, two members of the miR-17~92 cluster, and miR-93–5p, a member of the paralog miR-106b~25 cluster (Fig. 2D/E). [score:6]
Further qRT-PCR analyses revealed that all detectable additional members the miR-17~92 and miR-106b~25 clusters were also downregulated upon silencing of endogenous E6/E7 expression (S3 Table). [score:6]
The 52 most abundant cellular miRNAs that were downregulated > 1.5-fold upon E6/E7 silencing in both deep sequencing and qRT-PCR analyses encompassed miR-17–5p and miR-19b-3p, two members of the miR-17~92 cluster, and miR-93–5p, a member of the paralog miR-106b~25 cluster (Fig. 2D/E). [score:4]
Four miRNAs encoded by the miR-17~92 and miR-106b~25 clusters (miR-17–5p, miR-20a-5p, miR-106b-5p, miR-93–5p) are grouped into the miR-17 family, according to their identical seed sequence, and target two binding sites in the 3’ UTR of p21 [66, 67]. [score:3]
S3 TablemiR-17~92 and miR-106b~25 levels upon silencing of endogenous E6/E7 expression. [score:3]
miR-17~92 and miR-106b~25 levels upon silencing of endogenous E6/E7 expression. [score:3]
The 23 miRNAs comprise several family members of the miR-378 family (miR-378a-3p, miR-378c, miR-378d, miR-378f), as well as members of the miR-17~92 and miR-106b~25 clusters (miR-17–5p, miR-19b-3p, miR-93–5p). [score:1]
The oncogenicity of miRNAs has been particularly well demonstrated for members of the miR-17~92 cluster (also called “oncomir-1”; coding for miR-17, miR-20a, miR-18a, miR-19a, miR-19b and miR-92a) and of its paralog cluster miR-106b~25 (coding for miR-106b, miR-93 and miR-25) [18]. [score:1]
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Other miRNAs from this paper: hsa-mir-21, hsa-mir-25, hsa-mir-31, hsa-mir-93, hsa-mir-155
Over-expressed miR-106b, miR-93, and miR-25 inhibit the synthesis of p21 [CIP1] and Bim (TGF-β downstream effectors) and therefore prevent cell cycle inhibition and apoptosis Mutations in TβRII that lead to insensivity of cell lines to TGF-β mediated growth inhibition have been previously described [194]. [score:10]
Over-expressed miR-106b, miR-93, and miR-25 inhibit the synthesis of p21 [CIP1] and Bim (TGF-β downstream effectors) and therefore prevent cell cycle inhibition and apoptosisMutations in TβRII that lead to insensivity of cell lines to TGF-β mediated growth inhibition have been previously described [194]. [score:10]
The relationship between TGF-β resistance and up-regulated level of miR-106b-25 cluster (miR-106b, miR-93, and miR-25) has been recently elucidated [193]. [score:4]
In turn, miR-106b and miR-93 regulate E2F1 expression, establishing a miRNA negative feedback loop. [score:4]
Conversely, miR-106b and miR-93 control E2F1 expression thus establishing negative feedback that prevents E2F1 self-activation. [score:3]
Over -expression of miR-106b, miR-93 and miR-25 decreases response of gastric cancer cells to TGF-β since they interfere with synthesis of TGF-β downstream effectors that promote cell cycle arrest and apoptosis, such as p21 [CIP1] and BIM, respectively [193] (Figure 5). [score:3]
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30
[+] score: 33
Interestingly, a high expression level of MYCN transactivates the miRNA 17-92 and miR-106b/25 clusters, which in turn, down modulates other different targets, such as the tumour suppressor p21, PTEN, contributing to tumorigenesis (Figure 3). [score:7]
Interestingly, the inhibition of miR-17-5p and/or miR-106-5p leads to the recovery of TRIM8 -mediated p53 tumour suppressor activity, which in turn strongly inhibits MYCN -dependent cell proliferation. [score:7]
It has been demonstrated that miR-17-5p and miR-106b-5p directly target the 3′UTR of TRIM8 and both transcriptionally and post-transcriptionally repress the expression of TRIM8, indicating that TRIM8 and miR-17-5p/miR-106b-5p may be part of the same circuit involved in ccRCC and glioma pathogenesis [20, 24]. [score:6]
The TRIM8 deficit, observed in patients affected by ccRCC, was explained by the up-regulation of the miR-17-5p and miR-106b-5p members of the miR-17-92 family, whose overexpression has an oncogenic effect by promoting tumour cell proliferation [38]. [score:6]
While the miR-106a/363 cluster is rarely expressed in adult human tissues, the miR-17-92 and miR-106b/25 clusters are emerging as key actors in a wide range of biological processes including tumorigenesis [39, 40, 41]. [score:3]
An increasing number of papers report that miR-106b-5p and miR-17-5p, above all the microRNAs of the miR-17-92 family, are overexpressed in many different chemo/radio-resistant cancers, including ccRCC, glioma, CRC, and CLL cell lines [22, 38, 39, 40, 41]. [score:3]
The human genome contains two paralogues of the miR-17-92 cluster: the miR-106b/25 cluster, located on chromosome 7 (7q22.1) in the 13th intron of the Mini-Chromosome Maintenance gene (MCM7), and the miR-106a/363 cluster, located on chromosome X (Xq26.2). [score:1]
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cgi?acc=GSE6838) recording the gene expression changes in cells transfected with hsa-miR-106b, and 21 were among the top 5% down-regulated genes (Additional file 6). [score:6]
By analogy to MYC, miR-106b, a target of MYC, is probably the most important miRNA since it has the largest number of targets among all miRNAs in the network. [score:5]
Of them, hsa-miR-378 is located in the intron of protein-coding genes PPARGC1B, an experimentally validated transcriptional targets of MYC [40], and another eight miRNAs (hsa-miR-17, hsa-miR-19a, hsa-miR-19b, hsa-miR-20b, hsa-miR-92, hsa-miR-106a, hsa-miR-25, and hsa-miR-106b) belong to three paralogous clusters located on chromosome 13 (the hsa-miR-17 cluster), chromosome X (the hsa-miR-106a cluster), and chromosome 7 (the hsa-miR-106b cluster), with the former two clusters having been proved to be regulated by MYC [41]. [score:4]
Click here for file Validation of part of predicted hsa-miR-106b targets by a miRNA-transfection dataset GSE6838. [score:3]
Validation of part of predicted hsa-miR-106b targets by a miRNA-transfection dataset GSE6838. [score:3]
For the 44 predicted targets of miR-106b, 38 were covered in the public dataset GSE6838 (http://www. [score:3]
The human cancer combinatory gene regulatory network is found to be a hierarchical scale-free network with MYC, hsa-miR-106b and has-let-7c being the most important regulators. [score:3]
In our network, MYC was predicted to regulate 10 miRNAs: miR-378, hsa-miR-17, hsa-miR-19a, hsa-miR-19b, hsa-miR-20b, hsa-miR-92, hsa-miR-106a, hsa-miR-25, and hsa-miR-106b, and hsa-miR-125b. [score:2]
Hsa-miR-106b and hsa-let-7c. [score:1]
While the hsa-miR-106 family have been implicated in breast cancer [43] and gastrointestinal tumor [44], our results furthermore suggest it may be a central miRNA underpinning the general tumorigenesis mechanism. [score:1]
For instance, a quick topology analysis of this network highlights the very important cancer-related transcription factor MYC and two remarkable miRNAs hsa-miR-106b and hsa-let-7c. [score:1]
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[+] score: 30
Over -expression of the miR-17/92 cluster or the miR-106b/25 cluster in 293T cells significantly decreased luciferase expression from pLSG-LMP1, indicating these miRNAs are indeed targeting the LMP1 3′UTR (Figure 6D). [score:7]
miR-17 and miR-20a are two of six miRNAs expressed from the miR-17/92 cluster, while miR-106b and miR-93 are expressed from the miR-106b/25 cluster [65], [66]. [score:5]
Three lines of evidence demonstrate that the LMP1 3′UTR is targeted by the c-myc-regulated miRNA clusters miR-17/92 and miR-106b/25. [score:4]
Interestingly, both miR-17/92 and miR-106b/25 are transcriptional targets of c-myc [65], [66]. [score:3]
D. miR-17/92 and miR-106b/25 inhibit the LMP1 3′UTR reporter. [score:3]
We tested eleven miRNA expression vectors, including six viral miRNAs (miR-BART1, miR-BART2, miR-BART3, miR-BART4, miR-BHRF1-1, and miR-BHRF1-2) and five cellular miRNAs or miRNA clusters (miR-155, miR-146a, miR-128, miR-17/92, and miR-106b/25) against the panel of 3′UTRs. [score:3]
As the cellular miRNAs for miR-17/92 and miR-106b/25 clusters are evolutionarily conserved in mammals, we wondered whether the target sites in the BHRF1 and LMP1 3′UTRs might also be conserved. [score:3]
The miR-17/20/106 sponge contains nine imperfect binding sites within the 3′UTR of GFP for miR-17, miR-20a, or miR-106a (Table S15); miR-106b and miR-93 differ from these three miRNAs in their 3′ non-seed sequences (Figure 6C, Table S1- S4). [score:1]
For miR-17/92 and miR-106b/25, regions encompassing the entire pre-miRNA clusters were cloned. [score:1]
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[+] score: 27
Using these hepatocyte and non-hepatocyte cell lines and primary tissues, we performed unsupervised clustering analysis by selecting 7 down-regulated miRNAs (miR-17-5p, miR-18a, miR-93, miR-106a, miR-106b, miR-130b and miR-375) and 4 up-regulated miRNAs (miR-21, miR-22, miR-122a and miR-182). [score:7]
Both up-regulated miRNAs (miR-21, miR-22, miR-122a and miR-182) and down-regulated miRNAs (miR-17-5p, miR-18a, miR-93, miR-106a, miR-106b, miR-130b and miR-375) were chosen as a parameter for comparison. [score:7]
Total RNA extracted from Dex/OSM treated AR42J-B13 cells (7 Days) and mock controls were used for Northern blot analysis using antisense probes against down-regulated miRNAs (miR-93, miR-106b and miR-130b) and up-regulated miRNAs (miR-21, miR-22, miR-122a and miR-182). [score:7]
Mature miRNA of miR-93, miR-106b, miR-130b, miR-21, miR-22 and miR-182 were differentially expressed after transdifferentiation. [score:3]
The pattern of coordinated reduction in expression of miR-25, miR-93, and miR-106b (Table 1) is due to the clustering of these three miRNA genes at intron 12 of Mcm7 on chromosome 12. [score:3]
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The relationship between miR-106b and Rb/E2F would provide another example of coordinated regulation of gene expression by miRNAs and transcription factors. [score:4]
Supporting these findings, we identified 'transcriptional regulation by Rb/E2F' as the most relevant pathway to the miR-106b target network (the score = 854; the score p-value = 7.21E-258) (Figure 3, Table 1 and Additional file 1). [score:4]
E2F1 activates transcription of miR-106b, while miR-106b targets E2F1, serving as a miRNA-directed negative feedback loop in gastric cancer cells [18]. [score:4]
Red nodes represent miR-106b direct target molecules predicted by Diana-microT 3.0, whereas white nodes exhibit additional nodes extracted automatically from the core contents of KeyMolnet to establish molecular connections. [score:4]
By the "neighboring" network-search algorithm, KeyMolnet illustrated a highly complex network of miR-106b targets that has the most statistically significant relationship with the pathway of 'transcriptional regulation by Rb/E2F'. [score:4]
Figure 3 Molecular network of miR-106b targets. [score:3]
A recent study showed that miR-106b is directly involved in posttranscriptional regulation of E2F1 [18]. [score:3]
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Both genders combined, the qPCR analysis (Figure 4) indicated 4.3 fold upregulation of miR-206 (p = 0.005) and 2 fold upregulation of miR-106b (p = 0.02) in patient versus control serum samples. [score:7]
Whether miR-206 and miR-106b have a functional role in human ALS pathogenesis needs further experimental focus, preferably using methodology that can reveal miRNA target genes and pathways directly in the affected tissues. [score:4]
Additionally, miR-106b has been implicated in brown adipocyte differentiation [74] and in suppression of autophagy in cultured myoblasts [75]. [score:3]
Sufficiently high levels of expression was found only in 10 miRNAs: miR-133a, miR-206, miR-1, miR-145, miR-24, miR-19b, miR-17, miR-106b, miR-20a and miR-21. [score:3]
It is known to be expressed from a conserved cluster including three miRNAs (mir-106b, mir-93 and miR-25) that are involved in cancer [72] and adult neural stem cell proliferation and differentiation [73]. [score:3]
The two miRNAs found to be elevated here, miR-206 and miR-106b, may provide ideal biomarkers as they can be sampled from blood. [score:1]
Very little is known about the other miRNA implicated in ALS patient samples, miR-106b. [score:1]
miR-206 and miR-106b are elevated in the circulation of ALS patients. [score:1]
Therefore, it may be plausible that miR-206 (and miR-106b) can be used in the future to screen potential candidate drugs or treatments for ALS. [score:1]
In conclusion, the increased circulating miR-206 and miR-106b may serve as biomarkers for ALS in humans. [score:1]
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Figure 5 Since miR-15b, miR-23a, miR-29a, miR-106b, miR-128, miR-192 and miR-494 were found downregulated and have been shown to induce chemoresistance (Figure 5), we evaluated the expression of some of them, including miR-15b (Hs04231486_s1), miR-23a (Hs03659093_s1) and miR-29a (Hs03849009_s1), through TaqMan microRNA expression assays (Supplementary Figure 4). [score:5]
Finally, given that PTEN has been shown to be a hypothetical gene target for miR106b and miR-494, BAX for miR-128, and BIM (or BCL2L11) for miR-192, their gene expression was analyzed by means of quantitative Real-time PCR analysis (Supplementary Figure 5). [score:5]
Figure 5Since miR-15b, miR-23a, miR-29a, miR-106b, miR-128, miR-192 and miR-494 were found downregulated and have been shown to induce chemoresistance (Figure 5), we evaluated the expression of some of them, including miR-15b (Hs04231486_s1), miR-23a (Hs03659093_s1) and miR-29a (Hs03849009_s1), through TaqMan microRNA expression assays (Supplementary Figure 4). [score:5]
We found that some miRNAs, including miR-15b, miR-23a, miR-29a, miR-106b, miR-128, miR-192 and miR-494, were downregulated in MDA-MB-231 cells under STS conditions. [score:4]
MiR-15b and miR-23a have been shown to increase Cisplatin-resistance in lung cancer cell line A549 [28] and in tongue squamous cell carcinoma [29], whereas miR-29a induced Adriamycin and Docetaxel resistance in breast cancer (BC) [30], miR-128 enhanced antiblastic resistance in BC cells targeting BAX [31], miR-192 promoted Cisplatin-resistance in lung cancer cells A549/DDP [32], and, finally, miR-106b and miR-494 conferred radioresistance and Sorafenib-resistance in colorectal cancer and hepatocellular carcinoma silencing PTEN and p21 [33– 35]. [score:3]
Among miRNAs involved in chemotherapy response, miR-26a, miR-106b, miR-128 and miR-192 were not found significantly deregulated. [score:2]
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Moreover, E6 can degrade p53 [27, 28], thus upregulating the expression of miR-17-5p, miR-20a-5p, and miR-106b-5p [29]. [score:6]
The qRT-PCR results demonstrated that miR-106b-5p (p = 0.000), miR-3653 (p = 0.000), miR-17-5p (p = 0.000), miR-96 (p = 0.000), miR-15a-5p (p = 0.000), miR-20a-5p (p = 0.000), and miR-21-5p (p = 0.000) were highly expressed in cancer tissues, while miR-497-5p (p = 0.016) was expressed at very low levels. [score:5]
Here, we identified eight types of miRNAs, namely, the highly expressed miR-15a-5p, miR-17-5p, miR-20a-5p, miR-21-5p, miR-96, miR-106b-5p, and miR-3653 as well as the poorly expressed miR-497-5p. [score:5]
These findings imply that miR-15a-5p, miR-17-5p, miR-20a-5p, miR-21-5p, and miR-106b-5p are molecular targets of HPV in vivo. [score:3]
E7 can mediate the degradation of pRB [30], which reduces the pRB-E2F1 complex and increases the expression of the transcription factor E2F1, resulting in an increase in miRNAs, including miR-106b-5p [31]. [score:3]
These miRNAs included miR-106b-5p, miR3653, miR-3188, miR-497-5p, miR-218-5p, miR-17-5p, miR-96, miR-15a-5p, miR-20a-5p, miR-21-5p, and miR-590-5p (Table 3). [score:1]
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As can be seen in Figure S1 in File S1, while miR-106a-5p was significantly upregulated by transfection of pre-miR-106a-5p and downregulated by transfection of anti-miR-106a-5p, the expression levels of miR-106b were unaffected. [score:9]
A set of 36 genes was identified as candidate miR-106a-5p targets (Figure 1C and Table 1) In order to validate the specificity of pre-miR-106a-5p and anti-miR-106a-5p and their off target effects, we transfected U251 cells with equal amounts of pre-ncRNA, pre-miR-106a-5p, anti-ncRNA or anti-miR-106a-5p, and the expression level of miR-106b, another member of the miR-106 family whose sequence is most similar to miR-106a-5p, was assessed by quantitative RT-PCR assay. [score:6]
Relative expression of miR-106b-5p after miR-106a-5p transfection. [score:3]
For comparison, the expression levels of miR-106b-5p in pre-ncRNA- or anti-ncRNA -transfected cells were arbitrarily set at 1. The results are presented as the mean ± SD of three independent experiments. [score:3]
miR-106a-5p belongs to the miR-17 family, which includes miR-17-5p, miR-20a, miR-20b, miR-106a-5p, miR-106b and miR-93. [score:1]
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Other miRNAs from this paper: hsa-mir-25, hsa-mir-93
Both miR-106b and miR-93 have also been shown to target E2F1 effectively inhibiting its translation [17]. [score:7]
Consistent with our observation that overexpression of miR-106b and miR-93 predict sensitivity to CHOP, E2F1 expression has previously been associated with poor survival of breast cancer patients treated with FEC [18]. [score:5]
The miR-106b-25 cluster (miR-106b, miR-93, and miR-25) is involved in E2F1 posttranscriptional regulation and Targets PTEN. [score:4]
miR-106b, miR-93 and miR-25 form a cluster, all expressed from the same intron. [score:3]
The clinically validated interactions are shown in the legend of Table 2 and Fig. 5. It has been demonstrated that miR-106b overrides a doxorubicin -induced DNA damage checkpoint [15]. [score:1]
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Again, it is possible that miR-106b simultaneously downregulates both E2F family transcription factors and downstream genes transcriptionally regulated by E2F, resulting in efficient inactivation of the whole miR-106b targetome network governed by the hub molecule E2F. [score:7]
Consistent with these observations, we identified ‘transcriptional regulation by Rb/E2F’ as the most relevant pathway to the miR-106b targetome network [17]. [score:4]
E2F1 activates transcription of miR-106b, while miR-106b targets E2F1, constituting a negative feedback loop in gastric cancer cells. [score:3]
A previous study showed that miR-106b directly regulates E2F1 at a posttranscriptional level [46]. [score:3]
A follow-up study showed that the levels of miR-106b that targets APP are also decreased in the anterior temporal cortex of AD [58]. [score:3]
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For example, miR-106b, miR-107, miR-130a, miR-34 [9], miR-93, miR-155, miR-181a, miR-21, miR-23a, miR-320a [8], miR-193b, miR-320b [13] are significantly up-regulated and miR-148a [11, 14], miR-330-5p [15], miR-373 [16] significantly down-regulated. [score:7]
The same occurs for miR-93 and miR-106b that belong to the same family, for miR-320a and miR-320b and for miR-19a and miR-19b (right part Figure 3A) that are clustered together, respectively, according to their miRComb targets. [score:3]
Interestingly, most of these miRNAs are coincident with those appearing in Table 1 (miR-374b, miR-148a, miR-181a, miR-373, miR-320a, miR-93, miR-106b, miR-497, miR-23a, miR-19b, miR-107, miR-15a, miR-330-5p, miR-144), indicating that, apart from being targeting many mRNAs, these miRNAs are participating in the most reliable interactions. [score:3]
Interestingly, among the miRNAs participating in the 50 most significant miRNA-mRNA interactions we can find: miR-106b, miR-93, miR-148a, miR-330-5p that could be interacting with more than 4 different targets at the same time. [score:3]
It is worth noting that these 10 miRNAs together (miR-374b, miR-148a, miR-181a, miR-373, miR-320a, miR-448, miR-93, miR-106b, miR-217, miR-539) could potentially be regulating 41% of the mRNAs significantly altered in PDAC. [score:2]
These miRNA-mRNA interactions are miR-106b-LRRC55, miR-21-PDCD4, miR-148a-YWHAB, miR-93-FAM129A, miR-330-5p-GPI, miR-330-5p-BHLHE40, miR-93-LRIG1, miR-23a-LRIG1, miR-148a-ARF4, miR-106b-FAM129A, miR-148a-ACVR1, miR-148a-CTTNBP2NL. [score:1]
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[+] score: 19
Previous study reported that miR-17-92 cluster has been reported to be upregulated during the clonal expansion stage of adipocyte differentiation, posi­tively regulating adipogenesis by targeting the tumor suppressor RB2/p130 [27] and knockdown of miR-106b and miR-93 significantly induced the expression of brown fat-specific genes and promoted the accumulation of lipid-droplet in differentiating brown adipocytes. [score:12]
In addition, ectopic expression of miR-106b and miR-93 suppressed the mRNA level of Ucp1 [28]. [score:5]
As shown in Fig 6, hsa-miR-15a-5p, hsa-miR-106b-5p, hsa-miR-181a-5p, hsa-let-7 family, hsa-miR-27a-3p, hsa-miR-130b-3p, hsa-miR-152/148a-3p and hsa-miR-26b-5p got the highest degree means, which indicated that these miRNAs had more weight in adipogenesis than others. [score:1]
In the present study, we found that hsa-miR-15a-5p, hsa-miR-106b-5p, hsa-miR-181a-5p, hsa-let-7 family, hsa-miR-27a-3p, hsa-miR-130b-3p, hsa-miR-152/148a-3p and hsa-miR-26b-5p got high degree means, which indicated that these miRNAs had a great weight in adipogenesis than others. [score:1]
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[+] score: 19
0000116.g005 Figure 5(A) CNE cells were transfected or co -transfected with miR-20a and miR-106b, which share the same binding site, or with miR-20a and miR-361, which target different binding sites. [score:3]
Computational predictions indicated that miR-20a, miR-20b, miR-17-5p, miR-106a, and miR-106b had binding sites in Construct I. With slightly relaxed criteria about free energy and conservation, miR-15b, miR-16, miR-17-5p, miR-20b, and miR-107 have computationally predicted target sites in Construct II reporters (Table 4). [score:3]
Among these 54 miRNAs, miR-16, miR-20a, miR-20b, let-7b, miR-17-5p, miR-27a, miR-106a, miR-106b, miR-107, miR-193a, miR-210, miR-320, and miR-361 were predicted to target VEGF. [score:3]
To investigate whether different combinations of miRNAs have different contributions towards VEGF regulation, we performed co-transfection experiments using miR-20a with miR-106b, which share the same binding site, and miR-20a with miR-361, which target their own binding sites. [score:2]
To test the specificity of prediction of miRNA target sites, we first did experiments with a luciferase activity assay to test: a) the effects of miR-106a and miR-106b on Construct II; and b) the effects of miR-15b and miR-16 on Construct I. We found that all of these miRNAs showed repression of 20–27% of luciferase activity. [score:2]
Compared to single transfection with miR-20a, miR-106b, or miR-361, co-transfection of miR-20a with miR-361 exhibited additive repression on VEGF expression, suggesting a coordinate action of these miRNAs (Fig. 5A). [score:2]
On the other hand, little difference was observed between co-transfection of cells with miR-20a and miR-106b. [score:1]
According to the criteria, no binding sites for miR-15b and miR-16 on Construct I and miR-106a and miR-106b on Construct II were found. [score:1]
This binding site is shared by 12 different miRNAs, according to the bioinformatics prediction, but only miR-17-5p, miR-20a, miR-20b, miR-106a, and miR-106b were detected in DFOM-untreated CNE cells. [score:1]
When the prediction was carried out with miRanda software, RNAhybrid, and FindTar algorithms separately, binding sites for miR-15b and miR-16 on Construct I and miR-106a and miR-106b on Construct II would be detected by one of these algorithms. [score:1]
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[+] score: 17
Down-regualtion of miR-106b induces epithelial-mesenchymal transition but suppresses metastatic colonization by targeting Prrx1 in colorectal cancer. [score:5]
MicroRNA-106b promotes colorectal cancer cell migration and invasion by directly targeting DLC1. [score:3]
Oddly, miR-106b has been reported to have both stimulatory (Feng et al., 2012; Zhang et al., 2015a) and inhibitory (Zheng et al., 2015a) effects on the migration and EMT of CRC cell lines. [score:3]
In contrast, there are concordant findings that miR-106b promotes CRC tumor cell metastasis (Feng et al., 2012; Zhang et al., 2015a; Zheng et al., 2015a), although one study implicated the anti-metastatic factor DLC1 (Zhang et al., 2015a) as the relevant miR-106b target, while the other implicated PRRX1 (Zheng et al., 2015a). [score:3]
Dicer (Iliou et al., 2014) and multiple miRNAs [including, miR-34a (Bu et al., 2013, 2016), miR-106b (Zheng et al., 2015a), miR-140 (Zhai et al., 2015), miR-146a (Hwang et al., 2014), miR-183 (Wellner et al., 2009), miR-200 (Wellner et al., 2009), miR-203 (Wellner et al., 2009), miR-215 (Jones et al., 2015), miR-302b (Zhu et al., 2012), miR-328 (Xu et al., 2012b), miR-363 (Tsuji et al., 2014), miR-371 (Li et al., 2015c) and miR-451 (Bitarte et al., 2011)] reportedly regulate CRC TICs. [score:2]
The mechanisms underlying the downstream effectors of miR-106b demand further scrutiny, in light of these disparate findings. [score:1]
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[+] score: 17
miR-106b, a member of miR-106∼25 cluster, has been shown to down regulate the expression levels of TGFBR2, SMAD2 and BMP family genes in CRC [84], miR-126-3p to suppress breast cancer metastasis [85], and miR-126-5p to inhibit the migration and invasiveness of prostate cancer cells [86]; the function of their corresponding miRNA* sequences observed in this study awaits further experimentation. [score:8]
The miR-17∼92 cluster has been reported to regulate B- and T-cell development by targeting Bim/PTEN [51], [71], and miR-106b-3p is implicated in the control of monocytopoiesis [72]. [score:5]
Notably, miR-106b-3p*, miR-126-5p* and miR-355-3p* were detected with higher expression levels than their corresponding mature miRNAs in all four libraries. [score:3]
Table S4 shows members of the miR-17∼92 cluster to be highly represented in A33-Exos and, to a lesser extent, miR-106b-3p. [score:1]
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[+] score: 17
presented in Figure 9 show that the level of expression of the pri-miR-25 transcript was higher than that of the pri-miR-106b transcript. [score:3]
from microarrays (Figure 3) and qRT-PCR (Figure 7) suggested that levels of expression of all members of the miR-106b-25 cluster (miR-106b, miR-25, and miR-93) were decreased in cells transfected with miR-20b mimic or with miR-363-5p mimic (Figures 7A,B). [score:3]
Results from microarrays (Figure 3) and qRT-PCR (Figure 7) suggested that levels of expression of all members of the miR-106b-25 cluster (miR-106b, miR-25, and miR-93) were decreased in cells transfected with miR-20b mimic or with miR-363-5p mimic (Figures 7A,B). [score:3]
Results presented in Figure 9 show that the level of expression of the pri-miR-25 transcript was higher than that of the pri-miR-106b transcript. [score:3]
Using the level of expression of the pri-miR-17 (5′-end) transcript as reference, that of pri-miR-92a-1(3′-end) was 4.6 ± 0.7 fold higher and those of pri-miR-106b (5′-end) and pri-miR-25 (3′-end) were 8.4 ± 2.0 - and 52.1 ± 4.1-fold higher, respectively. [score:3]
The levels of expression of hsa-pri-miR-17, hsa-pri-miR-92a-1, hsa-pri-miR-106b, hsa-pri-miR-25, hsa-pri-miR-106a, and hsa-pri-miR-92a-2 were measured in E10 cells after transfection with miR-19a, miR-20b -, miR-92a -, or miR-363-5p mimic. [score:1]
The miR-106b-25 cluster, located on human chromosome 7, encodes three miRNAs: miR-106b, miR-93, and miR-25. [score:1]
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[+] score: 17
Additionally, miR-106b may target ninjurin 2 (NINJ2), first cell surface adhesion molecule identified on neural cells [64], which is also downregulated in CC [65]. [score:6]
It has been reported that miR-106b could be an oncogene in cancer, in part because it can promote breast cancer invasion and metastasis by targeting two important tumor suppressors: BRMS1 and RB [61]. [score:5]
miR-106b is overexpressed in squamous cell carcinoma of the cervix (Table 1) [17] and is part of a cluster of miRNAs, along with miR-93 and miR-25, which are located within an intron of the minichromosome maintenance 7 (MCM7) gene. [score:3]
Reduction of NINJ2, via overexpression of miR-106b, could contribute to loss of adhesion and increased migration of CC cells (Figure 1). [score:3]
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[+] score: 17
For example, HPV16 E6/E7 upregulates all of the miRs of the oncogenic miR-106b~25 cluster (58, 59) and downregulates all of the miRs of the tumor-suppressive miR-34b~34c cluster (reviewed in reference 60). [score:9]
The miR-106b~25 cluster is known to be regulated by E2F family members (49), and a member of that cluster, miR-25-5p, is one of the top miRs upregulated by HPV16 E7. [score:5]
Poliseno L, Salmena L, Riccardi L, Fornari A, Song MS, Hobbs RM, Sportoletti P, Varmeh S, Egia A, Fe dele G, Rameh L, Loda M, Pandolfi PP 2010 Identification of the miR-106b~25 microRNA cluster as a proto-oncogenic PTEN -targeting intron that cooperates with its host gene MCM7 in transformation. [score:3]
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49
[+] score: 16
Other miRNAs from this paper: hsa-mir-106a, mmu-mir-106a, mmu-mir-106b
MicroRNA-106-5p (miR-106-5p) regulates SETD2 expression at the translational level by binding to the 3′-UTR of the SETD2 mRNA transcript. [score:6]
Xiang et al [118] showed that miR-106b-5p could bind to, and inhibit translation of, the SETD2 mRNA transcript in ccRCC. [score:5]
SETD2 levels increased by inhibiting miR-106b-5p and this resulted in suppression of cell proliferation and a G0/G1 cell cycle arrest. [score:5]
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50
[+] score: 15
The expression profile of infected and uninfected cells was evaluated using a miRNA microarray, and 16 miRNAs were reported to be up-regulated (miR-4290, miR-4279, miR-625*, miR-let-7e, miR-1290, miR-33a, miR-3686, miR-378, miR-1246, miR-767-5p, miR-320c, miR-720, miR-491-3p, miR-3647, miR-451 and miR-4286) and 4 down-regulated (miR-106b, miR-20a, miR-30b and miR-3653) during dengue infection. [score:7]
This analysis identified IL-6 and CCL3 as potential targets of miR-let-7e and MIF, CCL5 and CXCL1 as potential targets of miR-451, miR-106b and miR-4279, respectively. [score:5]
The lower levels of miR-106b and the higher levels of expression of CCL5 are compatible with a derepression mechanism. [score:3]
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51
[+] score: 15
An increased expression of miR-106/302 family members inhibits the tumor suppressor p21 and rescues human mammary epithelial cells from Ras -induced senescence [14]. [score:7]
The tumor suppressor p21, regulating transition through the cell cycle and acting downstream of p53, has already been associated with hsa-miR520 belonging to the miR-106/302 family [14]. [score:4]
Although detectable, neither miRNA-106b, nor miRNA-106a, miRNA-17-5, miRNA-93, and miRNA-20 were differentially expressed in our mo del. [score:3]
Recently, a role of the miR-106b seed family members in cisplatin resistance of testicular cancer has been described by another group [18]. [score:1]
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52
[+] score: 15
For top 10 downregulated microRNAs (hsa-miR-106b-5p, hsa-miR-26b-5p, hsa-miR-494, hsa-miR-425-5p, hsa-miR-363-3p, hsa-miR-15b-5p, hsa-miR-185-5p, hsa-miR-150-5p, hsa-miR-223-3p, hsa-miR-142-5p), we included those have been shown to be deregulated in cancer (having no controversial expression status; some of these microRNAs have been shown to be upregulated in some cancer types, whereas, downregulated in other cancer types), and have either expression data or functional studies in stem cells. [score:15]
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53
[+] score: 15
For instance, the paralog miRNA clusters miR-106a/363 (integrated by miR-106a, miR-363, miR-92-2, miR-19b-2, miR-20 and miR-18b), miR-106b/25 (compound of miR-106b, miR-25 and miR-93) and miR-17/92 (comprising miR-17, miR-18a, miR-19a, miR-20a, miR-19b-1 and miR-92a-1) are down-regulated upon differentiation, while clusters miR-29a/29b and miR221/222 are strongly up-regulated, suggesting an important role for coordinate regulatory miRNA networks during GIC differentiation. [score:8]
In addition, eight of the down-regulated miRNAs belong to the three paralog clusters miR-17/92, miR-106a/363 and miR-106b/25, while three of the up-regulated miRNAs are part of the miR-23/24 paralog clusters. [score:7]
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54
[+] score: 15
Other miRNAs from this paper: hsa-let-7f-1, hsa-let-7f-2, hsa-mir-15a, hsa-mir-16-1, hsa-mir-17, hsa-mir-18a, hsa-mir-19a, hsa-mir-19b-1, hsa-mir-19b-2, hsa-mir-20a, hsa-mir-21, hsa-mir-22, hsa-mir-24-1, hsa-mir-24-2, hsa-mir-25, hsa-mir-26a-1, hsa-mir-26b, hsa-mir-29a, hsa-mir-30a, hsa-mir-31, hsa-mir-92a-1, hsa-mir-92a-2, hsa-mir-93, hsa-mir-98, hsa-mir-99a, hsa-mir-100, hsa-mir-29b-1, hsa-mir-29b-2, hsa-mir-106a, hsa-mir-16-2, hsa-mir-196a-1, hsa-mir-199a-1, hsa-mir-148a, hsa-mir-30c-2, hsa-mir-30d, hsa-mir-7-1, hsa-mir-7-2, hsa-mir-7-3, hsa-mir-10a, hsa-mir-34a, hsa-mir-181a-2, hsa-mir-181b-1, hsa-mir-196a-2, hsa-mir-199a-2, hsa-mir-210, hsa-mir-181a-1, hsa-mir-214, hsa-mir-222, hsa-mir-223, hsa-mir-27b, hsa-mir-30b, hsa-mir-122, hsa-mir-125b-1, hsa-mir-130a, hsa-mir-135a-1, hsa-mir-135a-2, hsa-mir-140, hsa-mir-141, hsa-mir-142, hsa-mir-143, hsa-mir-145, hsa-mir-191, hsa-mir-9-1, hsa-mir-9-2, hsa-mir-9-3, hsa-mir-125a, hsa-mir-125b-2, hsa-mir-126, hsa-mir-127, hsa-mir-146a, hsa-mir-150, hsa-mir-186, hsa-mir-188, hsa-mir-195, hsa-mir-200c, hsa-mir-155, hsa-mir-181b-2, hsa-mir-29c, hsa-mir-30c-1, hsa-mir-34b, hsa-mir-34c, hsa-mir-301a, hsa-mir-30e, hsa-mir-26a-2, hsa-mir-363, hsa-mir-302c, hsa-mir-370, hsa-mir-373, hsa-mir-374a, hsa-mir-328, hsa-mir-342, hsa-mir-326, hsa-mir-135b, hsa-mir-338, hsa-mir-335, hsa-mir-345, hsa-mir-424, hsa-mir-20b, hsa-mir-146b, hsa-mir-520a, hsa-mir-518a-1, hsa-mir-518a-2, hsa-mir-500a, hsa-mir-513a-1, hsa-mir-513a-2, hsa-mir-92b, hsa-mir-574, hsa-mir-614, hsa-mir-617, hsa-mir-630, hsa-mir-654, hsa-mir-374b, hsa-mir-301b, hsa-mir-1204, hsa-mir-513b, hsa-mir-513c, hsa-mir-500b, hsa-mir-374c
Tumor suppressors targeted by this cluster include PTEN, and the proapoptotic BIM and miR-106b specifically promotes cell-cycle progression by targeting cyclin -dependent kinase inhibitors p21/cdkn1a. [score:9]
Interestingly, the miRNA clusters at locus 7q22 including miR-106b, miR-93, and miR-25 (overlapping miR-17~92 cluster) were also highly upregulated in MCL. [score:4]
In addition, miR-106b overrides doxorubicin -induced DNA damage checkpoint [60]. [score:1]
The cluster has two paralogs in the genome, miR-106a~363 on chromosome X in mice and humans consisting of six miRNAs, and miR-106b~25 on chromosome 5 in mice (chromosome 7 in humans) consisting of three miRNAs encoded from the 13th intron of the DNA-replication gene Mcm7 [29]. [score:1]
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55
[+] score: 15
It is also a validated target of two other clearly rhythmic miRNAs in the present study, i. e., miR-363-3p (p = 0.006) and miR-106b-5p (p = 0.006). [score:3]
Analysis of core clock gene mRNA sequences reveal that the CRY2 mRNA has two weakly interacting miRNAs among the 26 significantly fluctuating miRNAs found in this study, i. e., miR-106-5p and miR-24-3p while none targets CRY1. [score:3]
In turn, p21 effects the phosphorylation of Rb1, another validated target of miR-106-5p, and thereby affects cell cycling. [score:3]
miR-106b-5p (p = 0.006) targets CDKN1A (p21) as mentioned above in addition to PTEN which appears to be involved in the maintenance of circadian rhythm in mouse mo dels [53]. [score:3]
Finally, a histone acetyltransferase, KAT2B which is a circadian transcriptional co-activator of activators of clock genes [55] is targeted by miR-106b-5p. [score:3]
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56
[+] score: 14
Other miRNAs from this paper: hsa-mir-25, hsa-mir-93
Recently, Li Y et al. found that the miR-106b~25 cluster was overexpressed in HCC tissues as well as cell lines, suggesting an important role of miR-106b~25 cluster in carcinogenesis and development of HCC [19]. [score:4]
In the study by Li Y et al., knock-down studies for the miR-106b-25cluster, which includes miR-106b, miR-93 and miR-25, showed that the expression of the cluster was necessary for cell proliferation and for anchorage independent growth [19]. [score:4]
Poliseno L et al. found that miR-106b~25 cluster was aberrantly overexpressed in human prostate cancer, which potentiated cellular transformation both in vitro and in vivo. [score:3]
They demonstrated that the intronic miR-106b~25cluster cooperated with its host gene MCM7 in cellular transformation both in vitro and in vivo [17]. [score:1]
MiR-25 is a member of the miR-106b~25 cluster, which includes miR-106b, miR-93 and miR-25, that is located within intron 13 of the minichromosome maintenance protein 7(MCM7) gene on chromosome 7q22.1 [14, 15]. [score:1]
MiR-25 is a member of the miR-106b~25 cluster, which includes miR-106b, miR-93 and miR-25, that is located within intron 13 of the minichromosome maintenance protein 7 (MCM7) gene on chromosome 7q22.1 [14]. [score:1]
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57
[+] score: 13
[9] Complementing these results, pri-miR-106b, the pri-form of miR-106b, was upregulated in patient-derived neurospheres (P=0.0466; Supplementary Figure 3c), suggesting that the processing efficiency of pri-form to pre-form of miR-106b was lowered, probably due to reduced DGCR8 expression. [score:6]
Importantly, downregulation of miR-106b detected in patient neurospheres is also reported in schizophrenic brains [36] and Df(16)A [+/−] mice. [score:4]
[44] In the patient-derived neurospheres, the expression level of the pri-form of miR-106b was significantly increased, conforming to haploinsufficiency of DGCR8. [score:3]
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[+] score: 13
miR-758 and miR-106b also regulate post-transcriptional ABCA1 expression [13, 14]. [score:4]
Interestingly, miR106b has been recently reported to decrease ABCA1 expression and impair cellular cholesterol efflux in neuronal cells. [score:3]
Several miRNAs have been described to regulate lipid metabolism, including miR-122, miR-33, miR-758, and miR-106b [11– 14] (Table 1). [score:2]
Overall, these findings suggest an important role for miR-758 and miR106b in regulating neurological functions and might have important implications in the pathogenesis of AD through posttranscriptional repression of ABCA1. [score:2]
The data summarized in this paper pointed out that anti-miR-33, miR-758 therapy, and miR-106 may be useful for treating dyslipidemia and cardiovascular disorders. [score:1]
Moreover, Neuro2a cells transfected with miR-106b dramatically increase levels of secreted A β by increasing A β production and preventing A β clearance [14]. [score:1]
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59
[+] score: 13
The intensity of the yellow scale in the heat map corresponds to the mean log2 expression of miRNAs on the microarrays, as shown in the key on Figure 1. Expression of 3 related genomic clusters containing predominantly neuronal miRNAs; the miR-17 cluster (A), the miR-106a cluster (B) and the miR-106b cluster (C). [score:5]
In these cells, this phase follows the down-regulation of REST, which has been shown to repress transcription of a number of neural miRNAs including miR-124, miR-9, miR-21, miR-106b and miR-93 [16], [41]. [score:4]
0011109.g006 Figure 6Expression of 3 related genomic clusters containing predominantly neuronal miRNAs; the miR-17 cluster (A), the miR-106a cluster (B) and the miR-106b cluster (C). [score:3]
Among the 49 neuronal miRNAs in primary human neurons were members of 3 related genomic clusters; 4 members of the miR-17 cluster on chromosome 13 (miRNAs 17, 19a, 19b, and 20a; Fig. 6A), 3 members of the miR-106a cluster on chromosome X (miRNAs 19b, 20b, and 106a; Fig. 6B) and 2 members of the miR-106b cluster on chromosome 7 (miRNAs 106b and 93; Fig. 6C). [score:1]
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60
[+] score: 13
The top downregulated lung TIC -associated miRNAs include miR-23a, miR-130a, let-7 family, miR-513a-5p, miR-125b and miR-29a, whereas the top upregulated miRNAs include miR-1290, miR-130b, miR-1246, miR-630, miR-196a/b, miR-9/9* and miR-17∼92 cluster and its miR-106b∼25 analogues. [score:7]
Conversely, upregulation of miR-17∼92 cluster and its paralogues miR-106b∼25, which were elevated in lung TICs, was found in several other cancers 31, as these miRNAs promoted the rapid proliferation and undifferentiated phenotype of lung epithelial progenitor cells, as well as playing a role in embryonic lung development 32 33. [score:5]
Taqman miRNA probes were as follow: hsa-miR-1246 (462575_mat), hsa-miR-1290 (002863), hsa-miR-130a (000454), hsa-miR-130b (000456), hsa-miR-196a (241070_mat), hsa-miR-196b (002215), hsa-miR-630 (001563), hsa-let-7b-5p (002619), hsa-let-7c (000379), hsa-let-7d-5p (002283), hsa-let-7i (002221), hsa-miR-106b (000442), hsa-miR-125b (000449), hsa-miR-23a (000399), hsa-miR-25 (000403), hsa-miR-320c (241053_mat), hsa-miR-3667-5p (462350_mat), hsa-513-5p (002090), hsa-miR-9* (002231). [score:1]
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61
[+] score: 13
For the first set of MSCs only 3 miRNAs (miR-324-3p, miR-494-3p, and miR-1260a) were observed to be statistically significant (p < 0.05) between passages 3 and 7. For the second set of MSCs, 7 miRNAs (let-7i, miR-25-3p, miR-106b-5p, miR-130b-3p, miR-199a-5p, miR-365a-5p, and miR-1260a) were statistically significant between passages 4 and 8. MiR-1260a was found to be significantly different between early and late passages for both MSC sets; however, it was upregulated at passage 7 for the first MSC set and downregulated at passage 8 for the second MSC set. [score:7]
For the tested miRNAs not expressed from the microarray experiments, 2 miRNAs, miR-25-3p and miR-130b-3p, were observed to be expressed based on the studies while 1 miRNA, miR-106b-5p, was not. [score:5]
Another 3 miRNAs (miR-25-3p, miR-106b-5p, and miR-130b-3p) were not expressed in all MSC samples using the microarray platform and were evaluated by to confirm our results. [score:1]
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62
[+] score: 13
The studies of Stern-Ginossa et al. reported that miR-20a, miR-93 and miR-106b could control MICA and MICB expressions [16] and recent study of Tsukerman et al. also showed that MICB expressions were regulated by miR-10b [31]. [score:6]
Because of the previous study of Stern-Ginossaret al. reported that miRNAs (miR-20a, miR-93 and miR-106b) could downregulate MICA and MICB expression [16], two types of reporter mutants were generated. [score:6]
One type of constructs contained the mutated binding sites of both known miRNAs (miR-20a, miR-93 and miR-106b) and nine novel miRNAs (our candidate miRNAs, miR-320c, miR-320a, miR-320b, miR-320c, miR-320d, miR-542-3p, miR-641, miR-661 and miR-940) and another type contained only the mutated binding sites of known miRNAs as a positive control (Figure 3A). [score:1]
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[+] score: 12
Of all miRNAs, seven (hsa-miR-380*, hsa-miR-106b, hsa-miR-17, hsa-miR-144*, hsa-miR-558, hsa-miR-548d-3p, and hsa-miR-222) were significantly downregulated (adjusted two-tailed t-test P <0.05) in at least 13 of 19 disease conditions, representing the most non-specific miRNAs. [score:6]
Interestingly, among the most significant miRNAs downregulated in about 70% (13 of 19) of the analyzed diseases we found members of the miR-17 family, i. e., hsa-miR-17 and hsa-miR-106b. [score:6]
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64
[+] score: 12
Other miRNAs from this paper: hsa-let-7a-1, hsa-let-7a-2, hsa-let-7a-3, hsa-let-7b, hsa-let-7c, hsa-let-7d, hsa-let-7e, hsa-let-7f-1, hsa-let-7f-2, hsa-mir-15a, hsa-mir-16-1, hsa-mir-17, hsa-mir-18a, hsa-mir-20a, hsa-mir-21, hsa-mir-22, hsa-mir-23a, hsa-mir-24-1, hsa-mir-24-2, hsa-mir-25, hsa-mir-27a, hsa-mir-29a, hsa-mir-30a, hsa-mir-92a-1, hsa-mir-92a-2, hsa-mir-93, hsa-mir-101-1, hsa-mir-106a, hsa-mir-107, hsa-mir-16-2, hsa-mir-192, hsa-mir-196a-1, hsa-mir-199a-1, hsa-mir-129-1, hsa-mir-148a, hsa-mir-10b, hsa-mir-34a, hsa-mir-181b-1, hsa-mir-181c, hsa-mir-196a-2, hsa-mir-199a-2, hsa-mir-203a, hsa-mir-210, hsa-mir-212, hsa-mir-214, hsa-mir-215, hsa-mir-217, hsa-mir-218-1, hsa-mir-218-2, hsa-mir-221, hsa-mir-222, hsa-mir-223, hsa-mir-200b, hsa-let-7g, hsa-let-7i, hsa-mir-1-2, hsa-mir-15b, hsa-mir-27b, hsa-mir-122, hsa-mir-124-1, hsa-mir-124-2, hsa-mir-124-3, hsa-mir-125b-1, hsa-mir-130a, hsa-mir-141, hsa-mir-142, hsa-mir-143, hsa-mir-145, hsa-mir-153-1, hsa-mir-153-2, hsa-mir-9-1, hsa-mir-9-2, hsa-mir-9-3, hsa-mir-125a, hsa-mir-125b-2, hsa-mir-126, hsa-mir-129-2, hsa-mir-146a, hsa-mir-150, hsa-mir-185, hsa-mir-195, hsa-mir-206, hsa-mir-200c, hsa-mir-1-1, hsa-mir-155, hsa-mir-181b-2, hsa-mir-29c, hsa-mir-200a, hsa-mir-101-2, hsa-mir-34b, hsa-mir-34c, hsa-mir-130b, hsa-mir-376c, hsa-mir-375, hsa-mir-378a, hsa-mir-148b, hsa-mir-338, hsa-mir-335, hsa-mir-423, hsa-mir-20b, hsa-mir-429, hsa-mir-449a, hsa-mir-433, hsa-mir-451a, hsa-mir-193b, hsa-mir-520d, hsa-mir-503, hsa-mir-92b, hsa-mir-610, hsa-mir-630, hsa-mir-650, hsa-mir-449b, hsa-mir-421, hsa-mir-449c, hsa-mir-378d-2, hsa-mir-744, hsa-mir-1207, hsa-mir-1266, hsa-mir-378b, hsa-mir-378c, hsa-mir-378d-1, hsa-mir-378e, hsa-mir-378f, hsa-mir-378g, hsa-mir-378h, hsa-mir-4512, hsa-mir-378i, hsa-mir-203b, hsa-mir-451b, hsa-mir-378j
miR-106b and miR-93 abrogate TGFβ -induced apoptosis in GC cells by targeting the expression of BIM, encoding the pro-apoptotic protein BCL2-like 11, and thereby prevent apoptosis and cause tumor progression [26]. [score:5]
In addition, both miR-106b and miR-93 down-regulate p21, whereas miR-222 and miR-221 both control p27 and p57. [score:4]
Zhang R. Wang W. Li F. Zhang H. Liu J. MicroRNA-106b~25 expressions in tumor tissues and plasma of patients with gastric cancers Med. [score:2]
In a large-scale analysis, four circulating oncomiRs (miR-17-5p, miR-21, miR-106a and miR-106b) significantly distinguished GC patients from healthy controls and pre-operative from post-operative GC patients [185]. [score:1]
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65
[+] score: 11
The expression of miR-106a, miR-106b, miR-17-5p, miR-92, miR-93, miR-130a, miR-20a and miR-190 were much higher in EB than in either hES cells or adult cells (Figure 6, panel B). [score:3]
The expression of miR-106a, miR-106b, miR-17-5p, miR-92, miR-93, miR-190, miR-20a and miR-130 were highest in EB (panel B). [score:3]
For miR-106b, miR-92, miR-93, miR-130a and miR-190, the difference in their expression between EB and hES cells and between EB and adult cells were significant (P < 0.05). [score:3]
The second was located on chromosome 7 and includes miR-25, miR-93 and miR-106b. [score:1]
The members of miR-17-92 cluster and its paralogs such as miR-106a, miR-106b, miR-93, and miR-17-5p are related to DNA replication and cell mitosis in cancer cells [60- 62], moreover, miR-17-5p and miR-20a can induce heterochromatic features in promoters that undergo overlapping transcription and possess sequence complementarity to the miRNA seed region [63]. [score:1]
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66
[+] score: 11
From the group of miRNAs specific for HPV -positive tonsillar tumors, we choose upregulated miR-9 and miR-106b# whose deregulation was previously reported in HNC [50– 52]. [score:5]
The differential expression of six miRNAs (miR-106b#, miR-9, miR-16, miR-34a, miR-155, and miR-126) (P<0.05; FC>1.33) was confirmed in a larger set of 64 tumor samples, the fold change of miR-193b was equal to 1.23, but the trend of expression was also maintained. [score:5]
MiR-106b# and miR-9 were selected as specific for HPV -positive tonsillar tumors, miR-16, miR-34a, miR-193b, miR-31, miR-221, and miR-21 as specific for HPV -negative tumors, and miR-155, miR-126, and miR-205 as specific for tonsillar tumors of any etiology. [score:1]
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67
[+] score: 11
Second, TAL1 is a putative target of several miRNAs that are up-regulated in hematopoietic stem cells, such as hsa-miR-17-5p, hsa-miR-197, hsa-miR-106 and hsa-miR-20 [39], and of some that are down-regulated in differentiated megakaryocytes, such as hsa-miR-106 and hsa-miR-20 [40], suggesting that miRNAs might regulate TAL1 at different stages of hematopoietic development. [score:11]
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68
[+] score: 11
Other miRNAs from this paper: hsa-let-7a-1, hsa-let-7a-2, hsa-let-7a-3, hsa-let-7b, hsa-let-7c, hsa-let-7d, hsa-let-7e, hsa-let-7f-1, hsa-let-7f-2, hsa-mir-15a, hsa-mir-16-1, hsa-mir-17, hsa-mir-19b-1, hsa-mir-19b-2, hsa-mir-20a, hsa-mir-21, hsa-mir-24-1, hsa-mir-24-2, hsa-mir-26a-1, hsa-mir-26b, hsa-mir-29a, hsa-mir-30a, hsa-mir-98, hsa-mir-101-1, hsa-mir-29b-1, hsa-mir-29b-2, hsa-mir-106a, hsa-mir-16-2, hsa-mir-192, hsa-mir-148a, hsa-mir-30c-2, hsa-mir-30d, hsa-mir-7-1, hsa-mir-7-2, hsa-mir-7-3, hsa-mir-10a, hsa-mir-10b, hsa-mir-34a, hsa-mir-210, hsa-mir-215, hsa-mir-200b, 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-125b-1, hsa-mir-133a-1, hsa-mir-133a-2, hsa-mir-137, hsa-mir-138-2, hsa-mir-143, hsa-mir-144, hsa-mir-145, hsa-mir-152, hsa-mir-9-1, hsa-mir-9-2, hsa-mir-9-3, hsa-mir-125a, hsa-mir-125b-2, hsa-mir-126, hsa-mir-127, hsa-mir-138-1, hsa-mir-146a, hsa-mir-193a, hsa-mir-194-1, hsa-mir-206, hsa-mir-320a, hsa-mir-200c, hsa-mir-1-1, hsa-mir-155, hsa-mir-194-2, hsa-mir-29c, hsa-mir-30c-1, hsa-mir-200a, hsa-mir-302a, hsa-mir-101-2, hsa-mir-34b, hsa-mir-34c, hsa-mir-30e, hsa-mir-26a-2, hsa-mir-302b, hsa-mir-302c, hsa-mir-302d, hsa-mir-369, hsa-mir-371a, hsa-mir-340, hsa-mir-335, hsa-mir-133b, hsa-mir-146b, hsa-mir-519e, hsa-mir-519c, hsa-mir-519b, hsa-mir-519d, hsa-mir-519a-1, hsa-mir-519a-2, hsa-mir-499a, hsa-mir-504, hsa-mir-421, hsa-mir-320b-1, hsa-mir-320c-1, hsa-mir-320b-2, hsa-mir-190b, hsa-mir-301b, hsa-mir-302e, hsa-mir-302f, hsa-mir-320d-1, hsa-mir-320c-2, hsa-mir-320d-2, hsa-mir-320e, hsa-mir-371b, hsa-mir-499b
Other components of the DNA damage response are also targeted by miRNAs; the TP53 gene itself which encodes p53 is targeted by miR-504 and miR-125b in several cell lines [25, 26] whereas the CDKN1A/p21 gene was demonstrated to be directly regulated by miR-106b in samples from five different solid tumours (breast, colon, kidney, gastric, and lung) when compared with non-cancer control tissue [27]. [score:6]
Ivanovska I. Ball A. S. Diaz R. L. Magnus J. F. Kibukawa M. Schelter J. M. Kobayashi S. V. Lim L. Burchard J. Jackson A. L. MicroRNAs in the miR-106b family regulate p21/CDKN1A and promote cell cycle progression Mol. [score:2]
These closely overlap with those that regulate DNA damage checkpoints, including miR-34a, miR-24 and members of the miR-106b cluster [83]. [score:2]
Other DNA-damage associated miRNAs have also been associated with cellular senescence; the miR17-92 cluster and its paralogues the miR-106a and miR-106b clusters have also been implicated in cell senescence in several tissues and cell types [75, 84]. [score:1]
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69
[+] score: 11
miR-106b aberrantly expressed in a double transgenic mouse mo del for Alzheimer's disease targets TGF-beta type II receptor. [score:7]
Another study suggests a possible transient effect of Aβ plaque pathology on miRNA (miR-106b) expression (Wang et al., 2010), while miR-106b was also found to regulate APP mRNA levels (Hebert et al., 2009). [score:4]
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70
[+] score: 11
Both miR-93 and miR-106b directly target p21, resulting in its transcriptional silencing and impairment of its tumor-suppressing activity [14]. [score:6]
miR-25, miR-93, miR-106b, and miR-130 inhibit apoptosis by preventing the expression of the pro-apoptotic protein, Bim (Figure 2) [14]. [score:5]
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71
[+] score: 10
Other miRNAs from this paper: hsa-mir-17, hsa-mir-20a, hsa-mir-106a, hsa-mir-23b
A prototypical example: The micFFL involving E2F1 and RB1 as targets and a set of miRNAs (miR-106a,miR-106b, miR-17, miR-20a and miR-23b) as master regulators. [score:4]
Within the list of candidates with experimentally validated interactions we selected, as an example, the micFFLs involving E2F1 and RB1 as targets and a set of miRNAs (miR-106a, miR-106b miR-17 miR-20a and miR-23b) as master regulators (see Table S4). [score:4]
In the last section we discuss a prototypical example of this situation, i. e. the micFFL involving E2F1 as TF, RB1 as T and a set of miRNAs (miR-106a, miR-106b, miR-17, miR-20a and miR-23b) as master regulators. [score:2]
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72
[+] score: 10
Type of cells Processes involved Non-coding RNA Reference hESC Pluripotency, self-renewal, cell cycle and fate specification miR-302 Suh et al. (2004), Bar et al. (2008), Lipchina et al. (2011) hESC Inhibition of pluripotency miR-145 Xu et al. (2009) iPSC Pluripotency miR-17, miR-106b, and miR-106a Li et al. (2011) Fibroblasts to iPSC Reprogramming miR-302, miR-372 Anokye-Danso et al. (2011), 2012, Subramanyam et al. (2011) Fibroblasts to iPSC Reprogramming Combination of miR-302, miR-200c, and miR-369 Miyoshi et al. (2011) iPSC Reprogramming LincRNAs Loewer et al. (2010) hESC Neural differentiation LincRNAs Ng et al. (2012) iPS-derived neural progenitors Neural differentiation LincRNAs Lin et al. (2011) hESC Differentiation to neuroectoderm miR-200, miR-96 Du et al. (2013) hESC-derived neural stem cells Suppression of selfrenewal, neural differentiation miR-124, miR-125b and miR-9/9 Roese-Koerner et al. (2013) hESC Neural differentiation miR7 Liu et al. (2012) hESC Neural differentiation miR125 Boissart et al. (2012) hESC, human embryonic stem cells; iPSC, induced pluripotent stem cells. [score:5]
In the study of Li et al. (2011) was observed that three miRNA clusters: miR-17, miR-106b, and miR-106a were significantly upregulated that interfere with iRNA machinery directly connected with important reprogramming pathways: TGF-β signaling and cell cycle. [score:5]
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73
[+] score: 10
MiR-203 was indicated by a study [52] as an anti-metastatic miRNA in PC, intervening the advancement of the cancer via repressing a cohort of premetastatic targets; miR-93 was commonly overexpressed in PC patients and worked collectively with miR-106b and miR-375 to attenuate Capicua levels and facilitate PC progression [53]; a reduction or loss of miR-146b expression was suggested as an omen of PC invasion by the literature [54]; miR-486-5p, the 5p arm of the pre-miRNA for miR-486, stagnated the migration and invasion of PC by lowering the protein expression of Snail, a key regulator of the epithelial–mesenchymal transition for cancer metastasis [55]. [score:10]
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74
[+] score: 10
Of these 16 miRNAs, 9 were downregulated (let-7d, miR-106b, miR-122a, miR-141, miR-183, miR-195, miR-200a, miR-335, mir424) and 7 were upregulated (miR-100, miR-199a, miR-296, miR-29a, miR-29c, miR-99a, mir-494). [score:7]
Other miRNAs found differentially expressed in both tissues and cell lines are miR-146b, miR-508, miR-106b, miR-134, miR-155, miR-346, miR-422a, miR-424, miR-519a, miR-648, miR-662. [score:3]
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75
[+] score: 10
The miR-141, miR-29 family, miR-96 and miR-106b presented the highest increase in the expression levels (≥ 5 times fold up-regulated). [score:6]
The up-regulated miRNAs in all 21T cell lines, suggesting an early event in tumorigenesis include the oncomiRs miR-29a/b/c [18, 19], miR-141 [20, 21], miR106b [22] and miR-96 [23, 24]. [score:4]
[1 to 20 of 2 sentences]
76
[+] score: 10
MiR-20a and miR-106b negatively regulate autophagy induced by leucine deprivation via suppression of ULK1 expression in C2C12 myoblasts. [score:6]
Upregulation of miR-20a and miR-106b is involved in the acquisition of malignancy of pediatric brainstem gliomas. [score:4]
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77
[+] score: 10
miR-103, miR-106b, and miR-424 were significantly up-regulated in GPI [high]-patients and IFM high-risk (Supplementary Table S6A). [score:4]
Of these, miR-106b correlates with BUB1 (see subsequent paragraph) being part of the expression -based proliferation index by Zhan et al. [7]. [score:3]
miR-106b is also correlated to TMPO as part of the UAMS 70-gene risk-score [38]. [score:1]
miR-19b and miR-106b are members of the miR-17–92 cluster and correlated to genes, e. g. BUB1 and BUB1B, that have been described as components of the mitotic checkpoint control [40]. [score:1]
Seventeen correlations were negative, twelve positive, and five miRNAs (miR-19b, miR-103, miR-106b, miR-424, and miR-623) were correlated with more than one mRNA. [score:1]
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[+] score: 10
Silencing of Bcr-Abl provokes a downregulation of these lncRNAs; among them, beta globin locus transcript 3 (non-protein coding) (lncRNA-BGL3) acts as a tumor suppressor transcript acting as a ceRNA for those miRNAs that target the oncosuppressor PTEN, such as miR-17, miR-20 and miR-106. [score:10]
[1 to 20 of 1 sentences]
79
[+] score: 10
Other miRNAs from this paper: hsa-let-7a-1, hsa-let-7a-2, hsa-let-7a-3, hsa-let-7b, hsa-let-7c, hsa-let-7d, hsa-let-7e, hsa-let-7f-1, hsa-let-7f-2, hsa-mir-15a, hsa-mir-16-1, hsa-mir-17, hsa-mir-18a, hsa-mir-19a, hsa-mir-19b-1, hsa-mir-20a, hsa-mir-21, hsa-mir-22, hsa-mir-23a, hsa-mir-26a-1, hsa-mir-26b, hsa-mir-27a, hsa-mir-29a, hsa-mir-30a, hsa-mir-31, hsa-mir-33a, hsa-mir-92a-1, hsa-mir-92a-2, hsa-mir-93, hsa-mir-96, hsa-mir-29b-1, hsa-mir-29b-2, hsa-mir-103a-2, hsa-mir-103a-1, hsa-mir-16-2, hsa-mir-197, hsa-mir-199a-1, hsa-mir-208a, hsa-mir-148a, hsa-mir-30c-2, hsa-mir-30d, hsa-mir-7-1, hsa-mir-7-2, hsa-mir-7-3, hsa-mir-34a, hsa-mir-181a-2, hsa-mir-181b-1, hsa-mir-181c, hsa-mir-199a-2, hsa-mir-204, hsa-mir-210, hsa-mir-181a-1, hsa-mir-221, hsa-mir-222, hsa-mir-223, hsa-mir-224, hsa-mir-200b, hsa-let-7g, hsa-let-7i, hsa-mir-1-2, hsa-mir-15b, hsa-mir-27b, hsa-mir-30b, hsa-mir-122, hsa-mir-124-1, hsa-mir-124-2, hsa-mir-124-3, hsa-mir-125b-1, hsa-mir-130a, hsa-mir-132, hsa-mir-133a-1, hsa-mir-133a-2, hsa-mir-138-2, hsa-mir-140, hsa-mir-141, hsa-mir-142, hsa-mir-143, hsa-mir-145, hsa-mir-9-1, hsa-mir-9-2, hsa-mir-9-3, hsa-mir-125a, hsa-mir-125b-2, hsa-mir-126, hsa-mir-138-1, hsa-mir-146a, hsa-mir-193a, hsa-mir-194-1, hsa-mir-195, hsa-mir-206, hsa-mir-320a, hsa-mir-200c, hsa-mir-1-1, hsa-mir-155, hsa-mir-181b-2, hsa-mir-194-2, hsa-mir-29c, hsa-mir-30c-1, hsa-mir-200a, hsa-mir-34b, hsa-mir-34c, hsa-mir-130b, hsa-mir-30e, hsa-mir-26a-2, hsa-mir-363, hsa-mir-365a, hsa-mir-365b, hsa-mir-369, hsa-mir-370, hsa-mir-371a, hsa-mir-375, hsa-mir-378a, hsa-mir-133b, hsa-mir-423, hsa-mir-448, hsa-mir-429, hsa-mir-486-1, hsa-mir-146b, hsa-mir-181d, hsa-mir-520c, hsa-mir-499a, hsa-mir-509-1, hsa-mir-532, hsa-mir-33b, hsa-mir-637, hsa-mir-320b-1, hsa-mir-320c-1, hsa-mir-320b-2, hsa-mir-378d-2, hsa-mir-509-2, hsa-mir-208b, hsa-mir-509-3, hsa-mir-103b-1, hsa-mir-103b-2, hsa-mir-320d-1, hsa-mir-320c-2, hsa-mir-320d-2, hsa-mir-378b, hsa-mir-320e, hsa-mir-378c, hsa-mir-378d-1, hsa-mir-378e, hsa-mir-378f, hsa-mir-378g, hsa-mir-378h, hsa-mir-378i, hsa-mir-371b, hsa-mir-499b, hsa-mir-378j, hsa-mir-486-2
Overexpression of miR-106b determines mitochondrial dysfunction and insulin resistance in C2C12 myotubes by targeting mitofusin-2. Notably, expression of this miRNA is improved following TNF-α treatment, suggesting that its enhanced production under chronic low-grade inflammation may represent a valuable link between mitochondrial alteration and T2D [117]. [score:7]
miR-106b, highly expressed in the muscle of diabetic subjects, has been associated to skeletal muscle insulin resistance and T2D. [score:3]
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80
[+] score: 9
2013.01.007 23333246 [85] Wu H, Wang F, Hu S, Yin C, Li X, Zhao S, Wang J, Yan X. MiR-20a and miR-106b negatively regulate autophagy induced by leucine deprivation via suppression of ULK1 expression in C2C12 myoblasts. [score:6]
[37] For example, ULK1 (unc-51 like autophagy activating kinase 1) is targeted by MIR20A and MIR106; [85] BECN1/beclin 1 by MIR30A, MIR376B and MIR519A; [86-89] RAB5A (RAB5A, member RAS oncogene family) by MIR101 and MIR630; [89,90] RB1CC1/FIP200 (RB1 inducible coiled-coil 1) by MIR224; [91] and ATGs by MIR30A, MIR181A, MIR374A, MIR630, MIR376B, MIR204, MIR224, MIR375, MIR519A, MIR885, and MIR-101. [score:3]
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However, VDR -dependent co-regulation of miR-106b also appears to modulate the precise timing of CDKN1A accumulation and expression of p21 [(waf1/cip1)] in a feed-forward loop and determine the final extent of the cell cycle arrest. [score:4]
1α,25(OH) [2]D [3] regulates the DNA helicase MCM7 (Khanim et al., 2004) that encodes the miR-106b, in intron 13 of the MCM7 gene, and together these co-regulation processes control p21 [(waf1/cip1)] through the balance of MCM7 and CDKN1A (Saramaki et al., 2006; Ivanovska et al., 2008) (Figure 1). [score:3]
MicroRNAs in the miR-106b family regulate p21/CDKN1A and promote cell cycle progression. [score:2]
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82
[+] score: 9
Increased expression of hsa-miR-638 was only observed in MHCC97H cells treated by ESC, while the expression of hsa-miR-106b-5p did not change in any of these two cancer cell lines. [score:5]
Among of them, 12miRNAs (hsa-miR-139-5p, hsa-miR-638, hsa-miR-107, hsa-miR-331-3p, hsa-miR-21-3p, hsa-miR-134-5p, hsa-miR-16-1-3p, hsa-miR-339-5p, hsa-miR-106b-5p, hsa-miR-423-3p, hsa-miR-491-3p, hsa-miR-24-3p) were related to cancers. [score:1]
According to the references, we selected hsa-miR-107, hsa-miR-638, hsa-miR-106b-5p to be verified with real-time PCR in MHCC97H and HepG2 cells. [score:1]
hsa-miR-107, hsa-miR-638, hsa-miR-106b-5p were selected to be validated with real-time PCR method in HepG2 and MHCC97H cells. [score:1]
According to the professional knowledge and literature (Table  2), 3 differential miRNAs (hsa-miR-107, hsa-miR-638, hsa-miR-106b-5p) that related to cancers were singled out for real-time PCR validation. [score:1]
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83
[+] score: 9
All six miRNAs were overexpressed in HCC when compared to the adjacent normal liver, with miR-17 and miR-106b (p value<0.001) being the most overexpressed and miR20-b being minimally overexpressed (p value=0.03) (Figure 1A). [score:6]
The miR 17 family (miR 17, miR 20a, miR 20b, miR106a, miR106b, miR 93) is a part of this cluster and few studies have shown that over -expression of miR-17 family promotes HCC progression and cancer metastasis [10, 11]. [score:3]
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84
[+] score: 9
The levels of miR-30b* and miR-106b, which were significantly decreased by XPO5 knockdown, were not influenced by XPO1 inhibition (Figure 4G and 4H), showing that XPO5 is their main transporter. [score:4]
The levels of (G) miR-30b* and (H) miR-106b were not affected by XPO1 inhibition. [score:3]
The levels of the miRNAs miR-302c, miR-302c*, miR-125b, miR-196a, miR-155, miR-527, miR-30b*, miR-106b, miR-373 and miR-497* were chosen to exemplify the effect of XPO5 knockdown on the cytoplasmic level of miRNAs. [score:2]
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85
[+] score: 9
Out of 81 miRNAs examined and followed by two criteria (statistical significance and 2 -FC), the expression of three H [2]O [2] -downregulated miRNAs (let-7i, miR-106b, and miR-128) was significantly downregulated by curcumin pretreatment. [score:9]
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86
[+] score: 9
miR-93-5p, as a member of the microRNA gene cluster miR-106b~25 (miR-106b, miR-93, and miR-25), is expressed in primary stem cells [21] and normal tissue [22] as well as in pathological contexts, such as tumour development [23], ageing [24], bone formation [25], and cardiovascular disease [26]. [score:6]
Repetitive magnetic stimulation promotes neural stem cells proliferation by upregulating MiR-106b in vitro. [score:3]
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87
[+] score: 9
This downregulation of Pur-α in monocytes was attributed to the robust expression of a group of miRNAs that included miR-15a, miR-15b, miR-16, miR-20a, miR-106b, and miR-93, which all directly targeted the 3′UTR of Pur-α [229]. [score:9]
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88
[+] score: 9
Also, miR-125a-5p/-351, miR-200c/-429, miR-106b/-17, miR-363/-92b, miR-181b/-181d, miR-19a/-19b, let-7d/-7f, miR-18a/-18b, miR-128/-27b and miR-106a/-291a-3p pairs exhibited significant synergy and their association to aging and/or cardiovascular diseases is supported in many cases by a disease database and previous studies. [score:5]
Brett JO Renault VM Rafalski VA Webb AE Brunet A The microRNA cluster miR-106b ~ 25 regulates adult neural stem/progenitor cell proliferation and neuronal differentiationAging (Albany NY). [score:2]
We comment on the miR-106b/-17 pair which acquired the first rank. [score:1]
Age-related evidence for miR-106b is found in the work of Brett et al. [40] which associated it with neural stem cell proliferation and differentiation during aging. [score:1]
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89
[+] score: 9
VDR directly down-regulates miR-181a, co-regulates mir-106b, and finally leads to an up-regulation of p27. [score:9]
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90
[+] score: 8
Translation of E2F1 is inhibited by miR-106b and miR-93 (derived from this cluster). [score:5]
Both the evolutionary sequence analysis and the seed-sequence -based grouping partition these miRNAs into four families: the miR-106 family (miR-17, miR-20a/b, miR-106a/b, and miR-93), the miR-18 family (miR-18a/b), the miR-19 family (miR-19a/b-1/2), and the miR-92 family (miR-25, miR-92a-1/2, and miR-363). [score:1]
The cluster encodes three miRNAs: miR-106b, miR-93, and miR-25 [35, 39]. [score:1]
This creates a negative feedback loop between E2F1 activity, miR-106b/miR-93, and transcription of the Mcm7 gene. [score:1]
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91
[+] score: 8
Resveratrol and Pterostilbene decrease the levels of endogenous as well as exogenously expressed miR-17, miR-20a and miR-106b thereby upregulating their target PTEN [122] and eventually leading to reduced tumor growth in vivo. [score:8]
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92
[+] score: 8
Other miRNAs from this paper: hsa-mir-27a, hsa-mir-15b, hsa-mir-23b, hsa-mir-27b, hsa-mir-503
It bears noting that our analyses also showed that Pitx2c can increase Myf5 expression by down -regulating miR-106b (Figure 3B), thus expanding the Myf5 [+] satellite-cell population and revealing a role for Pitx2c in promoting satellite-cell populations more primed for myogenic commitment (Lozano-Velasco et al., 2015). [score:4]
Moreover, we have demonstrated that such Pitx2c effect on SCs proliferation is due to Pitx2c -mediated downregulation of the miRNAs miR-15b, miR-106b, miR-23b, and miR-503 (Figure 3B). [score:4]
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93
[+] score: 8
PTEN participates in two overlaps and targets hsa-miR-106b, hsa-miR-141, hsa-miR-17, hsa-miR-21, hsa-miR-26a and hsa-miR-494 whilst simultaneously being targeted by them. [score:5]
For example, the MCM7 gene codes for hsa-miR-106b, which targets PTEN. [score:3]
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94
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miR Targets Tumor Impact on metastasis Description miR-106a ∼ 363, miR-106b ∼ 25 BIM, p21 Gastric cancer The miR-106b-25 cluster is involved in E2F1 post-transcriptional regulation and may play a key role in the development of TGFβ resistance in gastric cancer E2F1 Prostate cancer microRNA expression becomes altered with the development and progression of prostate cancer. [score:8]
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95
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Interestingly, Panobinostat (LBH589), a pan deacetylase inhibitor tested in several clinical trials, stimulates the E2F1- and myc -mediated transcription of miR-106b. [score:3]
A striking example is provided by the action of a micro -RNA (miRNA), miR-106b, whose expression correlates with stabilization and activation of p73 in chronic lymphocytic leukemia (CLL) [148]. [score:3]
miR-106b interacts with the 3’UTR of Itch mRNA, and is a negative regulator of Itch protein levels. [score:2]
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96
[+] score: 8
Other miRNAs from this paper: hsa-mir-106a, hsa-mir-222, hsa-mir-3940
Moreover, neutralizing CXCL1 in hAdSCs’ CM by CXCL1 neutralizing antibody reversed the alteration of miR-106 expression back to 0.80 ± 0.08-fold of control, while hAdSCs’ CM with or without isotype control IgG antibody downregulated miR-106a expression to 0.47 ± 0.06-fold and 0.50 ± 0.07-fold of control, respectively (Fig.   6b). [score:8]
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97
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Among the miRNAs whose expression was suppressed by butyrate, members of the miR-106b family, including miR-17, miR-20a/b, miR-93 and miR-106a/b, regulate p21 translation and cancer cell proliferation [15, 16]. [score:8]
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98
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The predicted results of hsa-mir-106b are listed in Table 6. For hsa-mir-106b, we removed 31 related diseases associations and ranked candidate diseases based on the predictive result of the SRMDAP. [score:5]
For colorectal neoplasms and hsa-mir-106b, all top 50 predicted miRNAs and all top 10 predicted diseases have been confirmed by dbDEMC, miRCancr, HMDD, or the literature. [score:3]
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99
[+] score: 8
For example, miR-106b/93 and miR-221/222 are upregulated in gastric cancer tissues and control suppression of CDK protein inhibitors in a coordinated manner thereby stimulating tumor invasion and progression [199]. [score:8]
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100
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Overexpressed miR-125b [16] could function as an oncogene, whereas downregulated miRNAs, including miR-194 [17], miR-130b [18], miR-106b [19] and miR-34 [20], could work as tumor suppressors in aggressive ECs. [score:8]
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