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23 publications mentioning rno-mir-494

Open access articles that are associated with the species Rattus norvegicus and mention the gene name mir-494. Click the [+] symbols to view sentences that include the gene name, or the word cloud on the right for a summary.

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[+] score: 480
Western blot analysis showed a downregulation of dnmt3b in miR-494 -overexpressing Huh-7 cells and an upregulation in anti-miR-494 -transfected SNU182 cells (Fig. 2j), chosen based on miR-494 basal levels (Supplementary Fig.   S3A), demonstrating DNMT3B as a miR-494 direct target in HCC. [score:12]
Liu L Jiang Y Zhang H Greenlee AR Han Z Overexpressed miR-494 down-regulates PTEN gene expression in cells transformed by anti-benzo(a)pyrene-trans-7,8-dihydrodiol-9,10-epoxideLife Sci. [score:8]
Fig. 3MiR-494 targets CDKN2B, BBC3 and PTEN in HCC a QPCR and WB analyses of miR-494 and target genes in miR-494 overexpressing HepG2 and b Huh-7 cells. [score:7]
Specifically, through the modulation of epigenetic targets, miR-494 is able to remove DNA methylation tags and to trigger gene silencing of invasion-suppressor miRNAs leading to tumor metastasis [50], as well as to fine-tune its own expression by CpG island demethylation. [score:7]
MiR-494 overexpression increased cell cycle progression and promoted cell invasion and migration by targeting MCC and PTEN, whereas its inhibition decreased nodule size of MYC -driven mice liver tumors 18, 19. [score:6]
We showed that miR-494 upregulation results from simultaneous epigenetic changes, which is in agreement with previous studies describing the involvement of histone demethylation [46], but not DNA hypomethylation alone [17], in enhancing miR-494 expression in cancer cells. [score:6]
These findings demonstrated that an intricate network of epigenetic events regulate miR-494 transcription and that, in turn, it establishes complex feedback loops, by inhibiting DNMT3B and HDAC1 expression in HCC. [score:6]
MiR-494 in vivo silencing decreased PROM1 expression in miRNA -overexpressing xenografts (t-test; p = 0.002) (Fig.   1j), suggesting miR-494 influence on PROM1-specific regulation. [score:6]
In xenografts, miR-494 -mediated pten inhibition activated the PI3K/Akt oncogenic pathway favoring the accumulation of tumor-expanded myeloid-derived suppressor cells in tumor microenvironment and facilitating metastatic tumor spreading [20]. [score:5]
A decrease of p27, pten, and puma levels was displayed in miR-494-stably overexpressing cells, suggesting a long lasting inhibition in presence of a small miR-494 increase (Supplementary Fig.   S3C). [score:5]
Zhan MN MicroRNA-494 inhibits breast cancer progression by directly targeting PAK1Cell Death Dis. [score:5]
On the contrary, its decreased expression was detected in cholangiocarcinoma, breast, and gastrointestinal stromal tumors 31– 33, letting us to speculate that miR-494 might change its preferential target core depending on tissue context. [score:5]
Lower levels of these target genes were observed in tumors from miR-494 -overexpressing cells with respect to empty vector-derived tumors (t-test; p = 0.0004, p = 0.007, and p = 0.02, respectively) (Fig. 3f), further confirming our in vitro data. [score:5]
MiR-494 belongs to the widest miRNA cluster located in DLK1-DIO3 imprinted locus, which upregulation is found in a stem-like HCC subgroup with poor prognosis and is responsible, itself, for liver cancer development in mice 16– 18. [score:5]
MiR-494 -mediated caspase inhibition reflected cell viability and apoptosis variations, suggesting a central role for the caspase cascade in drug resistance of miR-494 -overexpressing cells. [score:5]
Aiming to rule out off-target effects, miR-494 -overexpressing cells were transfected with anti-miR-494 or controls before sorafenib administration (Supplementary Fig.   S5B). [score:5]
MiR-494 expression correlated with stem cell markers PROM1/CD133 and EPCAM in HCCs (Pearson’s correlation; p = 0.004; p = 0.006, respectively) (Fig.   1b, c), but not in cirrhosis, confirming miR-494 aberrant expression and its correlation with stemness markers as cancer-specific events [16]. [score:5]
Kim WK MicroRNA-494 downregulates KIT and inhibits gastrointestinal stromal tumor cell proliferationClin. [score:5]
β-actin was used to normalize qPCR and WB data a QPCR and WB analyses of miR-494 and target genes in miR-494 overexpressing HepG2 and b Huh-7 cells. [score:5]
g Box plot graph of miR-494 expression in HCC tumors divided on the basis of high or low HDAC1 and DNMT3B expression with respect to their median values. [score:5]
A recent paper reported a p53 -mediated hdac1 recruitment to PROM1 promoter causing a decrease of its transcription [44]; since we showed an inverse correlation between miR-494 and HDAC1 in HCCs, we can speculate that HDAC1 might participate to PROM1 regulation in miR-494 -overexpressing cells. [score:4]
An upregulation of pri-miR-494 was displayed in presence of epigenetic agents, with a stronger effect of DZNep-combined treatments (Fig.   2c). [score:4]
We also analyzed the multi-target activity of miR-494 as well as its complex epigenetic regulation and demonstrated miR-494 -associated mTOR pathway activation as a sorafenib resistance mechanism in HCC. [score:4]
Sun HB miR494 is an independent prognostic factor and promotes cell migration and invasion in colorectal cancer by directly targeting PTENInt. [score:4]
Our previous data reported an aberrant expression of circulating miR-494 in cirrhotic patients with HCC and a positive correlation between serum and tissue levels [22]; therefore, we wondered if miR-494 deregulation might represent a key event in hepatocarcinogenesis (Supplementary Fig.   S1 ). [score:4]
a–j U6RNA and β-actin were used as housekeeping genesTo study miR-494 role in vivo, we assayed miR-494 expression in DEN-HCC rats mirroring human disease complexity 23, 24. [score:4]
MiR-494 -overexpressing Huh-7 cells showed an enhanced resistance to doxorubicin challenge as determined by cell viability and caspase-3/7 assays (Fig. 6a), whereas its downregulation in SNU182 cells increased doxorubicin sensitivity (Fig. 6b), with only a marginal modulation of Akt/mTOR pathway. [score:4]
Epigenetic regulation of miR-494 expression in HCC. [score:4]
In line with previous findings describing an increase of miR-494 in 34% of tumor tissues and an upregulation of this miRNA cluster in a subclass of HCCs 17, 18, here we detected high miR-494 levels in 25% of tumors and an association with stemness-specific genes. [score:4]
a–j U6RNA and β-actin were used as housekeeping genes To study miR-494 role in vivo, we assayed miR-494 expression in DEN-HCC rats mirroring human disease complexity 23, 24. [score:4]
To ascertain miR/mRNA interaction, we mutated two miR-494 seed sequences exhibiting the highest likelihood of mRNA downregulation (Supplementary Fig. S2L). [score:4]
j QPCR analysis of miR-494 expression in xenograft mice following antagomiR-494 treatment. [score:3]
Any decrease of luciferase signal was detected for both mutated vectors in miR-494 -overexpressing cells (Fig. 2i). [score:3]
a, b, e, g PMXs: empty vector infected Huh-7 cells; miR-494: pMXs-miR-494 infected Huh-7 cells We next assessed miR-494 influence on stemness properties of HCC cells and observed that miR-494 overexpression increased PROM1, OCT4, and SOX2 core stemness genes, as well as ABCG2 transporter levels (Fig. 4d, e). [score:3]
We observed that miR-494 associated with sorafenib resistance in HCC preclinical mo dels and demonstrated that miR-494 -mediated mTOR pathway activation was responsible for decreased targeted therapy sensitization. [score:3]
c FACS Annexin-V plots of miR-494 overexpressing and control Huh-7 cells following doxorubicin treatment (10 µg/ml for 6 h). [score:3]
An increase of cell viability together with a decrease of caspase activity and cleavage were detected in Huh-7 cells following miR-494 enforced expression (Fig. 5c), whereas an opposite behavior was observed in anti-miR-494 -transfected SNU182 cells (Fig. 5d). [score:3]
a Box plot graph of miR-494 expression in responder (R) and non-responder nodules (NR) from Sorafenib treated HCC rats. [score:3]
a Cell images of miR-494 overexpressing Huh-7 cells or b miR-494 silenced SNU182 cells (10X magnification). [score:3]
Comparable data were obtained in miR-494 stably overexpressing cells (Supplementary Fig. S4A). [score:3]
k MSP analysis of the four tested CpG islands in miR-494 overexpressing and silenced (AM-494) HepG2 cells. [score:3]
d QPCR and western blot analyses of PROM1 expression in miR-494 or anti-miR-494 -transfected cells. [score:3]
f FACS analysis of PROM1 immunophenotype in miR-494 overexpressing and negative control (NC) Huh-7 cells. [score:3]
Fig. 7 a Box plot graph of miR-494 expression in responder (R) and non-responder nodules (NR) from Sorafenib treated HCC rats. [score:3]
MiR-494 overexpression in HepG2 and Huh-7 cells displayed a 27% and 23% increase of the S-phase cell population, respectively (t-test; p = 0.011, and p = 0.025) (Fig.   4c and Supplementary Fig. S2E), demonstrating that miR-494 is able to potentiate cell invasiveness and speed up cell cycle progression of HCC cells. [score:3]
In a hypoxia, miR-494 overexpression determined the activation of mTOR pathway, together with an increase of cell viability and a decrease of caspase-3/7 activity in Huh-7 cells. [score:3]
y-axis reports 2 [-ΔΔCt] values corresponding to miR-494 expression (log2 form). [score:3]
f QPCR analysis of miR-494 targets in the xenograft mo del. [score:3]
A demethylation pattern was observed in miR-494 -overexpressing cells, whereas a hypermethylation status was detected in miR-494-silenced cells, with CpG48 displaying the most significant variation (Fig. 2k). [score:3]
A 2.3-fold increase of invasive potential together with a 1.6-fold enhancement of migration capabilities were observed in miR-494 -overexpressing cells (t-test; p = 0.015 and p < 0.0001, respectively) (Fig.   4a, b). [score:3]
y-axis reports 2 [−ΔΔCt] values corresponding to miR-494 expression. [score:3]
y-axes report 2 [−ΔΔCt] values corresponding to miR-494 or PROM1 expression (log2 form). [score:3]
High mTOR phosphorylation levels in miR-494 -overexpressing cells let us to hypothesize a considerable involvement of this pathway in sorafenib sensitization (Fig.   6d and Supplementary Fig. S2A). [score:3]
The reporter assay showed a decreased luciferase activity of wild type, but not mutant (Supplementary Fig.   S3B, D), 3'UTR-vectors in miR-494 co -transfected with respect to control HepG2 cells (t-test; p < 0.05) (Fig.   3e), demonstrating PTEN, P27 and PUMA as miR-494 direct targets in HCC. [score:3]
FACS analysis showed a 1.6-fold increase of PROM1 positivity in miR-494 -overexpressing with respect to control cells (t-test; p < 0.0001) (Fig. 4f). [score:3]
At the light of our findings and because of incomplete data regarding epigenetic regulation of DLK1-DIO3 miRNAs in HCC [17], we investigated epigenetic auto-regulatory loops contributing to miR-494 expression. [score:3]
b Box plot graph of methylation status in HCC patients with high or low primary or mature miR-494 expression levels in tumor tissues with respect to matched non-tumor samples. [score:3]
In conclusion, this study illustrates the detrimental effect of miR-494 in sorafenib resistance via mTOR pathway activation and highlights its possible role as a therapeutic target and a candidate biomarker for patient stratification. [score:3]
Recently, Lim and coworkers validated MCC gene among miR-494 targets in HCC showing its implication in cell cycle transition, as demonstrated by functional analysis and silencing-specific experiments [18]. [score:3]
h Box plot graph of miR-494 or i PROM1 levels in control (pMXs) and miR-494 overexpressing tumor masses from xenograft mice. [score:3]
y-axes report 2 [-ΔΔCt] values corresponding to miR-494 levels (top graphs) or relative gene expression levels (bottom graphs). [score:3]
These findings let us to hypothesize that enhanced miR-494 levels, promoting oncogenic pathway activation and apoptotic signaling inhibition, might protect HCC cells against stressing events commonly observed in the tumor bulk, such as nutrient deprivation and hypoxia. [score:3]
a, b, e, g PMXs: empty vector infected Huh-7 cells; miR-494: pMXs-miR-494 infected Huh-7 cellsWe next assessed miR-494 influence on stemness properties of HCC cells and observed that miR-494 overexpression increased PROM1, OCT4, and SOX2 core stemness genes, as well as ABCG2 transporter levels (Fig. 4d, e). [score:3]
A 2.0-fold decrease of early apoptosis was observed in miR-494 -overexpressing cells (Fig. 5h), suggesting that miR-494 might strengthen cell resistance to nutrient deprivation by turning off the caspase pathway. [score:3]
A hypomethylation pattern was observed in 60% of tumors with respect to surrounding livers (Fig.   2a) in the absence of any association with primary and mature miR-494 levels (Fig.   2b), letting us to hypothesize DNA demethylation as a not a sufficient condition for miR-494 overexpression. [score:3]
Since miR-494 and miR-495 were shown to be the most potent cluster members influencing tumor cell proliferation [18], we also analyzed miR-495 expression in HCCs. [score:3]
f FACS Annexin-V plots of miR-494 overexpressing and control Huh-7 cells following sorafenib treatment (7.5 µM for 24 h). [score:3]
Strikingly, the fold-change between miR-494 -overexpressing and control cells was higher in vivo than in vitro (22.5 vs. [score:3]
Consistently, higher HIF1A levels were observed in miR-494 -overexpressing cells in basal and hypoxic conditions (Supplementary Fig. S4B, C), demonstrating the central role for miR-494 in cell survival following stressful events. [score:3]
c QPCR and WB analyses of miR-494 and target genes in miR-494 silenced SNU449, and d SNU182 cells. [score:3]
Regulatory loops involving epigenetic enzymes, such as dnmt3b, hdac1 and tet1, were assessed in HCC, highlighting the complexity of molecular events underlying miR-494 deregulation. [score:3]
a Correlation graph between miR-494 and miR-495 expression levels in tumor tissue from 28 randomly selected HCC patients. [score:3]
Western blot analysis showed an increase of akt, mtor, and ribosomal S6 phosphorylation levels in miR-494 -overexpressing Huh-7 cells (Fig.   5c), whereas miR-494 silencing determined a decrease of their phosphorylation in SNU182 cells (Fig.   5d). [score:3]
DNA sequence of precursor miR-494 was inserted between XhoI cloning sites of pMXs-miR-GFP/Puro retroviral expression vector according to the manufacturer's datasheet (Cell Biolabs, San Diego, USA). [score:3]
In starvation, an increase of cell viability and akt/mtor phosphorylation, together with decreased apoptotic markers were displayed in miR-494 -overexpressing Huh-7 cells (Fig. 5f). [score:3]
Fig. 5 a Cell images of miR-494 overexpressing Huh-7 cells or b miR-494 silenced SNU182 cells (10X magnification). [score:3]
NC: pre-miR negative control, NCi: anti-miR negative control Aiming to identify key pathways linked to miR-494 aberrant expression, we performed a computational analysis and focused our attention on CDKN1B/P27, PTEN, and BBC3/PUMA (Supplementary Fig.   S3B) due to their known roles in cell cycle progression, proliferation and apoptosis. [score:3]
e FACS Annexin-V plots of miR-494 overexpressing and control untreated Huh-7 (following 48 h of transfection). [score:3]
As frequently observed for cancer -associated miRNAs, miR-494 may behave as an oncogene or a tumor-suppressor gene in a tissue -dependent manner. [score:3]
Consistently, the xenograft mo del showed a lower doubling time (t-test; p = 0.044) (Fig.   7b) and a trend toward a higher tumor size (t-test; p = 0.124) (Fig.   7c) in miR-494 -overexpressing tumors, suggesting that miR-494 might influence tumor cell proliferation during sorafenib treatment. [score:3]
DNMT3B and DNMT3A are miR-494 hypothetical targets (Supplementary Fig. S2L), whereas HDAC1 does not display complementar -binding sites. [score:3]
MRNA levels were regulated as well, but at a lower extent and depending on cell context (Fig.   3a–d), letting us to speculate that co-regulatory mechanisms might be responsible for their fine-tuning following miR-494 modulation. [score:3]
Moreover, ERK1/2 [−] -dependent activation of miR-494 in non-small cell lung cancer induced tumor resistance to TRAIL treatment through BIM targeting [21]. [score:3]
The xenograft mo del was obtained by inoculating miR-494 stably overexpressing (pMXs-miR-494) Huh-7 cells. [score:3]
QPCR analysis verified miR-494 overexpression in pMXs-miR-494 Huh-7 cells (Supplementary Fig.   S2G) and in tumors derived from this cell clone in comparison with control cells (t-test; p = 0.006) (Fig.   1h). [score:3]
Liu K miR-494 promotes cell proliferation, migration and invasion, and increased sorafenib resistance in hepatocellular carcinoma by targeting PTENOncol. [score:3]
Annexin-V analysis strengthened these data showing a 2.0-fold decrease of early and late apoptosis in miR-494 -overexpressing cells after sorafenib administration (t-test; p < 0.05) (Fig. 6f). [score:3]
j WB analysis of dnmt3b in miR-494 overexpressing or silenced HCC cells. [score:3]
We investigated miR-494 expression in tumors and surrounding livers from 75 surgically resected HCC patients, showing a 2.4-fold upregulation of miR-494 in 25% of tumors compared to matched cirrhosis. [score:3]
y-axis reports relative miR-494 or pri-miR-494 expression values with respect to vehicle (DMSO) -treated samples. [score:3]
Fig. 1 a Correlation graph between miR-494 and miR-495 expression levels in tumor tissue from 28 randomly selected HCC patients. [score:3]
d Box plot graph of miR-494 expression in tumor (HCC) and non-tumor (NT) samples from the HCC rat mo del. [score:3]
Combination of low HDAC1 and DNMT3B levels strongly associated with higher miR-494 levels (t-test; p = 0.003) (Fig. 2g) and, consistently, a decrease of HDAC1 and DNMT3B mRNAs was detected in miR-494 -overexpressing cells (Fig. 2h). [score:3]
g WB analysis of apoptotic markers in miR-494 overexpressing Huh-7 cells following sorafenib or h sorafenib plus rapamycin treatment. [score:3]
6.7-folds, respectively) (Fig.   1h, Supplementary Fig. S2G), letting us to speculate that a possible crosstalk between tumor and stroma cells might contribute to miR-494 expression. [score:3]
MiR-494 overexpression enhanced cell resistance to sorafenib in Huh-7 cells, increasing cell viability, and decreasing caspase activity (Fig. 6d), whereas opposite results were displayed in anti-miR-494 -treated SNU182 cells (Fig. 6e). [score:3]
No variations in cell death were observed in untreated Huh-7 cells in the presence of miR-494 overexpression (Fig. 5e), letting us to speculate that increased viability might be due to a higher proliferation rather than an effective inactivation of apoptosis. [score:3]
h FACS Annexin-V plots of miR-494 overexpressing and control Huh-7 following 24 h of starvation. [score:3]
These data were confirmed by Annexin-V analysis displaying decreased early and late apoptotic events (1.4 and 1.3-folds, respectively) in miR-494 -overexpressing cells (t-test; p < 0.05) (Fig.   6c). [score:3]
MiR-494 upregulation and involvement in cancer progression was reported in lung, colorectal, and glioblastoma cancers, as well as in HCC 18, 19, 29, 30. [score:3]
Aiming to identify key pathways linked to miR-494 aberrant expression, we performed a computational analysis and focused our attention on CDKN1B/P27, PTEN, and BBC3/PUMA (Supplementary Fig.   S3B) due to their known roles in cell cycle progression, proliferation and apoptosis. [score:3]
Due to the well-established role of p27 as a G1/S checkpoint controller, we tested miR-494 involvement in cell cycle regulation. [score:2]
A 1.3-fold-change has been considered as a cutoff to discriminate between high or low primary and mature miR-494 expression levels in HCC vs. [score:2]
MiR-494 correlated with tumor size (Pearson’s correlation; p = 0.007) as well as with AFP, PROM1, and ABCG2 expression (Pearson’s correlation; p = 0.015, p = 0.034, and p = 0.023, respectively) (Fig.   1e–g, Supplementary Fig.   S2D); on the contrary, no correlation with EPCAM mRNA was found. [score:2]
NC: pre-miR negative control, NCi: anti-miR negative controlTo investigate if multiple epigenetic events might be involved in miR-494 regulation, HepG2 cells were treated with 5-Aza-2’-deoxycitidine (5-Aza), Trichostatin (TRC) and 3-Deazaneplanocin A (DZNep), inhibiting DNA methyl-transferases, histone deacetylases, and methyl-transferases. [score:2]
MiR-494 targets p27, pten, and puma in HCC. [score:2]
β-actin was used to normalize qPCR and WB data Since PTEN plays a pivotal role in cell motility and migration, we assessed invasion and migration capabilities of miR-494 -overexpressing Huh-7 cells by using a real-time cell analysis system as well as a wound healing assay. [score:2]
Cell viability assay displayed an association between high miR-494 basal levels and sorafenib resistance in HCC-derived cells (Fig.   7e), confirming a close relationship linking miR-494 expression to sorafenib response in preclinical mo dels. [score:2]
In agreement, a recent study showed that miR-494 -mediated pten regulation is involved in sorafenib resistance through the activation of PI3K/Akt pathway in HepG2 cells [38]. [score:2]
MiR-494 targets CDKN2B, BBC3 and PTEN in HCC. [score:2]
Li XT miR-494-3p regulates cellular proliferation, invasion, migration, and apoptosis by PTEN/AKT signaling in human glioblastoma cellsCell. [score:2]
a–j U6RNA and β-actin were used as housekeeping genes To have an insight on miR-494 regulation, a methylation-specific PCR (MSP) analysis of selected CpG islands (Supplementary Fig.   S2I) was conducted in HCC patients. [score:2]
MiR-494 is overexpressed in HCC and correlates with stem cell markers. [score:2]
Here, we showed that miR-494 regulates p27, pten, and puma in HCC cells and xenograft tumors, increasing cell cycle progression, cell survival in stressful conditions and enhancing invasive and clonogenic capabilities. [score:2]
Beside epigenetic regulation, our data suggested that post-transcriptional mechanisms might be involved in miRNA biogenesis determining final mature miR-494 levels. [score:2]
MiR-494 overexpression decreased p27, pten and puma proteins in HepG2 and Huh-7 cells (Fig.   3a, b), whereas its silencing increased their levels in SNU449 and SNU182 cells (Fig.   3c, d). [score:2]
MiR-494 is overexpressed in a HCC subgroup and correlates with tumor size and stemness markers in preclinical mo dels. [score:2]
Co-treatment with rapamycin sensitized miR-494 -overexpressing cells to sorafenib challenge when compared to sorafenib-only treated cells (Fig.   6g, h), demonstrating a strong participation of the mtor pathway in miR-494 -mediated sorafenib resistance, as confirmed by caspase inactivation and decreased PARP levels. [score:2]
To verify if DNMT3B regulation by miR-494 itself might be responsible for CpG island hypomethylation, a MSP analysis was performed in transfected HepG2 cells. [score:2]
TaqMan MicroRNA assays (Thermo Fisher Scientific) were used for quantifying miRNA-494 (ID: 002365) and miR-495 (ID:001108) expression, as previously described [8]. [score:2]
The mutagenesis of miR-494 seed sequence in BBC3, CDKN1B, and DNMT3B-3' UTR-containing vectors was performed by using QuikChange II Site-Directed Mutagenesis Kit (Agilent Technologies) following the manufacturer's instruction. [score:2]
Accordingly, miR-494 -overexpressing Huh-7 cells showed a higher clonogenic potential as demonstrated by colony-forming unit assay (t-test; p < 0.0001) (Fig. 4g and Supplementary Fig. S2F), further supporting miR-494 key role in modulating stem cell phenotype. [score:2]
MiR-494 overexpression correlates with sorafenib resistance in. [score:2]
To have an insight on miR-494 regulation, a methylation-specific PCR (MSP) analysis of selected CpG islands (Supplementary Fig.   S2I) was conducted in HCC patients. [score:2]
Accordingly, we showed the steady association between miR-494 and core stemness genes in preclinical mo dels, as well as in human HCCs, suggesting a key role for miR-494 in PROM1 transcriptional regulation. [score:2]
NC: pre-miR negative control, NCi: anti-miR negative control To investigate if multiple epigenetic events might be involved in miR-494 regulation, HepG2 cells were treated with 5-Aza-2’-deoxycitidine (5-Aza), Trichostatin (TRC) and 3-Deazaneplanocin A (DZNep), inhibiting DNA methyl-transferases, histone deacetylases, and methyl-transferases. [score:2]
MiR-494 basal expression levels (2 [−ΔΔCt]) of each cell line are reported in table below the graph. [score:2]
Any difference in tumor size, doubling time, and Ki67 staining was observed when comparing miR-494 with control Huh-7-derived masses, suggesting that higher miR-494 levels do not influence tumor attachment and proliferation in our xenograft mo del. [score:1]
In line, miR-494 silencing in serum-deprived SNU182 cells reduced cell viability and increased apoptotic markers (Fig. 5g). [score:1]
MiR-494 regulates AKT/mTOR pathway and increases cell survival during stress conditions. [score:1]
f Correlation graph between miR-494 and AFP or g PROM1 mRNA levels in tumor samples from HCC rats. [score:1]
NCi: anti-miR negative control, AM-494: anti-miR-494. [score:1]
The luciferase activity of wild-type DNMT3B-3'UTR-vector decreased in miR-494 co -transfected cells in comparison to control cells (t-test; p = 0.015) (Fig. 2i). [score:1]
b Correlation graph between miR-494 and PROM1 or c EPCAM mRNA levels in tumor samples from 38 HCC patients. [score:1]
A positive correlation between miR-494 and miR-495 was found in tumors (Pearson’s correlation; p = 0.002) but not in surrounding livers (Fig.   1a, Supplementary Fig. S2A), suggesting their possible involvement in hepatocytes malignant transformation. [score:1]
Mature miR-494 levels only partially mirrored pri-miRNA levels, letting us to speculate that other mechanisms might be responsible for its maturation process. [score:1]
Notably, our previous findings showed that circulating miR-494 levels correlated with tissue ones in HCC patients [22], suggesting this miRNA as a non-invasive biomarker. [score:1]
A further confirm was obtained in stable miR-494 Huh-7 cells displaying an increased resistance to sorafenib challenge with respect to control cells (Supplementary Fig. S5A). [score:1]
MiR-494 regulates invasion capability, cell cycle progression, and stem cell phenotype in HCC. [score:1]
Oligonucleotide transfection of pre-miR-494, anti-miR-494, or negative controls (100 nM, Thermo Fisher Scientific, Whaltam, USA) was obtained by using TransIT-X2 dynamic delivery system (Mirus Bio, Madison, USA) according to the manufacturer's instructions. [score:1]
QPCR analysis displayed an association between high miR-494 levels and sorafenib resistance in rat HCCs (t-test; p = 0.045) (Fig.   7a). [score:1]
e Correlation graph between tumor size and miR-494 levels in HCC animals. [score:1]
In this scenario, miR-494 deserves attention as a putative biomarker for the identification of a subgroup of epigenetically distinct HCCs. [score:1]
Since pten is the principal negative modulator of Akt/mTOR pathway, we analyzed miR-494 influence on the activation of its downstream signaling cascade. [score:1]
CTR: vehicle control mice, AM-494: anti-miR-494 injected mice. [score:1]
y-axis reports 2 [−ΔΔCt] values corresponding to miR-494 levels. [score:1]
A negative correlation between miR-494 and PUMA or PTEN mRNAs (Pearson’s correlations; p = 0.012 and p = 0.020, respectively) was found in the combined -treated group but not in the sorafenib-only one (Fig. 7f), suggesting these molecular pathways mediating miR-494 therapeutic effects. [score:1]
A positive correlation between PROM1 and EPCAM mRNAs was found in tumor and non-tumor tissues (Pearson’s correlation; p < 0.0001) (Supplementary Fig.   S2B, C), whereas no correlation between miR-494 and other stem -associated genes (AFP, NESTIN, CD90, and ABCG2) was found in HCCs. [score:1]
c QPCR of primary (pri-miR-494) or mature miR-494 levels in HepG2 cells following epigenetic treatments. [score:1]
We reported that a combined anti-miR-494 -based therapeutic strategy is more efficient in terms of tumor stabilization in comparison to sorafenib-only treatment in DEN-HCC rats. [score:1]
AM-494: anti-miR-494The efficacy of a combined miRNA -based strategy was assessed in the rat mo del following anti-miR-494 and sorafenib co-administration (Fig.   7f). [score:1]
β-actin was used to normalize WB dataSubsequently, we tested miR-494 biologic effect following sorafenib treatment. [score:1]
y-axis reports 2 [-ΔΔCt] values corresponding to miR-494 levels (log2 form). [score:1]
c Representative cell cycle images of miR-494 -transfected HepG2 cells. [score:1]
d Cell viability assay, caspase-3/7 activity assay and WB analysis in miR-494 overexpressing Huh-7 or e miR-494 silenced SNU182 cells following sorafenib administration. [score:1]
31% of nodules isolated from anti-miR-494-sorafenib with respect to sorafenib-only treated animals (χ [2] test; p < 0.05). [score:1]
Representative IHC images (20X magnification) of Ki67 staining in control (pMXs) and miR-494 overexpresing Huh-7-derived xenograft masses. [score:1]
NC: pre-miR negative control, NCi: anti-miR negative control, AM-494: anti-miR-494. [score:1]
c Cell viability assay, caspase-3/7 activity assay and WB analysis in untreated miR-494 overexpressing Huh-7 or d miR-494 silenced SNU182 cells. [score:1]
d Correlation graphs between miR-494 and DNMT3B or e HDAC1 or f DNMT3A mRNAs in HCCs (N = 30). [score:1]
x-axis reports 2 [−ΔΔCt] values corresponding to miR-494 levels transformed in a log2 form; y-axis represents tumor size (cm). [score:1]
NC: pre-miR negative control; NCi: anti-miR negative control; AM-494: anti-miR-494. [score:1]
AM-494: anti-miR-494 The efficacy of a combined miRNA -based strategy was assessed in the rat mo del following anti-miR-494 and sorafenib co-administration (Fig.   7f). [score:1]
An increase of caspase activity was detected in anti-miRNA -treated miR-494 Huh-7 cells, resembling the value of empty vector cells (Supplementary Fig.   S5C). [score:1]
β-actin was used to normalize WB data Subsequently, we tested miR-494 biologic effect following sorafenib treatment. [score:1]
In the bottom part are illustrated percentage graphs representing treatment efficacy together with correlation graphs between miR-494 and PUMA or PTEN mRNA levels in tumor samples from sorafenib-only and anti-miR-494-sorafenib treated animals. [score:1]
A negative correlation between miR-494 and DNMT3B or HDAC1 mRNAs was observed in tumors (Pearson’s correlations; p = 0.006 and p = 0.018) (Fig.   2d, e), whereas a trend toward a negative correlation was detected with DNMT3A (Pearson’s correlation; p = 0.075) (Fig. 2f); on the contrary, no correlation was found with HDAC2, HDAC3, or HDAC4. [score:1]
Higher miR-494 levels were detected in 83% of HCCs with respect to non-tumor samples with a 4.6-folds increase (t-test; p = 0.002) (Fig.   1d). [score:1]
β-actin was used to normalize WB data To investigate the role of miR-494 in sorafenib response in vivo, miR-494 expression was analyzed in HCCs from DEN -treated rats receiving sorafenib intragastrically. [score:1]
a Cell viability assay, caspase-3/7 activity assay and WB analysis in miR-494 overexpressing Huh-7 or b miR-494 silenced SNU182 cells following doxorubicin treatment. [score:1]
To investigate the role of miR-494 in sorafenib response in vivo, miR-494 expression was analyzed in HCCs from DEN -treated rats receiving sorafenib intragastrically. [score:1]
Anti-miR-494 administration in both mo dels is described in Supplementary Material. [score:1]
No modulation of protein total amount was observed (Fig.   5c, d), suggesting a miR-494 -mediated post-transcriptional activation of this pathway. [score:1]
These data showed the involvement of miR-494 in HCC pathogenesis as well as in stem cell phenotype of liver tumors. [score:1]
In line, a positive but not strong correlation between primary and mature miR-494 was observed in HCC patients and cells (Supplementary Fig.   S2J, K). [score:1]
MiR-494 regulates response to treatments in HCC cells. [score:1]
PMXs and pMXs-miR-494 Huh-7 cells were seeded (25,000 cells/well) in serum free medium in the upper chamber. [score:1]
y-axis reports relative miR-494 values with respect to negative controls (NC or pMXs). [score:1]
pGL3: empty reporter vector, NC: pre-miR negative control, NCi: anti-miR negative control, AM-494: anti-miR-494. [score:1]
MiR-494 is epigenetically regulated in HCC. [score:1]
Fig. 6 a Cell viability assay, caspase-3/7 activity assay and WB analysis in miR-494 overexpressing Huh-7 or b miR-494 silenced SNU182 cells following doxorubicin treatment. [score:1]
f Cell viability assay, caspase-3/7 activity assay, and WB analysis in miR-494 overexpressing Huh-7 or g miR-494 silenced SNU182 cells in starvation condition. [score:1]
Nevertheless, as observed in human and rat HCCs, higher PROM1 levels were displayed in miR-494-derived tumors (t-test; p = 0.045) (Fig.   1i, Supplementary Fig. S2H). [score:1]
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Subsequent in vitro cell experiments showed that PTEN mRNA and protein expression were markedly down-regulated after miR-494 mimics transfection and up-regulated after miR-494 inhibitor transfection, confirming PTEN as a downstream target of miR-494. [score:13]
Consistently, PTEN protein expression was also obviously down-regulated after miR-494 mimics transfection and up-regulated after miR-494 inhibitor transfection (Figure 4D). [score:11]
To locate the target gene of miR-494, we searched the miRNA target prediction databases PicTar and TargetScan. [score:7]
All experiments were performed in triplicate, and data were represented as mean ± S. D. PTEN is a downstream target gene of miR-494To identify the downstream target gene of miR-494, bioinformatics analyses (PicTar and TargetScan) were performed. [score:7]
All experiments were performed in triplicate, and data were represented as mean ± S. D. To identify the downstream target gene of miR-494, bioinformatics analyses (PicTar and TargetScan) were performed. [score:5]
As shown in Figure 4C, PTEN mRNA expression was significantly reduced by miR-494 mimics (P=0.008) and enhanced by miR-494 inhibitor (P=0.000). [score:5]
AML12 cells at 70% confluence in six-well plates were transfected with 50 nM of miR-494 mimics, miR-494 inhibitor, mimics NC, or inhibitor NC (GenePharma Biotech) using Lipofectamine 3000 transfection agent. [score:5]
We therefore hypothesized that miR-494 might inhibit the expression of PTEN, which activates the PI3K/AKT pathway and reduces the H/R -induced hepatic apoptosis. [score:5]
In our study, we found that miR-494 up-regulated the phosphorylation level of AKT in AML12 cells. [score:4]
Further, the expression of PTEN mRNA in AML12 cells treated with miR-494 mimics or miR-494 inhibitor was compared by qRT-PCR. [score:4]
In conclusion, our study showed that miR-494 protected rats against hepatic I/R injury through down -regulating its downstream target gene PTEN, leading to the activation of PI3K/AKT signaling pathway. [score:4]
Moreover, revealed that the HIRI rats with lower hepatic miR-494 expression had obviously higher PTEN level in the liver when compared with sham-operated rats, indicating a negative association between miR-494 level and PTEN expression (Figure 4E). [score:4]
As shown in Figure 3C,D, the apoptosis rate of miR-494 mimics was significantly lower than that in mimics NC group (P=0.002), and the expression of apoptosis-related proteins cle-PARP and cle-Caspase-3 was also significantly reduced (P=0.014 and 0.038, respectively), suggesting that miR-494 decreased H [2]O [2] -induced apoptosis of hepatic AML12 cells. [score:3]
PTEN is a downstream target gene of miR-494. [score:3]
miR-494 suppressed the luciferase activities of the construct containing the 3′-UTR of PTEN. [score:3]
Prediction of miR-494 targets. [score:3]
Prediction of miR-494 targetsBoth PicTar (http://pictar. [score:3]
As shown in Figure 1D, miR-494 in HIRI group was significantly down-regulated at least two fold when compared with sham surgery group (P=0.007). [score:3]
We then examined the expression levels of miR-494. [score:3]
Previous studies have shown that miR-494 can specifically target PTEN, leading to the activation of the PI3K/AKT pathway during various pathophysiologic processes including cell apoptosis, tumor metastasis, and angiogenesis [18, 29, 30]. [score:3]
Overexpression of miR-494 exerts protective effects against hypoxia/ischemia -induced apoptosis in human hepatic L02 cells via the modulation of PI3K/Akt pathway [18]. [score:3]
html) were used to identify potential downstream targets of miR-494. [score:3]
The protective effect of miR-494 in HIRI rats is associated with PI3K/AKT signaling pathwayTo further explore the molecular mechanism underlining the protective effect of miR-494 in HIRI rats, we examined the expression of proteins in rat liver, including PTEN, p-AKT, AKT, and the downstream effectors of PI3K/AKT pathway (p-mTOR, mTOR, p-p70S6K, and p70S6K). [score:3]
In the present study, we found that miR-494 in HIRI group was significantly down-regulated by at least two fold when compared with sham surgery group. [score:3]
All together, these results suggested that miR-494 effectively alleviated the I/R injuries in rat liver via inhibiting the cell apoptosis. [score:3]
All these findings confirmed PTEN as the downstream target gene of miR-494. [score:3]
Figure 4PTEN is a downstream target gene of miR-494(A) miR-494 -binding sequences in the 3′-UTR of PTEN and mutated sequence of PTEN 3′-UTR. [score:3]
In the present study, we further established an in vitro oxidative stress mo del by H [2]O [2] treatment, and found that the expression of miR-494 in hepatic AML12 cells was dose -dependent decrease. [score:3]
Differentially expressed miR-494 has been reported in rats with cerebral I/R injury [16]. [score:3]
PTEN was identified as one of the candidate targets of miR-494 (Figure 4A). [score:3]
miR-494 expression was normalized to U6. [score:3]
To further explore the molecular mechanism underlining the protective effect of miR-494 in HIRI rats, we examined the expression of proteins in rat liver, including PTEN, p-AKT, AKT, and the downstream effectors of PI3K/AKT pathway (p-mTOR, mTOR, p-p70S6K, and p70S6K). [score:3]
PTEN was identified as one of the candidate targets of miR-494. [score:3]
Figure 5 miR-494 protected liver I/R injury in rats through activating PTEN/PI3K/AKT signaling pathway(A, B) analysis comparing PTEN, p-AKT, AKT, p-mTOR, mTOR, p-p70S6K, and p70S6K expression in sham surgery, HIRI, HIRI + agomir-NC, HIRI + agomir- miR-494 groups (n=6); *, P<0.05 and **, P<0.01 compared with sham surgery group. [score:2]
It was found that miR-494 mimics significantly suppressed the luciferase activity of the 3′-UTR wild-type of PTEN (P=0.006), but not that of the pMIR-PTEN-mut or pMIR group, when compared with the mimics NC group (Figure 4B). [score:2]
It was found that agomir- miR-494 significantly decreased serum ALT, AST, LDH, and GLDH levels, liver MDA, TOA, and OSI concentration, hepatocyte apoptosis rate, liver expression of apoptosis -associated proteins (cleaved PARP, cleaved caspase-3, and Bax), hepatocyte necrosis and DNA fragment, when compared with agomir-NC rats. [score:2]
After agomir- miR-494 treatment, the PTEN level in rat liver was significantly inhibited, and p-AKT, p-mTOR, and p-p70S6K were increased compared with agomir-NC group (P<0.05 or 0.01), indicating that miR-494 protected rat liver against I/R injury through activating the PI3K/AKT signaling pathway. [score:2]
In contrast, the cleaved caspase-3 expression in HIRI + agomir- miR-494 group was only slightly higher compared with sham group. [score:2]
AML-12 cells were treated with H [2]O [2] (0–400 µM) for 6 h, and miR-494 mRNA expression was decreased in a dose -dependent manner when compared with control cells without H [2]O [2] treatment (all P<0.05 or 0.01, Figure 3A). [score:2]
In order to analyze the regulatory role of miR-494 in I/R injury, we treated the HIRI rats with an intraperitoneal injection of agomir- miR-494 or agomir-NC. [score:2]
Subsequent luciferase reporter assay also confirmed that miR-494 specifically targetted 3′-UTR of PTEN gene. [score:2]
To elucidate the potential mechanism, we further examined the intracellular level of activated AKT, and found that p-AKT expression in miR-494 mimics was obviously higher compared with mimics NC group (Figure 3E), indicating that the protective effect of miR-494 against H [2]O [2] -induced cell apoptosis was mediated through the activation of AKT. [score:2]
miR-494 attenuated hepatic I/R injury in ratsIn order to analyze the regulatory role of miR-494 in I/R injury, we treated the HIRI rats with an intraperitoneal injection of agomir- miR-494 or agomir-NC. [score:2]
After agomir- miR-494 treatment, the PTEN level in rat liver was significantly inhibited, and p-AKT, p-mTOR, and p-p70S6K was increased compared with agomir-NC group (P<0.05 or 0.01). [score:2]
miR-494 protected liver I/R injury in rats through activating PTEN/PI3K/AKT signaling pathway. [score:1]
To analyze the regulatory role of miR-494 in hepatic I/R injury, we treated the HIRI rats with an intraperitoneal injection of agomir- miR-494 or agomir-NC, and compared the pathophysiological changes in the liver in the two groups. [score:1]
Moreover, liver histology from HIRI + agomir- miR-494 rats revealed obvious reduction in I/R -induced hepatocellular necrosis and improvement of cell integrity (Figure 1E). [score:1]
Further, AML-12 cells were transfected with miR-494 mimics or mimics NC, and treated with 200 µM H [2]O [2] for 6 h at all indicated time points. [score:1]
Figure 2 miR-494 protected against liver I/R injury in SD ratsSD rats (n=6 rats per group) were sham operated or subjected to 60-min liver ischemia followed by 6-h reperfusion. [score:1]
Figure 1 miR-494 protected against liver I/R injury in SD ratsSD rats (n=6 rats per group) were sham-operated or subjected to 60-min liver ischemia followed by 6-h reperfusion. [score:1]
DNA fragment was significantly reduced in agomir- miR-494 treated rats (P=0.001, Figure 2H). [score:1]
miR-494 decreased H [2]O [2] -induced apoptosis of hepatic AML12 cells by activating AKTIn order to simulate hepatic I/R injury, we further established an in vitro H [2]O [2] -induced apoptosis mo del. [score:1]
Yellow or brown stained cells were positive for cleaved caspase-3. Liver tissues collected from sham, HIRI, HIRI + agomir-NC, and HIRI + agomir- miR-494 groups (n=6) was homogenized. [score:1]
The cardioprotective effects of miR-494 against I/R -induced myocardium injury are also dependent on Akt activation [17]. [score:1]
miR-494 reduced the H [2]O [2] -induced apoptosis of hepatic AML12 cells by activating AKT in vitro. [score:1]
The protective effect of miR-494 in HIRI rats is associated with PI3K/AKT signaling pathway. [score:1]
miR-494 alleviates the I/R -induced myocardium injury in a mouse mo del through activating the AKT signaling pathway [17]. [score:1]
miR-494 protected against liver I/R injury in SD rats. [score:1]
The relative expression of miR-494 was calculated using small nuclear RNA U6 (snU6) as the internal control. [score:1]
However, the potential in vivo role of miR-494 in hepatic I/R injury remains unknown. [score:1]
Taken together, miR-494 protected rat liver against I/R injury through activating the PI3K/AKT signaling pathway. [score:1]
HEK293T cells at 70% confluence were cotransfected with 500 ng of pMIR-PTEN-wt/pMIR-PTEN-mut and 50 nM of miR-494 mimics/mimics C,G(enePharma Biotech) using a Lipofectamine 3000 transfection kit (Invitrogen). [score:1]
HIRI rats were treated with agomir- miR-494 or agomir-NC. [score:1]
miR-494 decreased H [2]O [2] -induced apoptosis of hepatic AML12 cells by activating AKT. [score:1]
IHF demonstrated a markedly lower number of TUNEL -positive cells in HIRI + agomir- miR-494 group (Figure 2E). [score:1]
org) to predict the 3′-UTR sequence for miR-494. [score:1]
These results suggested that miR-494 effectively alleviated the liver I/R injuries. [score:1]
SD rats were randomly divided into sham, HIRI, HIRI + agomir-NC (negative control), and HIRI + agomir- miR-494 groups (n=6 in each group). [score:1]
Moreover, the activity of apoptosis -associated proteins PARP and caspase-3 was decreased after transfection of miR-494 mimics, suggesting that miR-494 reduced the H [2]O [2] -induced apoptosis of AML12 cells via activating the AKT pathway. [score:1]
AML12 cells at 70% confluence were transfected with 50 nM of miR-494 mimics or mimics NC. [score:1]
miR-494 attenuated hepatic I/R injury in rats. [score:1]
Rats in HIRI + agomir- miR-494 were given an intraperitoneal injection of 20 μl of 500 pmol agomir- miR-494 (GenePharma Biotech, Shanghai, China)/day for 7 days prior to ischemia. [score:1]
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Overexpression of miR-494 inhibited PTEN expression by targeting its 3′-UTR and further promoted the activity of PI3K/AKT signaling pathways, leading to the inhibition of neuronal apoptosis. [score:11]
In conclusion, our study has revealed that the downregulation of lncRNA-XIST inhibited neuronal apoptosis by upregulating miR-494 in SCI rats. [score:9]
LncRNA-XIST Targets miR-494 and Inhibited Its Expression. [score:7]
As shown in Figure 5C, lncRNA-XIST expression decreased after overexpression of miR-494, whereas it increased after inhibition of miR-494. [score:7]
In HCC, upregulation of miR-494 decreased cell apoptosis by targeting PTEN, a pro-apoptotic gene [47]. [score:6]
These results suggest that lncRNA-XIST knockdown inhibited the expression of PTEN by competitively binding with miR-494, resulting in promotion of the activation of the AKT/mTOR pathway, thus alleviating apoptosis after SCI. [score:6]
Moreover, it was found that the expression level of PTEN was significantly decreased following miR-494 knockdown, whereas it was increased with miR-494 overexpression (Figure 6F). [score:6]
MiR-494 mimic, miR-494 inhibitor and the corresponding negative control (mimics NC and inhibitor NC) were purchased from Shanghai GenePharma Co. [score:5]
The expression of miR-494 and lncRNA-XIST in tissue was, respectively, normalized to the expression of U6 and GAPDH. [score:5]
Li N. Zhao X. Wang L. Zhang S. Cui M. He J. miR-494 suppresses tumor growth of epithelial ovarian carcinoma by targeting IGF1RTumour Biol. [score:5]
Song L. Liu D. Wang B. He J. Zhang S. Dai Z. Ma X. Wang X. miR-494 suppresses the progression of breast cancer in vitro by targeting CXCR4 through the Wnt/β-catenin signaling pathwayOncol. [score:5]
These data suggest that miR-494 regulates the activation of the PI3K/AKT pathway by targeting PTEN. [score:4]
Romano G. Acunzo M. Garofalo M. di Leva G. Cascione L. Zanca C. Bolon B. Condorelli G. Croce C. M. MiR-494 is regulated by ERK1/2 and modulates TRAIL -induced apoptosis in non-small-cell lung cancer through BIM down-regulationProc. [score:4]
Thus, lncRNA-XIST could negatively regulate miR-494 expression, probably through their interaction in SCI rats. [score:4]
Sun H. B. Chen X. Ji H. Wu T. Lu H. W. Zhang Y. Li H. Li Y. M. miR494 is an independent prognostic factor and promotes cell migration and invasion in colorectal cancer by directly targeting PTENInt. [score:4]
Previous studies have shown that miR-494 is upregulated in several cancers [45, 46, 47, 48, 49]. [score:4]
The results showed that overexpression of miR-494 significantly decreased the luciferase activity of wt-XIST-3′UTR, whereas knockdown of miR-494 increased luciferase activity. [score:4]
Furthermore, we explored whether lncRNA-XIST could modulate the expression of miR-494. [score:3]
Moreover, the interactions among expression of lncRNA-XIST, miR-494, and phosphorylated AKT were also studied in order to reveal the underlying mechanisms of XIST shRNA in the attenuation of neuronal apoptosis in SCI rats. [score:3]
Luciferase reporter plasmids plus miR-494 mimics, miR-494 inhibitor or miR-NC were co -transfected into HEK 293T cells using Lipofectamine 2000 (Invitrogen). [score:3]
Liu K. Liu S. Zhang W. Jia B. Tan L. Jin Z. Liu Y. miR-494 promotes cell proliferation, migration and invasion, and increased sorafenib resistance in hepatocellular carcinoma by targeting PTENOncol. [score:3]
Likewise, cells co -transfected with miR-494 mimic, miR-494 inhibitor, and XIST-mut-3′UTR, showed no obvious change in their luciferase activity (Figure 5B). [score:3]
In addition, we found that miR-494 expression was increased after knockdown of lncRNA-XIST, whereas it was reduced after transfection with Lv-wt-XIST compared with Lv-mut-XIST (Figure 5D). [score:3]
According to the results of these analyses we focused on miR-494, a known oncogenic microRNA inhibiting cancer cell apoptosis. [score:3]
Transfection of miR-494 Mimics and Inhibitor. [score:3]
According to miR-494 analysis, oligonucleotides containing human lncRNA-XIST 3′UTR target sequence were annealed and cloned into the pmirGLO plasmids (Promega, Madison, WI, USA) to form the reporter vector XIST-wild-type (pmirGLO-XIST-Wt). [score:3]
On this basis, it is proposed that the XIST/miR-494/PTEN/AKT axis might represent a promising therapeutic target for the future treatment of SCI. [score:3]
These results demonstrate that PTEN was a target gene for miR-494 in the SCI rat mo del. [score:3]
Interestingly, in the present study PTEN was predicted by the bioinformatic tools to be a miR-494 target. [score:3]
Using bioinformatics databases, we found that lncRNA-XIST contains several target binding sites for miR-494. [score:3]
As shown in Figure 6G, Western blot analysis showed that the expression of PTEN was decreased and the phosphorylation levels of AKT and mTOR were increased after agomir-miR-494 treatment in rat spinal cord tissues. [score:3]
Analysis by qRT-PCR revealed that SCI resulted in a significant reduction in the expression of miR-494 on day 1, day 3, and day 7, post-injury (Figure 6A). [score:3]
LncRNA-XIST Regulates Apoptosis through the Mopping up of miR-494 in the Rat SCI Mo del. [score:2]
A luciferase reporter assay was used to test whether lncRNA-XIST targets miR-494. [score:2]
Overall, our findings have not only revealed the important role of the XIST/miR-494/PTEN/PI3K/AKT signaling pathway in the development of SCI, but have also implicated both XIST and miR-494 as having potential therapeutic value in the future treatment of SCI. [score:2]
Following on from the above findings, we sought to further explore whether the miR-494/PTEN/AKT/mTOR axis was involved in the anti-apoptotic effects of lncRNA-XIST knockdown in the SCI rat mo del. [score:2]
Our findings have also demonstrated that lncRNA-XIST exerted a pro-apoptotic effect by mopping up miR-494, thereby negatively regulating the PI3K/AKT signaling pathway in SCI rats. [score:2]
Collectively, these data indicate that agomir-miR-494 treatment had a protective effect and significantly improved SCI recovery and are, therefore, in accordance with the results obtained following lncRNA-XIST knockdown in SCI mo del rats. [score:2]
In the present study, we first confirmed that miR-494 improved recovery from SCI and that it attenuated apoptosis in SCI rats, in accordance with the results of the lncRNA-XIST knockdown experiments. [score:2]
However, the role of miR-494 in regulating the effects of XIST on SCI has not previously been studied. [score:2]
: lncRNA-XIST forward 5′-CGGGTCTCTTCAAGGACATTTAGCC-3′, and reverse 5′-GCACCAATACAGAGGAATGGAGGG-3′; GAPDH forward, 5′-GAAGATGGTGATGGGATTTC-3′, and reverse, 5′-GAAGGTGAAGGTCGGAGT-3′; miR-494 forward, 5′-TGACCTGAAACATACACGGGA-3′ and reverse, 5′-TATCGTTGTACTCCACTCCTTGAC-3′; U6 forward, 5′-AAAGACCTGTACGCCAACAC-3′ and reverse, 5′-GTCATACTCCTGCTTGCTGAT-3′. [score:1]
Furthermore, we also found that Lv-XIST significantly increased miR-494 level in spinal cord samples of SCI rats at different time points (Figure 5F). [score:1]
To test the binding specificity, the corresponding mutant was created by mutating the miR-494 seed region binding site (seed sequence binding fragment 5′-CACCGC-3′ changed to 5′-AGUACCG-3′), which were named as pmirGLO-XIST-Mt. [score:1]
Subsequently, we enforced miR-494 expression by using agomir-miR-494 to evaluate the therapeutic effect of miR-494 on SCI. [score:1]
Furthermore, we also found that agomir-miR-494 attenuated apoptosis after SCI (Figure 6D). [score:1]
Further studies indicated that an inverse correlation existed between lncRNA-XIST and miR-494. [score:1]
As a result, we hypothesized that miR-494 could also exert a protective role in SCI. [score:1]
It has recently been shown that miR-494 plays an anti-apoptotic role in several different tumors [27]. [score:1]
To test this, we first measured the expression of miR-494 in rat spinal cord tissue after contusion SCI. [score:1]
The potential miR-494 binding sites in the 3′-UTR of PTEN are illustrated in Figure 6E. [score:1]
However, the functional role of miR-494 in this process was still unknown. [score:1]
In previous studies we have demonstrated that miR-494 exerts an anti-apoptotic role in SCI (in press). [score:1]
Next, we investigated whether the expression of lncRNA-XIST is inversely correlated with that of miR-494. [score:1]
These data indicate that there was reciprocal repression between XIST and miR-494. [score:1]
2.6. miR-494 Attenuates Apoptosis after SCI through the PTEN/AKT/mTOR Pathway. [score:1]
The binding sites between lncRNA-XIST and miR-494 are illustrated in Figure 5A. [score:1]
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Other miRNAs from this paper: rno-let-7d, rno-mir-34c, rno-mir-138-2, rno-mir-138-1, rno-mir-296
Compared to their expression in WKY rats, miR-138, miR-138*, miR-296, miR-34C*, and miR-494 expressions were significantly downregulated (Fig.   2e) in SHRs, results consistent with those of the miRNA microarray. [score:7]
To investigate the roles of the miRNAs that were screened out in the SHR brain, we next analyzed the potential target of them and interestingly found that the 3′untranslated region of Bhlhb2 mRNA contained the target sequence of all miR-494, 34c*, 296, 138*, and 138 (Fig.   2d). [score:5]
These suggested that there was a strong reverse correlation between the expressions of Nr3c1 and the miRNA (miR-138, miR-138*, miR-296, miR-34C*, and miR-494) and that Nr3c1 might be the main molecule responsible for the regulation. [score:4]
The common potential target of miR-138*, miR-138, miR-296, miR-34C*, and miR-494 focused on the mRNA of Bhlhb2 (Fig.   2d), which encodes a basic helix-loop-helix domain-containing protein. [score:3]
All the miRNAs except miR-494 significantly inhibited the reporter activity (Fig.   4e). [score:3]
Among them, miR-138 and 296 inhibited Bhlhb2 the most and miR-494 the least. [score:3]
Therefore, the lentivirus pLL3.7 vectors containing miRNA precursors were transfected into both PC12H and CBRH-7919 cells and the overexpression of miR-494, 34c*, 296, 138*, and 138 was confirmed (Fig.   4a). [score:3]
a The overexpression of miR-494, 34c*, 296, 138*, and 138 was validated by in PC12 and CBRH-7919 cells 24 h after transfection of the miRNA precursors. [score:3]
Bioinformatics analysis predicted that the upstream sequences of miR-138-1, miR-138-2, miR-296, miR-34c*, and miR-494 genes would have putative binding sites of Nr3c1 and transcription factors including CUX1, Pou1f1, Nf1, and Sp1 (Fig.   2b). [score:1]
analysis predicted that the upstream sequences of miR-138-1, miR-138-2, miR-296, miR-34c*, and miR-494 genes would have putative binding sites of Nr3c1 and transcription factors including CUX1, Pou1f1, Nf1, and Sp1 (Fig.   2b). [score:1]
Nr3c1 and transcription factors (Pou1f1, Sp1, Nf1, and CUX1) all have putative binding sites upstream of either the miR-138*, miR-138, miR-296, miR-34C*, or miR-494 genes or the Bhlhb2 gene (Supplemental Table 2, Fig.   2d). [score:1]
The precursors of miR-138, miR-138*, miR-296, miR-34c*, and miR-494 were obtained by PCR from rat genomic DNA and cloned into Hpa I and Xho I sites of lentivirus pLL3.7. [score:1]
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Four differentially expressed miRNAs in the lung had functions in cell differentiation, protein expression and apoptosis, including promotion of muscle differentiation (miR-206), regulation of cholangiocyte expression factor (miR-98), targeting pro-apoptotic and antiapoptotic proteins (miR-494), myeloid lineage development and promoting granulocytic differentiation, and suppression of erythrocytic differentiation (miR-223). [score:13]
To our surprise, miR-494 (which targets proapoptotic and antiapoptotic proteins) was differentially expressed in the lungs of the infected animals [36, 41]. [score:5]
It was found that miR-494, miR-365 and miR-451 were present in liver, miR-206, miR-468 and miR-691 in spleen, and miR-223, miR-98 and miR-206 in lung. [score:1]
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Furthermore, several miRs, including miR-210 (which regulates angiogenesis) [14], miR-199a (which modulates hypoxia-inducible factor-1 α (HIF-1 α) expression) [16], and miR-494 (which upregulates p-Akt, HIF-1 α, and heme oxygenase-1 expression) [17], protect cells from hypoxia- or ischemia -induced damage. [score:9]
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In response to 4 hours of mechanical stretch, rno-miR-322, let-7f, miR-103, miR-126, miR-494, miR-126*, miR-130b and miR-195 were significantly dysregulated (Fig.   7A and Supplementary Dataset  5), so we sought potential mRNA targets for these dysregulated miRNAs among the stretch-regulated genes in 4 and 12 hours timepoints. [score:6]
In response to 1 hour of mechanical stretching, only one miRNA, rno-miR-130b showed differential expression compared to controls (P < 0.05), whereas 8 miRNAs (rno-miR-322, rno-let-7f, rno-miR-103, rno-miR-126, rno-miR-494, rno-miR-126*, rno-miR-130b, rno-miR-195; P < 0.05) were dysregulated in response to 4 hours of stretch (Supplemental Dataset  5). [score:3]
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8
[+] score: 8
Other miRNAs from this paper: mmu-mir-30a, mmu-mir-101a, mmu-mir-125a, mmu-mir-125b-2, mmu-mir-132, mmu-mir-134, mmu-mir-135a-1, mmu-mir-138-2, mmu-mir-142a, mmu-mir-150, mmu-mir-154, mmu-mir-182, mmu-mir-183, mmu-mir-24-1, mmu-mir-194-1, mmu-mir-200b, mmu-mir-122, mmu-mir-296, mmu-mir-21a, mmu-mir-27a, mmu-mir-92a-2, mmu-mir-96, rno-mir-322-1, mmu-mir-322, rno-mir-330, mmu-mir-330, rno-mir-339, mmu-mir-339, rno-mir-342, mmu-mir-342, rno-mir-135b, mmu-mir-135b, mmu-mir-19a, mmu-mir-100, mmu-mir-139, mmu-mir-212, mmu-mir-181a-1, mmu-mir-214, mmu-mir-224, mmu-mir-135a-2, mmu-mir-92a-1, mmu-mir-138-1, mmu-mir-181b-1, mmu-mir-125b-1, mmu-mir-194-2, mmu-mir-377, mmu-mir-383, mmu-mir-181b-2, rno-mir-19a, rno-mir-21, rno-mir-24-1, rno-mir-27a, rno-mir-30a, rno-mir-92a-1, rno-mir-92a-2, rno-mir-96, rno-mir-100, rno-mir-101a, rno-mir-122, rno-mir-125a, rno-mir-125b-1, rno-mir-125b-2, rno-mir-132, rno-mir-134, rno-mir-135a, rno-mir-138-2, rno-mir-138-1, rno-mir-139, rno-mir-142, rno-mir-150, rno-mir-154, rno-mir-181b-1, rno-mir-181b-2, rno-mir-183, rno-mir-194-1, rno-mir-194-2, rno-mir-200b, rno-mir-212, rno-mir-181a-1, rno-mir-214, rno-mir-296, mmu-mir-376b, mmu-mir-370, mmu-mir-433, rno-mir-433, mmu-mir-466a, rno-mir-383, rno-mir-224, mmu-mir-483, rno-mir-483, rno-mir-370, rno-mir-377, mmu-mir-542, rno-mir-542-1, mmu-mir-494, mmu-mir-20b, mmu-mir-503, rno-mir-376b, rno-mir-20b, rno-mir-503-1, mmu-mir-1224, mmu-mir-551b, mmu-mir-672, mmu-mir-455, mmu-mir-490, mmu-mir-466b-1, mmu-mir-466b-2, mmu-mir-466b-3, mmu-mir-466c-1, mmu-mir-466e, mmu-mir-466f-1, mmu-mir-466f-2, mmu-mir-466f-3, mmu-mir-466g, mmu-mir-466h, mmu-mir-504, mmu-mir-466d, mmu-mir-872, mmu-mir-877, rno-mir-466b-1, rno-mir-466b-2, rno-mir-466c, rno-mir-872, rno-mir-877, rno-mir-182, rno-mir-455, rno-mir-672, mmu-mir-466l, mmu-mir-466i, mmu-mir-466f-4, mmu-mir-466k, mmu-mir-466j, rno-mir-551b, rno-mir-490, rno-mir-1224, rno-mir-504, mmu-mir-466m, mmu-mir-466o, mmu-mir-466c-2, mmu-mir-466b-4, mmu-mir-466b-5, mmu-mir-466b-6, mmu-mir-466b-7, mmu-mir-466p, mmu-mir-466n, mmu-mir-466b-8, rno-mir-466d, mmu-mir-466q, mmu-mir-21b, mmu-mir-21c, mmu-mir-142b, mmu-mir-466c-3, rno-mir-322-2, rno-mir-503-2, rno-mir-466b-3, rno-mir-466b-4, rno-mir-542-2, rno-mir-542-3
Both ACTH and 17α-E2 up-regulated the expression of miRNA-212, miRNA-132, miRNA-154, miRNA-494, miRNA-872, miRNA-194, and miRNA-24-1, but reduced the expression of miRNA-322, miRNA-20b, miRNA-339, miRNA-27a, miRNA-551b, and miRNA-1224. [score:8]
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9
[+] score: 6
We found that miR-142, miR-200c, miR-212, miR-325, miR-361, miR-376c, miR-429, and miR-494 overexpression could down-regulate the CRH mRNA level (p < 0.05; Figure 6A), and there was no difference between these miRNAs and the negative miRNA control (p > 0.05) in terms of cell viability (Supplementary Figure S2A). [score:6]
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10
[+] score: 4
Validation of a selected few by qPCR identified 10 miRNAs - miR-133b-3p, miR-208b-3p, miR-21-5p, miR-125a-5p, miR-125b-5p, miR-126-3p, miR-210-3p, miR-29a-3p, miR-494-3p and miR-320a, that were significantly up-regulated in HF myocardium compared to normal controls. [score:3]
MiR-210-3p is closely related to hypoxia 41, 42, and interestingly, both miR-320a and miR-494 are reported to be associated with cardiac apoptosis induced by ischemia 43, 44. [score:1]
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11
[+] score: 4
For example, in rats with ischemic acute kidney injury (AKI), miR-21 was induced after renal ischemia in kidney tissues, and miR-494 was upregulated [21, 22]. [score:4]
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12
[+] score: 4
Two of the other miRNAs, miR-375 and miR-494, also showed the same pattern of up-regulation in LII without reaching statistical significance in the layered samples. [score:4]
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13
[+] score: 3
miR-494 targets both proapoptotic and antiapoptotic proteins for cardioprotective effects against I/R -induced injury by activating the Akt pathway [15]. [score:3]
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14
[+] score: 3
Interestingly, in the “early” and “late” response phases, Ets1 and Nfat5, are targeted by only a single miRNA, i. e., miR-193 and miR-494, respectively. [score:3]
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15
[+] score: 3
Similarly, miR-494 activates Akt signaling and targets both pro-apoptotic and anti-apoptotic proteins, leading to cardio-protection against I/R -induced injury [10]. [score:3]
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16
[+] score: 2
Other miRNAs from this paper: hsa-mir-494
Kang et al. [33] reported that microRNA-494 enhanced apoptosis of degenerative human NPCs regulated by NF-κB. [score:2]
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17
[+] score: 2
In parallel an increase in the levels of miR-31, and miR-494 that were implicated in dystrophin and mitochondrial regulation and an increase in DNMT3a and DNMT3b proteins and global DNA methylation levels suggest that hHcy plays a causal role in enhanced fatigability through mitochondrial dysfunction which involves epigenetic changes. [score:2]
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18
[+] score: 1
At about E13, when the first waves of neurons are produced from neural progenitor cells in rat cortex [25], we found that 4 miRNAs were particularly high at this stage, including rno-miR-199a-3p, rno-miR-494, rno-miR-182, and rno-miR-7a, suggesting important roles of these miRNAs in neurogenesis. [score:1]
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19
[+] score: 1
Specially, several miRNAs including miRNA-320 [15], miRNA-21 [16] and miRNA-494 [17] are involved in myocardial ischemia. [score:1]
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20
[+] score: 1
Other miRNAs from this paper: 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-23a, hsa-mir-24-1, hsa-mir-24-2, hsa-mir-27a, hsa-mir-30a, hsa-mir-32, hsa-mir-92a-1, hsa-mir-92a-2, hsa-mir-93, hsa-mir-107, hsa-mir-129-1, hsa-mir-30c-2, hsa-mir-139, hsa-mir-181c, hsa-mir-204, hsa-mir-212, hsa-mir-181a-1, hsa-mir-222, hsa-mir-15b, hsa-mir-23b, hsa-mir-132, hsa-mir-138-2, hsa-mir-140, hsa-mir-142, hsa-mir-129-2, hsa-mir-138-1, hsa-mir-146a, hsa-mir-154, hsa-mir-186, rno-mir-324, rno-mir-140, rno-mir-129-2, rno-mir-20a, rno-mir-7a-1, rno-mir-101b, hsa-mir-29c, hsa-mir-296, hsa-mir-30e, hsa-mir-374a, hsa-mir-380, hsa-mir-381, hsa-mir-324, rno-mir-9a-1, rno-mir-9a-3, rno-mir-9a-2, rno-mir-15b, rno-mir-17-1, rno-mir-18a, rno-mir-19b-1, rno-mir-19b-2, rno-mir-19a, rno-mir-21, rno-mir-23a, rno-mir-23b, rno-mir-24-1, rno-mir-24-2, rno-mir-27a, rno-mir-29c-1, rno-mir-30e, rno-mir-30a, rno-mir-30c-2, rno-mir-32, rno-mir-92a-1, rno-mir-92a-2, rno-mir-93, rno-mir-107, rno-mir-129-1, rno-mir-132, rno-mir-138-2, rno-mir-138-1, rno-mir-139, rno-mir-142, rno-mir-146a, rno-mir-154, rno-mir-181c, rno-mir-186, rno-mir-204, rno-mir-212, rno-mir-181a-1, rno-mir-222, rno-mir-296, rno-mir-300, hsa-mir-20b, hsa-mir-431, rno-mir-431, hsa-mir-433, rno-mir-433, hsa-mir-410, hsa-mir-494, hsa-mir-181d, hsa-mir-500a, hsa-mir-505, rno-mir-381, rno-mir-409a, rno-mir-374, rno-mir-20b, hsa-mir-551b, hsa-mir-598, hsa-mir-652, hsa-mir-655, rno-mir-505, hsa-mir-300, hsa-mir-874, hsa-mir-374b, rno-mir-466b-1, rno-mir-466b-2, rno-mir-466c, rno-mir-874, rno-mir-17-2, rno-mir-181d, rno-mir-380, rno-mir-410, rno-mir-500, rno-mir-598-1, rno-mir-674, rno-mir-652, rno-mir-551b, hsa-mir-3065, rno-mir-344b-2, rno-mir-3564, rno-mir-3065, rno-mir-1188, rno-mir-3584-1, rno-mir-344b-1, hsa-mir-500b, hsa-mir-374c, rno-mir-29c-2, rno-mir-3584-2, rno-mir-598-2, rno-mir-344b-3, rno-mir-466b-3, rno-mir-466b-4
A second pattern was about the opposite: miR-466b-1-3p, miR-494-3p and miR-598-5p displayed significantly decreased plasma levels during latency, and a tendency to return to the control levels in the chronic stage (Supplementary Fig. S7B). [score:1]
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[+] score: 1
Furthermore, several miRNAs, such as miR-199a and miR-214 [14], miR-494 [15], miR-499 [16], and miR-24 [17] are known to protect cells from hypoxia- or ischemia -induced damage. [score:1]
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22
[+] score: 1
MiR-29 [8] and miR-494-3p [9] were also associated with osteogenesis after a mechanical stimulus. [score:1]
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23
[+] score: 1
Other miRNAs from this paper: hsa-let-7a-1, hsa-let-7a-2, hsa-let-7a-3, hsa-let-7b, hsa-let-7c, hsa-let-7d, hsa-let-7e, hsa-let-7f-1, hsa-let-7f-2, hsa-mir-16-1, hsa-mir-17, hsa-mir-21, hsa-mir-23a, hsa-mir-24-1, hsa-mir-24-2, hsa-mir-25, hsa-mir-26a-1, hsa-mir-26b, hsa-mir-30a, hsa-mir-31, hsa-mir-96, hsa-mir-99a, hsa-mir-16-2, hsa-mir-30c-2, hsa-mir-30d, hsa-mir-182, hsa-mir-183, hsa-mir-211, hsa-mir-217, hsa-mir-218-1, hsa-mir-218-2, hsa-mir-221, hsa-mir-222, hsa-let-7g, hsa-let-7i, hsa-mir-15b, hsa-mir-23b, hsa-mir-30b, hsa-mir-125b-1, hsa-mir-132, hsa-mir-143, hsa-mir-145, hsa-mir-191, hsa-mir-125a, hsa-mir-125b-2, hsa-mir-126, hsa-mir-184, hsa-mir-190a, hsa-mir-195, rno-mir-322-1, rno-let-7d, rno-mir-335, rno-mir-342, rno-mir-135b, hsa-mir-30c-1, hsa-mir-299, hsa-mir-30e, hsa-mir-26a-2, hsa-mir-379, hsa-mir-382, hsa-mir-342, hsa-mir-135b, hsa-mir-335, rno-let-7a-1, rno-let-7a-2, rno-let-7b, rno-let-7c-1, rno-let-7c-2, rno-let-7e, rno-let-7f-1, rno-let-7f-2, rno-let-7i, rno-mir-15b, rno-mir-16, rno-mir-17-1, rno-mir-21, rno-mir-23a, rno-mir-23b, rno-mir-24-1, rno-mir-24-2, rno-mir-25, rno-mir-26a, rno-mir-26b, rno-mir-30c-1, rno-mir-30e, rno-mir-30b, rno-mir-30d, rno-mir-30a, rno-mir-30c-2, rno-mir-31a, rno-mir-96, rno-mir-99a, rno-mir-125a, rno-mir-125b-1, rno-mir-125b-2, rno-mir-126a, rno-mir-132, rno-mir-143, rno-mir-145, rno-mir-183, rno-mir-184, rno-mir-190a-1, rno-mir-191a, rno-mir-195, rno-mir-211, rno-mir-217, rno-mir-218a-2, rno-mir-218a-1, rno-mir-221, rno-mir-222, rno-mir-299a, hsa-mir-384, hsa-mir-20b, hsa-mir-409, hsa-mir-412, hsa-mir-489, hsa-mir-494, rno-mir-489, rno-mir-412, rno-mir-543, rno-mir-542-1, rno-mir-379, rno-mir-382, rno-mir-409a, rno-mir-20b, hsa-mir-542, hsa-mir-770, hsa-mir-190b, hsa-mir-543, rno-mir-466c, rno-mir-17-2, rno-mir-182, rno-mir-190b, rno-mir-384, rno-mir-673, rno-mir-674, rno-mir-770, rno-mir-31b, rno-mir-191b, rno-mir-299b, rno-mir-218b, rno-mir-126b, rno-mir-409b, rno-let-7g, rno-mir-190a-2, rno-mir-322-2, rno-mir-542-2, rno-mir-542-3
These include rno-miR-195, rno-miR-125a-5p, rno-let-7a, rno-miR-16, rno-miR-30b-5p, rno-let-7c, rno-let-7b, rno-miR-125b-5p, rno-miR-221, rno-miR-222, rno-miR-26a, rno-miR-322, rno-miR-23a, rno-miR-191, rno-miR-30 family, rno-miR-21, rno-miR-126, rno-miR-23b, rno-miR-145 and rno-miR-494. [score:1]
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