pre-miRNA Information | |
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pre-miRNA | hsa-mir-23a |
Genomic Coordinates | chr19: 13836587 - 13836659 |
Synonyms | MIRN23A, hsa-mir-23a, miRNA23A, MIR23A |
Description | Homo sapiens miR-23a stem-loop |
Comment | This miRNA was previously named miR-23 . This finding was later retracted after the discovery that the regulated gene was human homolog of ES1 (HES1), whose function is unknown. |
RNA Secondary Structure | ![]() |
Associated Diseases | ![]() |
Mature miRNA Information | ||||||||||
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Mature miRNA | hsa-miR-23a-5p | |||||||||
Sequence | 9| GGGGUUCCUGGGGAUGGGAUUU |30 | |||||||||
Evidence | Experimental | |||||||||
Experiments | Cloned | |||||||||
SNPs in miRNA |
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Putative Targets |
miRNA Expression profile | |
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Human miRNA Tissue Atlas | |
miRNAs in Extracellular Vesicles |
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Circulating MicroRNA Expression Profiling |
Gene Information | |||||||||||||||||||||
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Gene Symbol | AS3MT | ||||||||||||||||||||
Synonyms | CYT19 | ||||||||||||||||||||
Description | arsenite methyltransferase | ||||||||||||||||||||
Transcript | NM_020682 | ||||||||||||||||||||
Expression | |||||||||||||||||||||
Putative miRNA Targets on AS3MT | |||||||||||||||||||||
3'UTR of AS3MT (miRNA target sites are highlighted) |
>AS3MT|NM_020682|3'UTR
1 ATCTATAGCCAACCAGGGGACCACAGTAGTGGGCAAGAGTGATCTGCATGTTTTTTAACCTGCTTTTCCCCATAGCACAG
81 ACCATAAGAAACAACAAATGGGGCCGGGCACAGTGGCTCATGCCTATAATCCCAGCACTTTGGGAGGCCGAGGCAGGCAG
161 ATCACCTGAGGTCAGGAGTTTGATACCAGCCTGGCCAACATGGTGAAATCCTGTCTCTACCAAAAATACAAAAAAAATTA
241 GCTGGGCATGGTGGTGCACACCTATAGTCTCAGCTACTCGGGAGGCTGAGGCAGGAGAATTGCTTGAACCCAGGAAGTAG
321 AGGCTGCAGTGAGTAAGCATCACGCCACTGTACTCCAGCCTGGGCAACAGAGCAAGACTCTGTCTCAAAAGCAAAAAAAA
401 AAAAAAAAAAAGAAAGAAAGAAAAAGAAAACAACAAATGGCAGAGAGCCACCATATTCCAAATCACTGAAAAAAATAAAT
481 GAATTATTTTTATTTATTTATTTATTTTTTTGAGATGGAGTCTCGGTCTGTTGCCCAGGCTGAAGTGCAGTGGCCCCATC
561 TCAACTCACTGCAAGCTCCACCTCCTGGGTTCACGCCATTCTCCTGCCTCAGACTCCCAAGTAGCTGGGACTACAGGCAC
641 CTACCACCATGCCCAGCTAATTTTTTGTATTTTTAGTAGAGACGGGGTTTCACCATGTTAGCCAGGATGGTCTTGATCTC
721 CTGACCTCGTGATCCGCCCGCCTCGGCCTCCCAAAGTGCTGGGATTACAAGCATGAGCCACTGCGCCCGGCCATAAATGA
801 ATTATTTTTAAGAGGCATTGATTAAAGATTCACAGCAAATCACTAGTTAAGCAGATTTTTTTTCTATTTCCTACTTCAAA
881 GTTCTGGTGCCACATAGTGGTCAGAAATGGAACAGAGAAGCTGTCTTAAGCCTTGTTCAAGAAGCAGGAAAGGCATCAGA
961 AGAAGTAACAGTTGGCAGAGGGTCTCAGGAAAAACATCTTCCTTCTGATCTTTTGCATAGCACCTTTTGGAATTTTCATC
1041 ATGTTTGCTTATTAAACAAAGCTCCTACTGCCATCATACTAATCATGCAAAAAGATTGCCAAATCATGTTTGGTAGGAGG
1121 ACTTTTGAGGTAGCTTTTGAACAAATGTTTTTTTCTTTTTTCTTTTTTTTTGCAATAAAGAAAACAAATTAATCATAAAA
1201 AAAAAAAAA
Target sites
Provided by authors
Predicted by miRanda
DRVs
SNPs
DRVs & SNPs
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miRNA-target interactions (Predicted by miRanda) |
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DRVs in gene 3'UTRs | |||||||||||||||||||||
SNPs in gene 3'UTRs |
Experimental Support 1 for Functional miRNA-Target Interaction | |||||||
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miRNA:Target | ---- | ||||||
Validation Method |
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Conditions | HEK293S | ||||||
Location of target site | 3'UTR | ||||||
Tools used in this research | TargetScan , miRTarCLIP , Piranha | ||||||
Original Description (Extracted from the article) |
...
HITS-CLIP data was present in GSM1084040. RNA binding protein: AGO2. Condition:CLIP_noarsenite_rep1
... - Karginov FV; Hannon GJ, 2013, Genes & development. |
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miRNA-target interactions (Provided by authors) |
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Article |
- Karginov FV; Hannon GJ - Genes & development, 2013
When adapting to environmental stress, cells attenuate and reprogram their translational output. In part, these altered translation profiles are established through changes in the interactions between RNA-binding proteins and mRNAs. The Argonaute 2 (Ago2)/microRNA (miRNA) machinery has been shown to participate in stress-induced translational up-regulation of a particular mRNA, CAT-1; however, a detailed, transcriptome-wide understanding of the involvement of Ago2 in the process has been lacking. Here, we profiled the overall changes in Ago2-mRNA interactions upon arsenite stress by cross-linking immunoprecipitation (CLIP) followed by high-throughput sequencing (CLIP-seq). Ago2 displayed a significant remodeling of its transcript occupancy, with the majority of 3' untranslated region (UTR) and coding sequence (CDS) sites exhibiting stronger interaction. Interestingly, target sites that were destined for release from Ago2 upon stress were depleted in miRNA complementarity signatures, suggesting an alternative mode of interaction. To compare the changes in Ago2-binding patterns across transcripts with changes in their translational states, we measured mRNA profiles on ribosome/polysome gradients by RNA sequencing (RNA-seq). Increased Ago2 occupancy correlated with stronger repression of translation for those mRNAs, as evidenced by a shift toward lighter gradient fractions upon stress, while release of Ago2 was associated with the limited number of transcripts that remained translated. Taken together, these data point to a role for Ago2 and the mammalian miRNAs in mediating the translational component of the stress response.
LinkOut: [PMID: 23824327]
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Experimental Support 2 for Functional miRNA-Target Interaction | |||||||
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miRNA:Target | ---- | ||||||
Validation Method |
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Conditions | Prostate Tissue | ||||||
Location of target site | 3'UTR | ||||||
Tools used in this research | TargetScan , miRTarCLIP , Piranha | ||||||
Original Description (Extracted from the article) |
...
PAR-CLIP data was present in SRX1760631. RNA binding protein: AGO2. Condition:AGO-CLIP-22RV1_B
... - Hamilton MP; Rajapakshe KI; Bader DA; Cerne et al., 2016, Neoplasia (New York, N.Y.). |
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miRNA-target interactions (Provided by authors) |
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Article |
- Hamilton MP; Rajapakshe KI; Bader DA; Cerne et al. - Neoplasia (New York, N.Y.), 2016
MicroRNA (miRNA) deregulation in prostate cancer (PCa) contributes to PCa initiation and metastatic progression. To comprehensively define the cancer-associated changes in miRNA targeting and function in commonly studied models of PCa, we performed photoactivatable ribonucleoside-enhanced cross-linking immunoprecipitation of the Argonaute protein in a panel of PCa cell lines modeling different stages of PCa progression. Using this comprehensive catalogue of miRNA targets, we analyzed miRNA targeting on known drivers of PCa and examined tissue-specific and stage-specific pathway targeting by miRNAs. We found that androgen receptor is the most frequently targeted PCa oncogene and that miR-148a targets the largest number of known PCa drivers. Globally, tissue-specific and stage-specific changes in miRNA targeting are driven by homeostatic response to active oncogenic pathways. Our findings indicate that, even in advanced PCa, the miRNA pool adapts to regulate continuing alterations in the cancer genome to balance oncogenic molecular changes. These findings are important because they are the first to globally characterize miRNA changes in PCa and demonstrate how the miRNA target spectrum responds to staged tumorigenesis.
LinkOut: [PMID: 27292025]
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CLIP-seq Support 1 for dataset GSM1084040 | |
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Method / RBP | HITS-CLIP / AGO2 |
Cell line / Condition | HEK293S / CLIP_noarsenite_rep1 |
Location of target site | ENST00000369880.3 | 3UTR | GAGGCUGAGGCAGGAGAAUUGCUUGAACCCAGGAAG |
Tools used in this analysis | TargetScan, miRTarCLIP, and Piranha |
Article / Accession Series | PMID: 23824327 / GSE44404 |
CLIP-seq Viewer | Link |
MiRNA-Target Expression Profile | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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MiRNA-Target Expression Profile (TCGA) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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131 hsa-miR-23a-5p Target Genes:
Functional analysis:
ID![]() |
Target | Description | Validation methods |
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Strong evidence | Less strong evidence | |||||||||||
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MIRT038958 | ATF1 | activating transcription factor 1 | ![]() |
1 | 1 | |||||||
MIRT057661 | LCOR | ligand dependent nuclear receptor corepressor | ![]() |
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2 | 2 | ||||||
MIRT395438 | NFKBID | NFKB inhibitor delta | ![]() |
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2 | 2 | ||||||
MIRT463884 | WNT7B | Wnt family member 7B | ![]() |
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2 | 4 | ||||||
MIRT475804 | HDGF | heparin binding growth factor | ![]() |
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2 | 2 | ||||||
MIRT478528 | CTNS | cystinosin, lysosomal cystine transporter | ![]() |
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2 | 2 | ||||||
MIRT479278 | CHD4 | chromodomain helicase DNA binding protein 4 | ![]() |
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2 | 6 | ||||||
MIRT492564 | PPM1L | protein phosphatase, Mg2+/Mn2+ dependent 1L | ![]() |
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2 | 2 | ||||||
MIRT500353 | ZNF385A | zinc finger protein 385A | ![]() |
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2 | 2 | ||||||
MIRT509788 | CHAF1B | chromatin assembly factor 1 subunit B | ![]() |
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2 | 4 | ||||||
MIRT511566 | HIST3H2BB | histone cluster 3 H2B family member b | ![]() |
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2 | 4 | ||||||
MIRT525450 | GPATCH2L | G-patch domain containing 2 like | ![]() |
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2 | 2 | ||||||
MIRT539558 | CNKSR3 | CNKSR family member 3 | ![]() |
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2 | 4 | ||||||
MIRT540034 | DNAJC28 | DnaJ heat shock protein family (Hsp40) member C28 | ![]() |
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2 | 4 | ||||||
MIRT540225 | SAMD5 | sterile alpha motif domain containing 5 | ![]() |
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2 | 2 | ||||||
MIRT540242 | RGS17 | regulator of G protein signaling 17 | ![]() |
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2 | 2 | ||||||
MIRT540871 | ZBTB24 | zinc finger and BTB domain containing 24 | ![]() |
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2 | 2 | ||||||
MIRT559065 | C19orf47 | chromosome 19 open reading frame 47 | ![]() |
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2 | 4 | ||||||
MIRT560685 | HIST1H1T | histone cluster 1 H1 family member t | ![]() |
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2 | 2 | ||||||
MIRT565593 | SLC35G1 | solute carrier family 35 member G1 | ![]() |
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2 | 2 | ||||||
MIRT565642 | SKI | SKI proto-oncogene | ![]() |
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2 | 2 | ||||||
MIRT576747 | Tmem127 | transmembrane protein 127 | ![]() |
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2 | 2 | ||||||
MIRT607712 | LIMS1 | LIM zinc finger domain containing 1 | ![]() |
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2 | 2 | ||||||
MIRT615682 | NAV2 | neuron navigator 2 | ![]() |
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2 | 2 | ||||||
MIRT617337 | ZSCAN2 | zinc finger and SCAN domain containing 2 | ![]() |
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2 | 2 | ||||||
MIRT617378 | FAM227A | family with sequence similarity 227 member A | ![]() |
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2 | 2 | ||||||
MIRT620855 | SERPING1 | serpin family G member 1 | ![]() |
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2 | 2 | ||||||
MIRT625112 | SLC1A5 | solute carrier family 1 member 5 | ![]() |
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2 | 2 | ||||||
MIRT625124 | NUP93 | nucleoporin 93 | ![]() |
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2 | 2 | ||||||
MIRT625898 | LINC00632 | long intergenic non-protein coding RNA 632 | ![]() |
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2 | 2 | ||||||
MIRT626016 | XRCC2 | X-ray repair cross complementing 2 | ![]() |
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2 | 2 | ||||||
MIRT626481 | ADAT1 | adenosine deaminase, tRNA specific 1 | ![]() |
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2 | 2 | ||||||
MIRT626573 | MED7 | mediator complex subunit 7 | ![]() |
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2 | 2 | ||||||
MIRT626814 | PRR11 | proline rich 11 | ![]() |
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2 | 2 | ||||||
MIRT628136 | HM13 | histocompatibility minor 13 | ![]() |
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2 | 2 | ||||||
MIRT630771 | MSANTD3 | Myb/SANT DNA binding domain containing 3 | ![]() |
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2 | 2 | ||||||
MIRT633133 | C6orf132 | chromosome 6 open reading frame 132 | ![]() |
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2 | 2 | ||||||
MIRT636950 | APTX | aprataxin | ![]() |
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2 | 2 | ||||||
MIRT637802 | GGPS1 | geranylgeranyl diphosphate synthase 1 | ![]() |
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2 | 2 | ||||||
MIRT638622 | GSR | glutathione-disulfide reductase | ![]() |
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2 | 4 | ||||||
MIRT642196 | SMAGP | small cell adhesion glycoprotein | ![]() |
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2 | 2 | ||||||
MIRT645121 | HES2 | hes family bHLH transcription factor 2 | ![]() |
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2 | 2 | ||||||
MIRT645344 | AGTPBP1 | ATP/GTP binding protein 1 | ![]() |
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2 | 2 | ||||||
MIRT646564 | ALDH5A1 | aldehyde dehydrogenase 5 family member A1 | ![]() |
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2 | 2 | ||||||
MIRT649243 | TRIM65 | tripartite motif containing 65 | ![]() |
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2 | 2 | ||||||
MIRT651810 | USP49 | ubiquitin specific peptidase 49 | ![]() |
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2 | 2 | ||||||
MIRT652137 | TRPM7 | transient receptor potential cation channel subfamily M member 7 | ![]() |
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2 | 2 | ||||||
MIRT652668 | TIMELESS | timeless circadian clock | ![]() |
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2 | 2 | ||||||
MIRT655894 | NEK9 | NIMA related kinase 9 | ![]() |
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2 | 2 | ||||||
MIRT656564 | LYRM7 | LYR motif containing 7 | ![]() |
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2 | 2 | ||||||
MIRT657194 | IKZF3 | IKAROS family zinc finger 3 | ![]() |
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2 | 2 | ||||||
MIRT657907 | GDE1 | glycerophosphodiester phosphodiesterase 1 | ![]() |
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2 | 2 | ||||||
MIRT660207 | BMPR1A | bone morphogenetic protein receptor type 1A | ![]() |
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2 | 2 | ||||||
MIRT660619 | ANKS4B | ankyrin repeat and sterile alpha motif domain containing 4B | ![]() |
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2 | 2 | ||||||
MIRT660826 | AGO3 | argonaute 3, RISC catalytic component | ![]() |
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2 | 2 | ||||||
MIRT660986 | ABHD2 | abhydrolase domain containing 2 | ![]() |
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2 | 2 | ||||||
MIRT662232 | PGBD4 | piggyBac transposable element derived 4 | ![]() |
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2 | 2 | ||||||
MIRT663691 | ZNF347 | zinc finger protein 347 | ![]() |
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2 | 2 | ||||||
MIRT665577 | TUBD1 | tubulin delta 1 | ![]() |
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2 | 2 | ||||||
MIRT666149 | SP2 | Sp2 transcription factor | ![]() |
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2 | 2 | ||||||
MIRT666310 | SLC22A3 | solute carrier family 22 member 3 | ![]() |
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2 | 2 | ||||||
MIRT666457 | SCRG1 | stimulator of chondrogenesis 1 | ![]() |
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2 | 2 | ||||||
MIRT667716 | KIAA1468 | KIAA1468 | ![]() |
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2 | 2 | ||||||
MIRT668329 | FKBP5 | FK506 binding protein 5 | ![]() |
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2 | 2 | ||||||
MIRT668370 | FBXO47 | F-box protein 47 | ![]() |
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2 | 2 | ||||||
MIRT669304 | C17orf75 | chromosome 17 open reading frame 75 | ![]() |
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2 | 2 | ||||||
MIRT669538 | ALG9 | ALG9, alpha-1,2-mannosyltransferase | ![]() |
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2 | 2 | ||||||
MIRT671681 | ADK | adenosine kinase | ![]() |
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2 | 2 | ||||||
MIRT672177 | MRE11A | MRE11 homolog, double strand break repair nuclease | ![]() |
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2 | 2 | ||||||
MIRT673604 | HPSE | heparanase | ![]() |
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2 | 2 | ||||||
MIRT673749 | ZNF333 | zinc finger protein 333 | ![]() |
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2 | 2 | ||||||
MIRT674807 | FAM229B | family with sequence similarity 229 member B | ![]() |
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2 | 2 | ||||||
MIRT675286 | ARL10 | ADP ribosylation factor like GTPase 10 | ![]() |
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2 | 2 | ||||||
MIRT675391 | SVOP | SV2 related protein | ![]() |
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2 | 2 | ||||||
MIRT675788 | MED28 | mediator complex subunit 28 | ![]() |
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2 | 2 | ||||||
MIRT676151 | OGFOD1 | 2-oxoglutarate and iron dependent oxygenase domain containing 1 | ![]() |
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2 | 2 | ||||||
MIRT676499 | GJD3 | gap junction protein delta 3 | ![]() |
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2 | 2 | ||||||
MIRT676621 | CSNK1E | casein kinase 1 epsilon | ![]() |
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2 | 2 | ||||||
MIRT676644 | GTDC1 | glycosyltransferase like domain containing 1 | ![]() |
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2 | 2 | ||||||
MIRT676711 | METTL14 | methyltransferase like 14 | ![]() |
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2 | 2 | ||||||
MIRT676809 | SHROOM4 | shroom family member 4 | ![]() |
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2 | 2 | ||||||
MIRT677036 | FOXO3 | forkhead box O3 | ![]() |
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2 | 2 | ||||||
MIRT677062 | NT5C2 | 5'-nucleotidase, cytosolic II | ![]() |
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2 | 2 | ||||||
MIRT677086 | SMIM15 | small integral membrane protein 15 | ![]() |
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2 | 2 | ||||||
MIRT677193 | MURC | caveolae associated protein 4 | ![]() |
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2 | 2 | ||||||
MIRT677273 | SNRPD1 | small nuclear ribonucleoprotein D1 polypeptide | ![]() |
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2 | 2 | ||||||
MIRT677345 | POC1A | POC1 centriolar protein A | ![]() |
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2 | 2 | ||||||
MIRT677504 | SLC10A6 | solute carrier family 10 member 6 | ![]() |
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2 | 2 | ||||||
MIRT677526 | OCIAD2 | OCIA domain containing 2 | ![]() |
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2 | 2 | ||||||
MIRT677661 | UGGT1 | UDP-glucose glycoprotein glucosyltransferase 1 | ![]() |
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2 | 2 | ||||||
MIRT677727 | SSR1 | signal sequence receptor subunit 1 | ![]() |
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2 | 2 | ||||||
MIRT677803 | PNPLA3 | patatin like phospholipase domain containing 3 | ![]() |
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2 | 2 | ||||||
MIRT678144 | SLC4A4 | solute carrier family 4 member 4 | ![]() |
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2 | 2 | ||||||
MIRT678376 | VTA1 | vesicle trafficking 1 | ![]() |
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2 | 2 | ||||||
MIRT678708 | DHTKD1 | dehydrogenase E1 and transketolase domain containing 1 | ![]() |
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2 | 2 | ||||||
MIRT678868 | FAM118A | family with sequence similarity 118 member A | ![]() |
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2 | 2 | ||||||
MIRT679039 | LACTB | lactamase beta | ![]() |
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2 | 2 | ||||||
MIRT679081 | PURB | purine rich element binding protein B | ![]() |
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2 | 2 | ||||||
MIRT679137 | SYK | spleen associated tyrosine kinase | ![]() |
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2 | 2 | ||||||
MIRT679299 | SSBP2 | single stranded DNA binding protein 2 | ![]() |
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2 | 2 | ||||||
MIRT679741 | CABP4 | calcium binding protein 4 | ![]() |
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2 | 2 | ||||||
MIRT679946 | AS3MT | arsenite methyltransferase | ![]() |
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2 | 2 | ||||||
MIRT679976 | E2F2 | E2F transcription factor 2 | ![]() |
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2 | 2 | ||||||
MIRT683628 | MTO1 | mitochondrial tRNA translation optimization 1 | ![]() |
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2 | 2 | ||||||
MIRT683901 | PSMB9 | proteasome subunit beta 9 | ![]() |
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2 | 2 | ||||||
MIRT684172 | MOG | myelin oligodendrocyte glycoprotein | ![]() |
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2 | 2 | ||||||
MIRT684231 | C20orf144 | chromosome 20 open reading frame 144 | ![]() |
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2 | 2 | ||||||
MIRT685403 | C1orf158 | chromosome 1 open reading frame 158 | ![]() |
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2 | 2 | ||||||
MIRT686253 | ZBTB8B | zinc finger and BTB domain containing 8B | ![]() |
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2 | 2 | ||||||
MIRT687513 | NCKAP1 | NCK associated protein 1 | ![]() |
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2 | 2 | ||||||
MIRT688243 | FITM2 | fat storage inducing transmembrane protein 2 | ![]() |
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2 | 2 | ||||||
MIRT688315 | FAM151B | family with sequence similarity 151 member B | ![]() |
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2 | 2 | ||||||
MIRT688733 | CNDP1 | carnosine dipeptidase 1 | ![]() |
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2 | 2 | ||||||
MIRT689031 | ANGPTL3 | angiopoietin like 3 | ![]() |
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2 | 2 | ||||||
MIRT698207 | TMEM248 | transmembrane protein 248 | ![]() |
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2 | 2 | ||||||
MIRT699859 | SAR1A | secretion associated Ras related GTPase 1A | ![]() |
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2 | 2 | ||||||
MIRT709954 | TRUB2 | TruB pseudouridine synthase family member 2 | ![]() |
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2 | 2 | ||||||
MIRT711541 | MSH3 | mutS homolog 3 | ![]() |
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2 | 2 | ||||||
MIRT712077 | WDR37 | WD repeat domain 37 | ![]() |
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2 | 2 | ||||||
MIRT715312 | POLR2E | RNA polymerase II subunit E | ![]() |
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2 | 2 | ||||||
MIRT715725 | PIAS2 | protein inhibitor of activated STAT 2 | ![]() |
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2 | 2 | ||||||
MIRT715748 | HSD11B1L | hydroxysteroid 11-beta dehydrogenase 1 like | ![]() |
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2 | 2 | ||||||
MIRT717604 | DSTYK | dual serine/threonine and tyrosine protein kinase | ![]() |
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2 | 2 | ||||||
MIRT717875 | CYP20A1 | cytochrome P450 family 20 subfamily A member 1 | ![]() |
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2 | 2 | ||||||
MIRT718042 | NIPAL2 | NIPA like domain containing 2 | ![]() |
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2 | 2 | ||||||
MIRT718829 | CDT1 | chromatin licensing and DNA replication factor 1 | ![]() |
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2 | 2 | ||||||
MIRT724037 | CAMK2N2 | calcium/calmodulin dependent protein kinase II inhibitor 2 | ![]() |
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2 | 2 | ||||||
MIRT733305 | TNF | tumor necrosis factor | ![]() |
1 | 0 | |||||||
MIRT734941 | HSPA1B | heat shock protein family A (Hsp70) member 1B | ![]() |
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3 | 0 | |||||
MIRT737343 | IGF2 | insulin like growth factor 2 | ![]() |
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3 | 0 | |||||
MIRT737546 | PTEN | phosphatase and tensin homolog | ![]() |
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2 | 0 |
miRNA-Drug Associations | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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