pre-miRNA Information | |
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pre-miRNA | hsa-mir-6818 |
Genomic Coordinates | chr22: 30007049 - 30007113 |
Description | Homo sapiens miR-6818 stem-loop |
Comment | None |
RNA Secondary Structure | ![]() |
Mature miRNA Information | |||||||||||||||||||
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Mature miRNA | hsa-miR-6818-5p | ||||||||||||||||||
Sequence | 6| UUGUGUGAGUACAGAGAGCAUC |27 | ||||||||||||||||||
Evidence | Experimental | ||||||||||||||||||
Experiments | Meta-analysis | ||||||||||||||||||
SNPs in miRNA |
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Putative Targets |
Gene Information | |||||||||||||||||||||
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Gene Symbol | RHOC | ||||||||||||||||||||
Synonyms | ARH9, ARHC, H9, RHOH9 | ||||||||||||||||||||
Description | ras homolog family member C | ||||||||||||||||||||
Transcript | NM_001042678 | ||||||||||||||||||||
Other Transcripts | NM_001042679 , NM_175744 | ||||||||||||||||||||
Expression | |||||||||||||||||||||
Putative miRNA Targets on RHOC | |||||||||||||||||||||
3'UTR of RHOC (miRNA target sites are highlighted) |
>RHOC|NM_001042678|3'UTR 1 GATCCCCAAGGCCTTTCCTACATGCCCCCTCCCTTCACAGGGGTACAGAAATTATCCCCCTACAACCCCAGCCTCCTGAG 81 GGCTCCATGCTGAAGGCTCCCATTTTCAGTTCCCTCCTGCCCAGGACTGCATTGTTTTCTAGCCCCGAGGTGGTGGCACG 161 GGCCCTCCCTCCCAGCGCTCTGGGAGCCACGCCTATGCCCTGCCCTTCCTCAGGGCCCCTGGGGATCTTGCCCCCTTTGA 241 CCTTCCCCAAAGGATGGTCACACACCAGCACTTTATACACTTCTGGCTCACAGGAAAGTGTCTGCAGTAGGGGACCCAGA 321 GTCCCAGGCCCCTGGAGTTGTTTTCGGCAGGGGCCTTGTCTCTCACTGCATTTGGTCAGGGGGGCATGAATAAAGGCTAC 401 AGGCTCCAACGTGAAAAAAAAAAAAAAAAAA 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 | HEK293 | |||||||||
Disease | 389.0 | |||||||||
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 GSM714644. RNA binding protein: AGO2. Condition:completeT1
... - Kishore S; Jaskiewicz L; Burger L; Hausser et al., 2011, Nature methods. |
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miRNA-target interactions (Provided by authors) |
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Article |
- Kishore S; Jaskiewicz L; Burger L; Hausser et al. - Nature methods, 2011
Cross-linking and immunoprecipitation (CLIP) is increasingly used to map transcriptome-wide binding sites of RNA-binding proteins. We developed a method for CLIP data analysis, and applied it to compare CLIP with photoactivatable ribonucleoside-enhanced CLIP (PAR-CLIP) and to uncover how differences in cross-linking and ribonuclease digestion affect the identified sites. We found only small differences in accuracies of these methods in identifying binding sites of HuR, which binds low-complexity sequences, and Argonaute 2, which has a complex binding specificity. We found that cross-link-induced mutations led to single-nucleotide resolution for both PAR-CLIP and CLIP. Our results confirm the expectation from original CLIP publications that RNA-binding proteins do not protect their binding sites sufficiently under the denaturing conditions used during the CLIP procedure, and we show that extensive digestion with sequence-specific RNases strongly biases the recovered binding sites. This bias can be substantially reduced by milder nuclease digestion conditions.
LinkOut: [PMID: 21572407]
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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 | HCT116 |
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 ERX177599. RNA binding protein: AGO2. Condition:p53_D_AGO_CLIP_2_1
PAR-CLIP data was present in ERX177611. RNA binding protein: AGO2. Condition:p53_D_AGO_CLIP_3_1
... - Krell J; Stebbing J; Carissimi C; Dabrowska et al., 2016, Genome research. |
Article |
- Krell J; Stebbing J; Carissimi C; Dabrowska et al. - Genome research, 2016
DNA damage activates TP53-regulated surveillance mechanisms that are crucial in suppressing tumorigenesis. TP53 orchestrates these responses directly by transcriptionally modulating genes, including microRNAs (miRNAs), and by regulating miRNA biogenesis through interacting with the DROSHA complex. However, whether the association between miRNAs and AGO2 is regulated following DNA damage is not yet known. Here, we show that, following DNA damage, TP53 interacts with AGO2 to induce or reduce AGO2's association of a subset of miRNAs, including multiple let-7 family members. Furthermore, we show that specific mutations in TP53 decrease rather than increase the association of let-7 family miRNAs, reducing their activity without preventing TP53 from interacting with AGO2. This is consistent with the oncogenic properties of these mutants. Using AGO2 RIP-seq and PAR-CLIP-seq, we show that the DNA damage-induced increase in binding of let-7 family members to the RISC complex is functional. We unambiguously determine the global miRNA-mRNA interaction networks involved in the DNA damage response, validating them through the identification of miRNA-target chimeras formed by endogenous ligation reactions. We find that the target complementary region of the let-7 seed tends to have highly fixed positions and more variable ones. Additionally, we observe that miRNAs, whose cellular abundance or differential association with AGO2 is regulated by TP53, are involved in an intricate network of regulatory feedback and feedforward circuits. TP53-mediated regulation of AGO2-miRNA interaction represents a new mechanism of miRNA regulation in carcinogenesis.
LinkOut: [PMID: 26701625]
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Experimental Support 3 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 SRX1760632. RNA binding protein: AGO2. Condition:AGO-CLIP-22RV1_C
... - Hamilton MP; Rajapakshe KI; Bader DA; Cerne et al., 2016, Neoplasia (New York, N.Y.). |
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 GSM714644 | |
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Method / RBP | PAR-CLIP / AGO2 |
Cell line / Condition | HEK293 / completeT1, repA |
Location of target site | ENST00000339083.7 | 3UTR | UCACACACCAGCACUUUAUACACUUCUGGCUCACAG |
Tools used in this analysis | TargetScan, miRTarCLIP, and Piranha |
Article / Accession Series | PMID: 21572407 / GSE28865 |
CLIP-seq Viewer | Link |
MiRNA-Target Expression Profile | |||||||
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MiRNA-Target Expression Profile (TCGA) | |||||||
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140 hsa-miR-6818-5p Target Genes:
Functional analysis:
ID![]() |
Target | Description | Validation methods |
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Strong evidence | Less strong evidence | |||||||||||
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MIRT071796 | RNF11 | ring finger protein 11 | ![]() |
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2 | 2 | ||||||
MIRT077120 | NKIRAS2 | NFKB inhibitor interacting Ras like 2 | ![]() |
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2 | 4 | ||||||
MIRT079951 | RNF138 | ring finger protein 138 | ![]() |
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2 | 2 | ||||||
MIRT102968 | EN2 | engrailed homeobox 2 | ![]() |
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2 | 4 | ||||||
MIRT115694 | MGRN1 | mahogunin ring finger 1 | ![]() |
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2 | 2 | ||||||
MIRT121074 | FGFRL1 | fibroblast growth factor receptor like 1 | ![]() |
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2 | 2 | ||||||
MIRT143171 | GLYR1 | glyoxylate reductase 1 homolog | ![]() |
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2 | 2 | ||||||
MIRT145635 | LASP1 | LIM and SH3 protein 1 | ![]() |
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2 | 2 | ||||||
MIRT282026 | ARID3B | AT-rich interaction domain 3B | ![]() |
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2 | 6 | ||||||
MIRT301684 | EP300 | E1A binding protein p300 | ![]() |
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2 | 2 | ||||||
MIRT328627 | AKIRIN1 | akirin 1 | ![]() |
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2 | 2 | ||||||
MIRT340977 | IPO5 | importin 5 | ![]() |
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2 | 2 | ||||||
MIRT371401 | STC2 | stanniocalcin 2 | ![]() |
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2 | 2 | ||||||
MIRT378008 | TMED7 | transmembrane p24 trafficking protein 7 | ![]() |
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2 | 4 | ||||||
MIRT445185 | CCDC88C | coiled-coil domain containing 88C | ![]() |
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2 | 2 | ||||||
MIRT447120 | DUSP16 | dual specificity phosphatase 16 | ![]() |
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2 | 2 | ||||||
MIRT449153 | SORCS2 | sortilin related VPS10 domain containing receptor 2 | ![]() |
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2 | 2 | ||||||
MIRT450200 | ABHD15 | abhydrolase domain containing 15 | ![]() |
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2 | 2 | ||||||
MIRT453853 | ZNF12 | zinc finger protein 12 | ![]() |
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2 | 2 | ||||||
MIRT459077 | LSM1 | LSM1 homolog, mRNA degradation associated | ![]() |
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2 | 2 | ||||||
MIRT461304 | MRPS27 | mitochondrial ribosomal protein S27 | ![]() |
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2 | 2 | ||||||
MIRT464137 | VPS28 | VPS28, ESCRT-I subunit | ![]() |
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2 | 2 | ||||||
MIRT468114 | SH3PXD2A | SH3 and PX domains 2A | ![]() |
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2 | 2 | ||||||
MIRT471401 | PDP2 | pyruvate dehyrogenase phosphatase catalytic subunit 2 | ![]() |
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2 | 2 | ||||||
MIRT478220 | DDX52 | DExD-box helicase 52 | ![]() |
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2 | 2 | ||||||
MIRT479695 | CCNT1 | cyclin T1 | ![]() |
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2 | 2 | ||||||
MIRT479779 | CCND1 | cyclin D1 | ![]() |
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2 | 2 | ||||||
MIRT484980 | UBE2V1 | ubiquitin conjugating enzyme E2 V1 | ![]() |
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2 | 8 | ||||||
MIRT485016 | TMEM189-UBE2V1 | TMEM189-UBE2V1 readthrough | ![]() |
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2 | 8 | ||||||
MIRT485034 | TMEM189 | transmembrane protein 189 | ![]() |
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2 | 8 | ||||||
MIRT485221 | PRICKLE1 | prickle planar cell polarity protein 1 | ![]() |
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2 | 2 | ||||||
MIRT490143 | TERF2IP | TERF2 interacting protein | ![]() |
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2 | 6 | ||||||
MIRT508908 | DOK6 | docking protein 6 | ![]() |
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2 | 6 | ||||||
MIRT513877 | HNRNPUL1 | heterogeneous nuclear ribonucleoprotein U like 1 | ![]() |
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2 | 4 | ||||||
MIRT515966 | C9orf156 | tRNA methyltransferase O | ![]() |
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2 | 4 | ||||||
MIRT517892 | CHAF1B | chromatin assembly factor 1 subunit B | ![]() |
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2 | 4 | ||||||
MIRT518660 | CLVS2 | clavesin 2 | ![]() |
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2 | 4 | ||||||
MIRT520027 | YOD1 | YOD1 deubiquitinase | ![]() |
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2 | 6 | ||||||
MIRT523884 | EPHA5 | EPH receptor A5 | ![]() |
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2 | 4 | ||||||
MIRT529237 | PORCN | porcupine O-acyltransferase | ![]() |
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2 | 2 | ||||||
MIRT535337 | PFN1 | profilin 1 | ![]() |
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2 | 2 | ||||||
MIRT537532 | EZR | ezrin | ![]() |
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2 | 2 | ||||||
MIRT537695 | ELOVL6 | ELOVL fatty acid elongase 6 | ![]() |
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2 | 2 | ||||||
MIRT538494 | CLOCK | clock circadian regulator | ![]() |
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2 | 2 | ||||||
MIRT539140 | ARHGAP35 | Rho GTPase activating protein 35 | ![]() |
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2 | 2 | ||||||
MIRT541380 | CDKN1A | cyclin dependent kinase inhibitor 1A | ![]() |
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2 | 2 | ||||||
MIRT545018 | PLP1 | proteolipid protein 1 | ![]() |
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2 | 2 | ||||||
MIRT547732 | KIF23 | kinesin family member 23 | ![]() |
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2 | 4 | ||||||
MIRT548257 | FBXL20 | F-box and leucine rich repeat protein 20 | ![]() |
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2 | 2 | ||||||
MIRT550372 | MYLK3 | myosin light chain kinase 3 | ![]() |
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2 | 2 | ||||||
MIRT551867 | TMEM47 | transmembrane protein 47 | ![]() |
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2 | 2 | ||||||
MIRT552289 | SNAP29 | synaptosome associated protein 29 | ![]() |
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2 | 2 | ||||||
MIRT552902 | VSNL1 | visinin like 1 | ![]() |
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2 | 8 | ||||||
MIRT552990 | VAMP4 | vesicle associated membrane protein 4 | ![]() |
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2 | 4 | ||||||
MIRT554729 | RHOC | ras homolog family member C | ![]() |
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2 | 2 | ||||||
MIRT555301 | PPP3CB | protein phosphatase 3 catalytic subunit beta | ![]() |
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2 | 2 | ||||||
MIRT556832 | KATNAL1 | katanin catalytic subunit A1 like 1 | ![]() |
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2 | 2 | ||||||
MIRT557523 | GPBP1L1 | GC-rich promoter binding protein 1 like 1 | ![]() |
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2 | 2 | ||||||
MIRT558238 | EDA2R | ectodysplasin A2 receptor | ![]() |
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2 | 2 | ||||||
MIRT558920 | CBX1 | chromobox 1 | ![]() |
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2 | 2 | ||||||
MIRT559198 | BLOC1S6 | biogenesis of lysosomal organelles complex 1 subunit 6 | ![]() |
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2 | 2 | ||||||
MIRT559611 | AMER1 | APC membrane recruitment protein 1 | ![]() |
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2 | 2 | ||||||
MIRT559769 | URGCP-MRPS24 | URGCP-MRPS24 readthrough | ![]() |
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2 | 4 | ||||||
MIRT564648 | ZNF487P | zinc finger protein 487 | ![]() |
1 | 1 | |||||||
MIRT565856 | NHS | NHS actin remodeling regulator | ![]() |
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2 | 2 | ||||||
MIRT569044 | ZNF655 | zinc finger protein 655 | ![]() |
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2 | 2 | ||||||
MIRT569154 | SIGMAR1 | sigma non-opioid intracellular receptor 1 | ![]() |
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2 | 2 | ||||||
MIRT569166 | DMD | dystrophin | ![]() |
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2 | 2 | ||||||
MIRT569205 | CASZ1 | castor zinc finger 1 | ![]() |
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2 | 2 | ||||||
MIRT569264 | BRWD3 | bromodomain and WD repeat domain containing 3 | ![]() |
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2 | 2 | ||||||
MIRT569431 | FLVCR1 | feline leukemia virus subgroup C cellular receptor 1 | ![]() |
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2 | 2 | ||||||
MIRT569476 | CTSE | cathepsin E | ![]() |
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2 | 2 | ||||||
MIRT570232 | NCAN | neurocan | ![]() |
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2 | 2 | ||||||
MIRT570519 | SHH | sonic hedgehog | ![]() |
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2 | 2 | ||||||
MIRT570680 | FZD5 | frizzled class receptor 5 | ![]() |
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2 | 2 | ||||||
MIRT572161 | CRK | CRK proto-oncogene, adaptor protein | ![]() |
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2 | 2 | ||||||
MIRT575142 | Cd93 | CD93 antigen | ![]() |
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2 | 3 | ||||||
MIRT575644 | Mitf | microphthalmia-associated transcription factor | ![]() |
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2 | 3 | ||||||
MIRT575653 | Synpo | synaptopodin | ![]() |
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2 | 4 | ||||||
MIRT576375 | Runx1t1 | runt-related transcription factor 1; translocated to, 1 (cyclin D-related) | ![]() |
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2 | 2 | ||||||
MIRT576388 | Fhl2 | four and a half LIM domains 2 | ![]() |
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2 | 3 | ||||||
MIRT576413 | Pla2g16 | phospholipase A2, group XVI | ![]() |
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2 | 2 | ||||||
MIRT576697 | Hps3 | HPS3, biogenesis of lysosomal organelles complex 2 subunit 1 | ![]() |
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2 | 3 | ||||||
MIRT606872 | CHST11 | carbohydrate sulfotransferase 11 | ![]() |
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2 | 4 | ||||||
MIRT606940 | GFRA1 | GDNF family receptor alpha 1 | ![]() |
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2 | 6 | ||||||
MIRT607025 | ZEB1 | zinc finger E-box binding homeobox 1 | ![]() |
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2 | 2 | ||||||
MIRT607028 | PPY | pancreatic polypeptide | ![]() |
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2 | 4 | ||||||
MIRT607081 | MITF | melanogenesis associated transcription factor | ![]() |
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2 | 3 | ||||||
MIRT607769 | HS6ST3 | heparan sulfate 6-O-sulfotransferase 3 | ![]() |
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2 | 6 | ||||||
MIRT607881 | SATB1 | SATB homeobox 1 | ![]() |
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2 | 2 | ||||||
MIRT607996 | BTBD9 | BTB domain containing 9 | ![]() |
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2 | 2 | ||||||
MIRT608124 | TSC22D2 | TSC22 domain family member 2 | ![]() |
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2 | 2 | ||||||
MIRT608132 | TGFBR2 | transforming growth factor beta receptor 2 | ![]() |
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2 | 2 | ||||||
MIRT608209 | ADAT2 | adenosine deaminase, tRNA specific 2 | ![]() |
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2 | 2 | ||||||
MIRT608337 | SPN | sialophorin | ![]() |
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2 | 2 | ||||||
MIRT608416 | SYNPO | synaptopodin | ![]() |
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2 | 5 | ||||||
MIRT608459 | CD93 | CD93 molecule | ![]() |
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2 | 3 | ||||||
MIRT608555 | SBK1 | SH3 domain binding kinase 1 | ![]() |
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2 | 6 | ||||||
MIRT608585 | PPP2R1B | protein phosphatase 2 scaffold subunit Abeta | ![]() |
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2 | 4 | ||||||
MIRT608785 | JAKMIP2 | janus kinase and microtubule interacting protein 2 | ![]() |
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2 | 4 | ||||||
MIRT608791 | CDH12 | cadherin 12 | ![]() |
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2 | 2 | ||||||
MIRT608816 | ONECUT3 | one cut homeobox 3 | ![]() |
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2 | 6 | ||||||
MIRT608876 | CNTF | ciliary neurotrophic factor | ![]() |
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2 | 6 | ||||||
MIRT608881 | CLIC6 | chloride intracellular channel 6 | ![]() |
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2 | 2 | ||||||
MIRT608894 | ZNF860 | zinc finger protein 860 | ![]() |
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2 | 2 | ||||||
MIRT608954 | GIMAP1 | GTPase, IMAP family member 1 | ![]() |
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2 | 4 | ||||||
MIRT609007 | HPS3 | HPS3, biogenesis of lysosomal organelles complex 2 subunit 1 | ![]() |
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2 | 3 | ||||||
MIRT609045 | INVS | inversin | ![]() |
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2 | 4 | ||||||
MIRT619037 | CASS4 | Cas scaffolding protein family member 4 | ![]() |
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2 | 2 | ||||||
MIRT625226 | RPSAP58 | ribosomal protein SA pseudogene 58 | ![]() |
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2 | 4 | ||||||
MIRT625545 | GABRB2 | gamma-aminobutyric acid type A receptor beta2 subunit | ![]() |
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2 | 2 | ||||||
MIRT627333 | TTLL7 | tubulin tyrosine ligase like 7 | ![]() |
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2 | 2 | ||||||
MIRT627954 | NLK | nemo like kinase | ![]() |
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2 | 2 | ||||||
MIRT629280 | UNC13A | unc-13 homolog A | ![]() |
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2 | 2 | ||||||
MIRT634982 | TNFAIP8 | TNF alpha induced protein 8 | ![]() |
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2 | 2 | ||||||
MIRT646129 | C1orf147 | chromosome 1 open reading frame 147 | ![]() |
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2 | 2 | ||||||
MIRT646370 | SLC22A6 | solute carrier family 22 member 6 | ![]() |
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2 | 2 | ||||||
MIRT652743 | TGFA | transforming growth factor alpha | ![]() |
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2 | 4 | ||||||
MIRT653984 | SEMA6A | semaphorin 6A | ![]() |
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2 | 2 | ||||||
MIRT660038 | C15orf61 | chromosome 15 open reading frame 61 | ![]() |
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2 | 2 | ||||||
MIRT663504 | NKAPL | NFKB activating protein like | ![]() |
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2 | 4 | ||||||
MIRT667117 | OCIAD2 | OCIA domain containing 2 | ![]() |
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2 | 2 | ||||||
MIRT683747 | C3orf36 | chromosome 3 open reading frame 36 | ![]() |
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2 | 2 | ||||||
MIRT683922 | SLC43A3 | solute carrier family 43 member 3 | ![]() |
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2 | 2 | ||||||
MIRT684101 | LHFP | LHFPL tetraspan subfamily member 6 | ![]() |
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2 | 2 | ||||||
MIRT684224 | FGF14 | fibroblast growth factor 14 | ![]() |
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2 | 2 | ||||||
MIRT685560 | SRD5A3 | steroid 5 alpha-reductase 3 | ![]() |
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2 | 2 | ||||||
MIRT687408 | NRXN1 | neurexin 1 | ![]() |
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2 | 2 | ||||||
MIRT687467 | NHSL2 | NHS like 2 | ![]() |
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2 | 2 | ||||||
MIRT687695 | LEPREL1 | prolyl 3-hydroxylase 2 | ![]() |
1 | 1 | |||||||
MIRT688094 | GLRA3 | glycine receptor alpha 3 | ![]() |
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2 | 2 | ||||||
MIRT688255 | FHL2 | four and a half LIM domains 2 | ![]() |
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2 | 3 | ||||||
MIRT688851 | CAMKK2 | calcium/calmodulin dependent protein kinase kinase 2 | ![]() |
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2 | 2 | ||||||
MIRT700293 | RABGEF1 | RAB guanine nucleotide exchange factor 1 | ![]() |
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2 | 2 | ||||||
MIRT704679 | CHST2 | carbohydrate sulfotransferase 2 | ![]() |
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2 | 2 | ||||||
MIRT706392 | PPID | peptidylprolyl isomerase D | ![]() |
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2 | 2 | ||||||
MIRT707388 | SLC35F6 | solute carrier family 35 member F6 | ![]() |
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2 | 2 | ||||||
MIRT707509 | PPP1R16B | protein phosphatase 1 regulatory subunit 16B | ![]() |
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2 | 2 | ||||||
MIRT709808 | AR | androgen receptor | ![]() |
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2 | 2 | ||||||
MIRT715491 | MAZ | MYC associated zinc finger protein | ![]() |
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2 | 2 |
miRNA-Drug Resistance Associations | ||||||||||||||||||||||||||||||||||||||||
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