Explanation
This regulatory network was inferred from the input dataset. The miRNAs and mRNAs are
presented as round and rectangle nodes respectively. The numerical value popped up upon mouse over the gene node is the log2 transformed fold-change of the gene expression between the two groups. All of the nodes are clickable, and the detailed information of the miRNAs/mRNAs and related cancer pathway will be displayed in another window. The edges between nodes are supported by both interactions (predicted or experimentally verified) and correlations learnt from cancer dataset. The numerical value popped up upon mouse over the edge is the correlation beat value (effect size) between the two nodes. The experimental evidences of the edges reported in previous cancer studies are highlighted by red/orange color. All of these information can be accessed by the "mouse-over" action. This network shows a full map of the miRNA-mRNA regulation of the input gene list(s), and the hub miRNAs (with the high network degree/betweenness centrality) would be the potential cancer drivers or tumor suppressors. The full result table can be accessed in the "Regulations" tab.
"miRNACancerMAP" is also a network visualization tool for users to draw their regulatory network by personal customization. Users can set the complexity of the network by limiting the number of nodes or edges. And the color of the nodes can be defined by different categories of the mRNAs and miRNAs, such as Gene-Ontology, pathway, and expression status. Users can also select to use network degree or network betweenness centrality to define the node size. And edges can be black or colored by the correlation. Purple edge means negative correlation (mostly found between miRNA and mRNA), and blue edge means positive correlation (found in PPI or miRNA-miRNA sponge effect). We can also add the protein-protein interactions (PPI) into the network. This result will show the cluster of genes regulated by some specific miRNAs. Additionally, miRNA-miRNA edges can be added by the "miRNA sponge" button, presenting some clusters of miRNAs that have the interactions via sponge effect.
miRNA-gene regulations
| Num | microRNA | Gene | miRNA log2FC | miRNA pvalue | Gene log2FC | Gene pvalue | Interaction | Correlation beta | Correlation P-value | PMID | Reported in cancer studies |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | hsa-miR-21-5p | ACBD5 | 1.05 | 0 | -0.31 | 0 | miRNAWalker2 validate | -0.12 | 0 | NA | |
| 2 | hsa-miR-21-5p | ANKRD46 | 1.05 | 0 | -0.33 | 0 | miRNAWalker2 validate; miRTarBase | -0.21 | 0 | 21219636 | Knockdown of miR-21 significantly increased the expression of ANKRD46 at both mRNA and protein levels; ANKRD46 is newly identified as a direct target of miR-21 in BC |
| 3 | hsa-miR-21-5p | ASRGL1 | 1.05 | 0 | -0.32 | 0 | miRNAWalker2 validate | -0.2 | 0 | NA | |
| 4 | hsa-miR-21-5p | ATRX | 1.05 | 0 | 0 | 0.99249 | miRNAWalker2 validate | -0.11 | 5.0E-5 | NA | |
| 5 | hsa-miR-21-5p | AUTS2 | 1.05 | 0 | -0.06 | 0.29094 | miRNAWalker2 validate | -0.12 | 0 | NA | |
| 6 | hsa-miR-21-5p | BASP1 | 1.05 | 0 | -0.49 | 0 | miRNAWalker2 validate; miRTarBase | -0.28 | 0 | NA | |
| 7 | hsa-miR-21-5p | CLIP4 | 1.05 | 0 | -0.3 | 0 | miRNAWalker2 validate | -0.12 | 0 | NA | |
| 8 | hsa-miR-21-5p | CPEB3 | 1.05 | 0 | -0.56 | 0 | miRNAWalker2 validate | -0.27 | 0 | NA | |
| 9 | hsa-miR-21-5p | DUSP8 | 1.05 | 0 | -0.18 | 0.03829 | miRNAWalker2 validate | -0.22 | 0 | NA | |
| 10 | hsa-miR-21-5p | EDIL3 | 1.05 | 0 | -0.62 | 7.0E-5 | miRNAWalker2 validate | -0.12 | 0.01175 | NA | |
| 11 | hsa-miR-21-5p | EGFR | 1.05 | 0 | 0.38 | 0.01555 | miRNAWalker2 validate; miRTarBase | -0.12 | 0.01176 | 20113523; 24012640; 20048743; 24198203; 24331411; 26563758; 19597153; 26026961 | Thus the miR-21 inhibitor might interrupt the activity of EGFR pathways independently of PTEN status;Further the expression of miR-21 is regulated by EGFR via the activation of β-catenin and AP-1; These data indicate that a feedback loop exists between miR-21 and EGFR; These results clarify a novel association between miR-21 and EGFR in the regulation of cancer cell progression;Downregulation of miR 21 inhibits EGFR pathway and suppresses the growth of human glioblastoma cells independent of PTEN status;In radically resected NSCLC patients the expression levels of miR-21 10b in patients with EGFR mutation were much higher than those without mutation;MiR 21 overexpression is associated with acquired resistance of EGFR TKI in non small cell lung cancer;Higher expression levels of miR-21 AmiR-27a and miR-218 detected in this study suggest potential roles of these miRNAs in primary resistance to EGFR-TKI in advanced NSCLC patients with EGFR exon 19 deletion mutations;MiR 21 is an EGFR regulated anti apoptotic factor in lung cancer in never smokers; The changes in expression of some of these miRNAs including miR-21 were more remarkable in cases with EGFR mutations than in those without these mutations; In the never-smoker-derived lung adenocarcinoma cell line H3255 with mutant EGFR and high levels of p-EGFR and miR-21 antisense inhibition of miR-21 enhanced AG1478-induced apoptosis; In a never-smoker-derived adenocarcinoma cell line H441 with wild-type EGFR the antisense miR-21 not only showed the additive effect with AG1478 but also induced apoptosis by itself; These results suggest that aberrantly increased expression of miR-21 which is enhanced further by the activated EGFR signaling pathway plays a significant role in lung carcinogenesis in never-smokers as well as in smokers and is a potential therapeutic target in both EGFR-mutant and wild-type cases;Nickel may contribute to EGFR mutation and synergistically promotes tumor invasion in EGFR mutated lung cancer via nickel induced microRNA 21 expression |
| 12 | hsa-miR-21-5p | EIF4A2 | 1.05 | 0 | -0.23 | 0.00025 | miRNAWalker2 validate; miRTarBase | -0.11 | 0 | NA | |
| 13 | hsa-miR-21-5p | ELAVL4 | 1.05 | 0 | -0.64 | 4.0E-5 | miRNAWalker2 validate | -0.42 | 0 | NA | |
| 14 | hsa-miR-21-5p | ELOVL4 | 1.05 | 0 | -0.17 | 0.03111 | miRNAWalker2 validate | -0.18 | 0 | NA | |
| 15 | hsa-miR-21-5p | FAM126B | 1.05 | 0 | -0.2 | 0.0006 | miRNAWalker2 validate | -0.14 | 0 | NA | |
| 16 | hsa-miR-21-5p | FBXL17 | 1.05 | 0 | -0.23 | 1.0E-5 | miRNAWalker2 validate | -0.11 | 0 | NA | |
| 17 | hsa-miR-21-5p | FMR1 | 1.05 | 0 | -0.17 | 0.00018 | miRNAWalker2 validate | -0.11 | 0 | NA | |
| 18 | hsa-miR-21-5p | GLCCI1 | 1.05 | 0 | -0.08 | 0.35291 | miRNAWalker2 validate | -0.22 | 0 | NA | |
| 19 | hsa-miR-21-5p | GPAM | 1.05 | 0 | -0.34 | 0 | miRNAWalker2 validate | -0.14 | 0 | NA | |
| 20 | hsa-miR-21-5p | GPD1L | 1.05 | 0 | -0.28 | 5.0E-5 | miRNAWalker2 validate | -0.13 | 0 | NA | |
| 21 | hsa-miR-21-5p | HAPLN1 | 1.05 | 0 | -0.79 | 1.0E-5 | miRNAWalker2 validate | -0.58 | 0 | NA | |
| 22 | hsa-miR-21-5p | HMGB3 | 1.05 | 0 | 0.11 | 0.09319 | miRNAWalker2 validate | -0.12 | 0 | NA | |
| 23 | hsa-miR-10b-5p | IGSF1 | 1.55 | 0 | -0.94 | 0 | miRNAWalker2 validate | -0.12 | 0 | NA | |
| 24 | hsa-miR-10b-5p | IPCEF1 | 1.55 | 0 | -0.64 | 0 | miRNAWalker2 validate | -0.11 | 0 | NA | |
| 25 | hsa-miR-21-5p | JMY | 1.05 | 0 | -0.19 | 0.00012 | miRNAWalker2 validate | -0.11 | 0 | NA | |
| 26 | hsa-miR-21-5p | JPH1 | 1.05 | 0 | -0.32 | 0.03054 | miRNAWalker2 validate | -0.11 | 0.01494 | NA | |
| 27 | hsa-miR-21-5p | KBTBD6 | 1.05 | 0 | -0.24 | 4.0E-5 | miRNAWalker2 validate | -0.18 | 0 | NA | |
| 28 | hsa-miR-21-5p | KBTBD7 | 1.05 | 0 | -0.29 | 0.00056 | miRNAWalker2 validate | -0.2 | 0 | NA | |
| 29 | hsa-miR-21-5p | LIFR | 1.05 | 0 | -0.39 | 3.0E-5 | miRNAWalker2 validate | -0.13 | 0 | NA | |
| 30 | hsa-miR-21-5p | LONRF2 | 1.05 | 0 | -0.34 | 0.00012 | miRNAWalker2 validate | -0.19 | 0 | NA | |
| 31 | hsa-miR-21-5p | LYRM7 | 1.05 | 0 | -0.12 | 0.01808 | miRNAWalker2 validate | -0.13 | 0 | NA | |
| 32 | hsa-miR-21-5p | MARCKS | 1.05 | 0 | -0.11 | 0.19006 | miRNAWalker2 validate; miRTarBase | -0.14 | 0 | 19302977 | MicroRNA 21 directly targets MARCKS and promotes apoptosis resistance and invasion in prostate cancer cells |
| 33 | hsa-miR-21-5p | MIB1 | 1.05 | 0 | -0.2 | 0.00153 | miRNAWalker2 validate | -0.12 | 0 | NA | |
| 34 | hsa-miR-21-5p | MOAP1 | 1.05 | 0 | -0.37 | 0 | miRNAWalker2 validate | -0.21 | 0 | NA | |
| 35 | hsa-miR-21-5p | MRAP2 | 1.05 | 0 | -0.13 | 0.49478 | miRNAWalker2 validate | -0.18 | 0.00191 | NA | |
| 36 | hsa-miR-21-5p | MTMR9 | 1.05 | 0 | -0.21 | 0.00012 | miRNAWalker2 validate | -0.13 | 0 | NA | |
| 37 | hsa-miR-21-5p | MYCBP2 | 1.05 | 0 | -0.35 | 0 | miRNAWalker2 validate | -0.16 | 0 | NA | |
| 38 | hsa-miR-21-5p | NBEA | 1.05 | 0 | -0.37 | 1.0E-5 | miRNAWalker2 validate | -0.24 | 0 | NA | |
| 39 | hsa-miR-21-5p | NFIB | 1.05 | 0 | -0.15 | 0.02989 | miRNAWalker2 validate; miRTarBase | -0.14 | 0 | NA | |
| 40 | hsa-miR-21-5p | PER3 | 1.05 | 0 | -0.56 | 0 | miRNAWalker2 validate | -0.16 | 0 | NA | |
| 41 | hsa-miR-21-5p | PIK3R1 | 1.05 | 0 | -0.26 | 0.00107 | miRNAWalker2 validate | -0.19 | 0 | 26676464 | PIK3R1 targeting by miR 21 suppresses tumor cell migration and invasion by reducing PI3K/AKT signaling and reversing EMT and predicts clinical outcome of breast cancer; Next we identified the PIK3R1 as a direct target of miR-21 and showed that it was negatively regulated by miR-21; Taken together we provide novel evidence that miR-21 knockdown suppresses cell growth migration and invasion partly by inhibiting PI3K/AKT activation via direct targeting PIK3R1 and reversing EMT in breast cancer |
| 42 | hsa-miR-21-5p | PPARA | 1.05 | 0 | -0.34 | 0 | miRNAWalker2 validate; miRTarBase | -0.11 | 0 | 22244963 | In the final integrative analysis of lung cancer related miR-21-targets analysis 24 hub genes were identified by overlap calculation suggesting that miR-21 may play an important role in the development and progression of lung cancer through JAK/STAT signal pathway MAPK signaling pathway Wnt signaling pathway cell cycle PPAR signaling pathway apoptosis pathway and other pathways |
| 43 | hsa-miR-21-5p | PPFIA4 | 1.05 | 0 | -0.31 | 0.00328 | miRNAWalker2 validate | -0.21 | 0 | NA | |
| 44 | hsa-miR-21-5p | PPIF | 1.05 | 0 | -0.14 | 0.07484 | miRNAWalker2 validate | -0.1 | 0 | NA | |
| 45 | hsa-miR-21-5p | PPM1L | 1.05 | 0 | -0.49 | 1.0E-5 | miRNAWalker2 validate | -0.2 | 0 | NA | |
| 46 | hsa-miR-21-5p | PRKCE | 1.05 | 0 | -0.44 | 0 | miRNAWalker2 validate | -0.25 | 0 | NA | |
| 47 | hsa-miR-21-5p | PTGFR | 1.05 | 0 | -0.54 | 0.00098 | miRNAWalker2 validate | -0.28 | 0 | NA | |
| 48 | hsa-miR-10b-5p | PTPRT | 1.55 | 0 | -1.27 | 0 | miRNAWalker2 validate | -0.18 | 0 | NA | |
| 49 | hsa-miR-21-5p | RAB11FIP2 | 1.05 | 0 | -0.29 | 0 | miRNAWalker2 validate | -0.14 | 0 | NA | |
| 50 | hsa-miR-21-5p | RASGRP1 | 1.05 | 0 | -0.46 | 0.0001 | miRNAWalker2 validate; miRTarBase | -0.21 | 0 | NA | |
| 51 | hsa-miR-21-5p | RUFY3 | 1.05 | 0 | -0.26 | 4.0E-5 | miRNAWalker2 validate | -0.12 | 0 | NA | |
| 52 | hsa-miR-21-5p | SAMD5 | 1.05 | 0 | -0.31 | 0.00676 | miRNAWalker2 validate | -0.18 | 0 | NA | |
| 53 | hsa-miR-21-5p | SASH1 | 1.05 | 0 | -0.34 | 0 | miRNAWalker2 validate | -0.16 | 0 | NA | |
| 54 | hsa-miR-21-5p | SERPINI1 | 1.05 | 0 | -0.81 | 0 | miRNAWalker2 validate | -0.29 | 0 | 22464652 | MicroRNA 21 inhibits Serpini1 a gene with novel tumour suppressive effects in gastric cancer; Molecular techniques include microRNA microarrays cDNA microarrays qRT-PCR for miR and mRNA expression transfection of MKN28 with miR-21 inhibitor or Serpini1 followed by Western blotting cell cycle analysis by flow cytometry and luciferase reporter assay; This search identified Serpini1 as a putative miR-21 target; Luciferase assays demonstrated direct interaction between miR-21 and Serpini1 3'UTR miR-21 and Serpini1 expression levels were inversely correlated in a subgroup of gastric cancers suggesting a regulatory mechanism that included both of these molecules; Taken together these data suggest that in a subgroup of gastric cancers miR-21 is upregulated inducing downregulation of Serpini1 which in turn releases the G1-S transition checkpoint with the end result being increased tumour growth |
| 55 | hsa-miR-21-5p | SFXN1 | 1.05 | 0 | -0.11 | 0.02885 | miRNAWalker2 validate | -0.11 | 0 | NA | |
| 56 | hsa-miR-21-5p | SLC9A6 | 1.05 | 0 | -0.36 | 0 | miRNAWalker2 validate | -0.17 | 0 | NA | |
| 57 | hsa-miR-21-5p | SMAD7 | 1.05 | 0 | -0.31 | 0 | miRNAWalker2 validate | -0.13 | 0 | 23372687; 27185036; 26531758 | Furthermore the expression of MSH2 and SMAD7 two important molecules involving TGF-β pathway was restored following miR-21 knockdown in both MCF-7 and Hs578T breast cancer cells;MicroRNA 21 Regulates Non Small Cell Lung Cancer Cell Invasion and Chemo Sensitivity through SMAD7; We performed bioinformatics analyses on the binding of microRNA-21 miR-21 to the 3'-UTR of SMAD7 mRNA and verified the biological effects of this binding using promoter luciferase reporter assay; Furthermore expression of miR-21 was found to be inhibited by Carboplatin and bioinformatics analyses showed that miR-21 targeted the 3'-UTR of SMAD7 mRNA to inhibit its translation which was confirmed by luciferase reporter assay; Carboplatin may upregulate SMAD7 through suppression of miR-21 to inhibit TGFβ receptor signaling mediated NSCLC cell invasion;MicroRNA 21 induces breast cancer cell invasion and migration by suppressing smad7 via EGF and TGF β pathways; The present study was undertaken to determine the association of miR-21 smad7 EGF and TGF-β with breast cancer cell invasion and migration and to identify the molecular mechanisms involved using immunohistochemistry and western blot analysis; Smad7 was confirmed to be a direct target of miR-21 by luciferase reporter and western blot assays; The downregulation of smad7 by miR-21 or sismad7 enhanced EGF-dependent invasion and migration as well as TGF-β-dependent invasion and migration; The actions of miR-21 were abrogated by expressing a modified smad7 cDNA resistant to miR-21; In conclusion our results demonstrated that plasma miR-21 levels may serve as a diagnostic marker in breast cancers whereas miR-21 promotes breast cancer cell proliferation and invasion by suppressing smad7 which enhances EGF and TGF-β pathways |
| 58 | hsa-miR-21-5p | STXBP5 | 1.05 | 0 | -0.33 | 0.00029 | miRNAWalker2 validate | -0.21 | 0 | NA | |
| 59 | hsa-miR-21-5p | TET1 | 1.05 | 0 | -0.33 | 0.00035 | miRNAWalker2 validate | -0.28 | 0 | NA | |
| 60 | hsa-miR-21-5p | TMEM56 | 1.05 | 0 | -0.73 | 0 | miRNAWalker2 validate | -0.19 | 0 | NA | |
| 61 | hsa-miR-21-5p | TNRC6B | 1.05 | 0 | -0.14 | 0.00667 | miRNAWalker2 validate | -0.11 | 0 | NA | |
| 62 | hsa-miR-21-5p | TRAPPC2 | 1.05 | 0 | -0.12 | 0.01017 | miRNAWalker2 validate | -0.11 | 0 | NA | |
| 63 | hsa-miR-21-5p | TRIM2 | 1.05 | 0 | -0.34 | 0 | miRNAWalker2 validate | -0.13 | 0 | NA | |
| 64 | hsa-miR-21-5p | TTC33 | 1.05 | 0 | -0.23 | 0 | miRNAWalker2 validate | -0.13 | 0 | NA | |
| 65 | hsa-miR-21-5p | VASH2 | 1.05 | 0 | 0.28 | 0.01096 | miRNAWalker2 validate | -0.19 | 0 | NA | |
| 66 | hsa-miR-21-5p | ZADH2 | 1.05 | 0 | -0.19 | 7.0E-5 | miRNAWalker2 validate | -0.11 | 0 | NA | |
| 67 | hsa-miR-21-5p | ZBTB20 | 1.05 | 0 | -0.07 | 0.51891 | miRNAWalker2 validate | -0.11 | 0.00084 | NA | |
| 68 | hsa-miR-21-5p | ZBTB47 | 1.05 | 0 | -0.33 | 0 | miRNAWalker2 validate | -0.16 | 0 | NA | |
| 69 | hsa-miR-21-5p | ZNF292 | 1.05 | 0 | -0.1 | 0.09652 | miRNAWalker2 validate | -0.12 | 0 | NA | |
| 70 | hsa-miR-21-5p | ZRANB1 | 1.05 | 0 | -0.33 | 0 | miRNAWalker2 validate | -0.15 | 0 | NA |
| Num | GO | Overlap | Size | P Value | Adj. P Value |
|---|
| Num | GO | Overlap | Size | P Value | Adj. P Value |
|---|
| Num | GO | Overlap | Size | P Value | Adj. P Value |
|---|
Over-represented Pathway
| Num | Pathway | Pathview | Overlap | Size | P Value | Adj. P Value |
|---|---|---|---|---|---|---|
| 1 | Phospholipase_D_signaling_pathway_hsa04072 | 3 | 146 | 0.01461 | 0.4159 | |
| 2 | Jak_STAT_signaling_pathway_hsa04630 | 3 | 162 | 0.01922 | 0.4159 | |
| 3 | Calcium_signaling_pathway_hsa04020 | 3 | 182 | 0.02601 | 0.4159 | |
| 4 | ErbB_signaling_pathway_hsa04012 | 2 | 85 | 0.03578 | 0.4159 | |
| 5 | Ras_signaling_pathway_hsa04014 | 3 | 232 | 0.04784 | 0.4159 | |
| 6 | HIF_1_signaling_pathway_hsa04066 | 2 | 100 | 0.04799 | 0.4159 | |
| 7 | Sphingolipid_signaling_pathway_hsa04071 | 2 | 118 | 0.06431 | 0.4437 | |
| 8 | FoxO_signaling_pathway_hsa04068 | 2 | 132 | 0.07811 | 0.4437 | |
| 9 | MAPK_signaling_pathway_hsa04010 | 3 | 295 | 0.08468 | 0.4437 | |
| 10 | Signaling_pathways_regulating_pluripotency_of_stem_cells_hsa04550 | 2 | 139 | 0.08533 | 0.4437 | |
| 11 | cGMP_PKG_signaling_pathway_hsa04022 | 2 | 163 | 0.1115 | 0.5269 | |
| 12 | cAMP_signaling_pathway_hsa04024 | 2 | 198 | 0.1526 | 0.5717 | |
| 13 | Focal_adhesion_hsa04510 | 2 | 199 | 0.1539 | 0.5717 | |
| 14 | Rap1_signaling_pathway_hsa04015 | 2 | 206 | 0.1624 | 0.5717 | |
| 15 | Regulation_of_actin_cytoskeleton_hsa04810 | 2 | 208 | 0.1649 | 0.5717 | |
| 16 | Endocytosis_hsa04144 | 2 | 244 | 0.2103 | 0.6433 | |
| 17 | Cytokine_cytokine_receptor_interaction_hsa04060 | 2 | 270 | 0.2438 | 0.6586 | |
| 18 | PI3K_Akt_signaling_pathway_hsa04151 | 2 | 352 | 0.3498 | 0.6897 |
