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. 2020 Feb 7;7(2):e673. doi: 10.1212/NXI.0000000000000673

Figure 5. Predicted signaling pathways (SiPas) and genes targeted by dysregulated CSF miRNAs in MS.

Figure 5

(A) Top enriched canonical pathways associated with the differentially expressed CSF miRNAs between each subgroup (Rel/Rem [orange bars], Rel/SC [blue bars], or Rem/SC [yellow bars]) are illustrated. Indicated pathways were found by performing Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis using the miRNet, mirPath, or Cytoscape stringApp databases. The columns on the left side of the graph indicate the number of databases from which a determined pathway was retrieved. The pathways retrieved by specific databases are indicated by the aforementioned color code (a void line indicates that a pathway was not found in the database from the corresponding column). On the right side, results are expressed as mean ± standard error of the enrichment score (−log10 of adjusted p value) obtained from the 3 databases, giving a score for the relative weight of a given SiPa between experimental subgroups; the dotted line designates the threshold of 1.3 (representing p value at 0.05). We identified SiPas consistent with MS pathogenesis such as cell cycle or apoptosis (Insulin, mTOR, Wnt, and ErbB SiPas with the following gene targets: MYC, CCND1, LMNB2, CDKN1A, MDM2, E2F3, TP53, NRAS, WEE1, MKNK2, BTG2, PMAIP1, TAOK1, DDI2, and NUFIP2), immunoregulation (TNF-α, NF-κB, TGF-β, FoxO SiPas, and gene targets: SMAD4, NFAT5, SP1, MYC, CCND1, SLC1A5, STAT3, BCL2, and XIAP), neuroprotective and neurodegenerative processes (axon guidance, ErbB, and neurotrophin SiPas with BCL2, TP53, VEGFA, EGFR, ZBTB18, PLAGL2, and TOR1AIP2 as targeted genes), and cancer-related SiPas (only glioma and myeloid leukemia were selected). (B) Cytoscape network representation of interactions between the 18 MS-associated miRNAs in the CSF and a panel of targeted genes extracted from the miRNet database. The resulting network comprises 47 nodes (the 18 dysregulated miRNAs with the 29 most represented genes) and 176 direct edges. The color code refers to the sets of miRNAs according to their differential expression across subgroups, as in A. miRNA = microRNA; NF-κB = nuclear factor kappa-light-chain-enhancer of activated B; Rel = relapsing MS; Rem = remitting MS; SC = symptomatic control TGF-β = transforming growth factor beta; TNF-α = tumor necrosis factor alpha.