Fig. 6.

Hypothesized role of miR-142-5p and miR-365a-3p in CML signaling. Schematic representation of the hypothesized effect of miR-142-5p and miR-365a-3p (indicated by red boxes) on CML linked pathways by targeting ABL2, cKIT, MCL1 and SRI (indicated by red circles). Ligands as EGFR, FGFR, PDGFR and SCF bind to cKIT and activate downstream signaling cascades, including RAS/RAF/MEK/ERK, PI3K/AKT and JAK2 [32–34]. In the RAS/RAF/MEK/ERK pathway [1], the GRB2/SOS complex activates a phosphorylation cascade that regulate proliferation and apoptosis[52]. PI3K/AKT pathway (2) is activated e.g. by growth factors and stimulates PI3K, mediating the conversion of PIP2 to PIP3. PIP3 translocates AKT to plasma membrane, where AKT regulates numerous proteins associated with proliferation, metabolism, apoptosis, including NFκB inducing inflammatory cytokines like IL-6[51, 88]. IL-6 activates the JAK/STAT pathway (3) where STAT translocates to nucleus, stimulating transcription of genes linked to cell proliferation, differentiation, survival and immune function as VEGF and BCL-2-family members like MCL1[43]. Upregulation of cKIT due to decreased miR-142-5p and miR-365a-3p expression might result in augmented proliferation, differentiation and survival. Downregulation of miR-142-5p might lead to upregulation of MCL1, facilitating cell survival. Both ABL1 and ABL2 stimulate RAC, Cortactin/N-WASP and WAVE/ABI1 (4) promoting migration and invasion through lamellipodia protrusion and actin/myosin filament contraction[24]. Downregulation of miR-142-5p would support metastasis through upregulation of ABL2. Sorcin regulates JAK/STAT, RAS/RAF/MEK/ERK, PI3K/AKT pathways and MMP expression, hence downregulation of miR-142-5p might increase sorcin and promote proliferation, differentiation, cell motility and survival[50, 62, 63]. Selection of miRNAs known to be linked to CML are illustrated in dashed boxes. MiR-29b-3p, miR-30a-5p, miR-30e-5p, miR-203-3p, miR-320a-3p, miR-424-5p, miR-451a and miR-23a-3p target BCR/ABL1, while miR-23a-3p, let-7b-5p and miR-130a-3p inhibit RAS [6, 7, 78]. MiR-130a-3p furthermore regulates BCL-2 and MCL1 expression [7]. Besides inhibiting BCL-2, miR-17/92 targets JAK2/STAT5 [7]. MiR-146a-5p and miR-150-5p contribute to CML carcinogenesis by upregulating MMPs [89]. Full gene names listed in Additional file 1: Table S3