miR-331-3p is involved in glucocorticoid resistance reversion by rapamycin through suppression of the MAPK signaling pathway

• DOI: 10.1007/s00280-020-04122-z
• Publication Date: 2020-08-10T11:02:50Z
• Authors: Marianna Lucafò; Daria Sicari; Andrea Chicco; Debora Curci; Arianna Bellazzo; Alessia Di Silvestre; Chiara Pegolo; Robert Autry; Erika Cecchin; Sara De Iudicibus; Licio Collavin; William Evans; Giuliana Decorti; Gabriele Stocco
• Keywords: 0301 basic medicine; Apoptosis; 03 medical and health sciences; Glucocorticoids; miRNA; Pharmacoepigenetics; Rapamycin; Glucocorticoid; Biomarkers, Tumor; Tumor Cells, Cultured; Humans; Rapamycin; Glucocorticoids; miRNA; Cell Proliferation; Sirolimus; 0303 health sciences; Antibiotics, Antineoplastic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; 3. Good health; Pharmacoepigenetic; Gene Expression Regulation, Neoplastic; MicroRNAs; Pharmacoepigenetics; Drug Resistance, Neoplasm; [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology; Original Article; Mitogen-Activated Protein Kinases

Abstract Glucocorticoids (GCs) are commonly used as therapeutic agents for immune-mediated diseases and leukemia. However, considerable inter-individual differences in efficacy have been reported. Several reports indicate that the inhibitor of mTOR rapamycin can reverse GC resistance, but molecular mechanism involved this synergistic effect has not fully defined. In context, we explored differential miRNA expression a GC-resistant CCRF-CEM cell line after treatment with alone or co-treatment methylprednisolone (MP). The analysis identified 70, 99 96 miRNAs were differentially expressed MP, their combination compared to non-treated controls, respectively. Two pathways exclusively altered result co-treatment: MAPK ErbB pathways. We validated only upregulated specifically by associated signaling, miR-331-3p. Looking miR-331-3p targets, MAP2K7, an essential component JNK/MAPK pathway, was identified. Interestingly, MAP2K7 downregulated during co-treatment, causing decrease terms JNK activity. mimic-transfected cells led significant levels promoted reversion resistance vitro. also GC-resistance patient leukemia taken at diagnosis. MP restores effectiveness through regulation different miRNAs, suggesting important role these pharmacoepigenetic factors response.