miR-331-3p is involved in glucocorticoid resistance reversion by rapamycin through suppression of the MAPK signaling pat
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ORIGINAL ARTICLE
miR‑331‑3p is involved in glucocorticoid resistance reversion by rapamycin through suppression of the MAPK signaling pathway Marianna Lucafò1 · Daria Sicari2,3 · Andrea Chicco4 · Debora Curci5 · Arianna Bellazzo6 · Alessia Di Silvestre5 · Chiara Pegolo6 · Robert Autry7 · Erika Cecchin8 · Sara De Iudicibus1 · Licio Collavin6 · William Evans7 · Giuliana Decorti1,4 · Gabriele Stocco6 Received: 12 December 2019 / Accepted: 3 August 2020 © The Author(s) 2020
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 the molecular mechanism involved in this synergistic effect has not been fully defined. In this context, we explored the differential miRNA expression in a GC-resistant CCRF-CEM cell line after treatment with rapamycin alone or in co-treatment with methylprednisolone (MP). The expression analysis identified 70, 99 and 96 miRNAs that were differentially expressed after treatment with MP, rapamycin and their combination compared to nontreated controls, respectively. Two pathways were exclusively altered as a result of the co-treatment: the MAPK and ErbB pathways. We validated the only miRNA upregulated specifically by the co-treatment associated with the MAPK signaling, miR-331-3p. Looking for miR-331-3p targets, MAP2K7, an essential component of the JNK/MAPK pathway, was identified. Interestingly, MAP2K7 expression was downregulated during the co-treatment, causing a decrease in terms of JNK activity. miR-331-3p in mimic-transfected cells led to a significant decrease in MAP2K7 levels and promoted the reversion of GC resistance in vitro. Interestingly, miR-331-3p expression was also associated with GC-resistance in patient leukemia cells taken at diagnosis. The combination of rapamycin with MP restores GC effectiveness through the regulation of different miRNAs, suggesting the important role of these pharmacoepigenetic factors in GC response. Keywords Glucocorticoids · Rapamycin · miRNA · Pharmacoepigenetics
Introduction
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00280-020-04122-z) contains supplementary material, which is available to authorized users. * Giuliana Decorti [email protected] 1
Institute for Maternal and Child Health, IRCCS “Burlo Garofolo”, Trieste, Italy
2
National Laboratory CIB (LNCIB), AREA Science Park, Trieste, Italy
3
Chemistry, Oncogenesis, Stress, Signaling (COSS), CLCC Eugene Marquis Inserm U1242, University of Rennes-1, Rennes, France
4
Department of Medicine, Surgery and Health Sciences, University of Trieste, Strada di Fiume 447, 34149 Trieste, Italy
Synthetic glucocorticoids (GCs), such as dexamethasone and methylprednisolone (MP), are commonly used in the treatment of inflammatory and immune diseases, leukemia 5
PhD School in Science of Reproduction an
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