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

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 non-treated 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.

Role of Autophagy and Apoptosis in Acute Lymphoblastic Leukemia

“…Overexpressing miR-331-3p inhibits MAP2K7 levels, leading to reverse the GC resistance in GC-resistant CCRF-CEM cell line. 82 MAP2K7 has been reported to enhance cancer cell proliferation, metastasis and progression. 83 , 84 Also miR-124 is abnormally expressed in cancers.…”

Anti-Leukemic Effects of Idesia polycarpa Maxim Branch on Human B-Cell Acute Lymphoblastic Leukemia Cells

“…One study found that miR-331-3p was specifically upregulated when methylprednisolone (MP), a glucocorticoid drug, was cotreated with rapamycin in a GC-resistant ALL cell line. This miR-331-3p targeted MAP2K7, which is an essential component of the JNK/MAPK pathway [32]. Another study suggests that long noncoding RNA, GAS5, levels in peripheral blood mononuclear cells (PBMCs) obtained from healthy donors are associated with responsiveness to MP; lower GAS5 levels were correlated with better responsiveness to MP.…”

MiRNAs in Hematopoiesis and Acute Lymphoblastic Leukemia

“…In ALL cell lines and prednisone-resistant patients’ samples, it was found that miR-124 and miR-331-3p were upregulated, potentially by repressing the glucocorticoids (GC) receptor expression and by the inhibition of the JNK/MAPK pathway [ 152 , 153 ]. By conducting a microarray analysis of ALL cases, it was found that miR-185-5p is overexpressed; furthermore, it was observed that its overexpression increases cell apoptosis and cycle arrest and decreases cell survival GC resistance cell line by targeting one component of the mammalian target of rapamycin complex, a pathway involved in several types of cancer and associated with GC resistance in hematological malignancies [ 154 ].…”