Journal Article

miR-146a-5p impairs melanoma resistance to kinase inhibitors by targeting COX2 and regulating NFkB-mediated inflammatory mediators

Vergani, Elisabetta, Valeri, Barbara, Frigerio, Simona, Gargiuli, Chiara, Vallacchi, Viviana, Vergani, Barbara, Santinami, Mario, Ferrero, Elisabetta, Gallino, Gianfrancesco, Leone, Biagio Eugenio, Lalli, Luca, Shahaj, Eriomina, Dugo, Matteo, Gomez Lira, Macarena, Mattavelli, Ilaria, Huber, Veronica, Sensi, Marialuisa, Ferrarini, Marina, Di Guardo, Lorenza, Del Vecchio, Michele, Tamborini, Elena, Rivoltini, Licia, Cossa, Mara, Rodolfo, Monica

2020

Overview

Background Targeted therapy with BRAF and MEK inhibitors has improved the survival of patients with BRAF-mutated metastatic melanoma, but most patients relapse upon the onset of drug resistance induced by mechanisms including genetic and epigenetic events. Among the epigenetic alterations, microRNA perturbation is associated with the development of kinase inhibitor resistance. Here, we identified and studied the role of miR-146a-5p dysregulation in melanoma drug resistance. Methods The miR-146a-5p-regulated NFkB signaling network was identified in drug-resistant cell lines and melanoma tumor samples by expression profiling and knock-in and knock-out studies. A bioinformatic data analysis identified COX2 as a central gene regulated by miR-146a-5p and NFkB. The effects of miR-146a-5p/COX2 manipulation were studied in vitro in cell lines and with 3D cultures of treatment-resistant tumor explants from patients progressing during therapy. Results miR-146a-5p expression was inversely correlated with drug sensitivity and COX2 expression and was reduced in BRAF and MEK inhibitor-resistant melanoma cells and tissues. Forced miR-146a-5p expression reduced COX2 activity and significantly increased drug sensitivity by hampering prosurvival NFkB signaling, leading to reduced proliferation and enhanced apoptosis. Similar effects were obtained by inhibiting COX2 by celecoxib, a clinically approved COX2 inhibitor. Conclusions Deregulation of the miR-146a-5p/COX2 axis occurs in the development of melanoma resistance to targeted drugs in melanoma patients. This finding reveals novel targets for more effective combination treatment. 4ZiY3nqT8xQ_yvPXVejWjw Video Abstract Graphical Abstract

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Antibodies / Apoptosis / Biomedical and Life Sciences / BRAF/MEK inhibitors / Celecoxib / Cell adhesion & migration / Cell Biology / Cell growth / Chromosome 5 / COX2 / Cyclooxygenase-2 / Cytokines / Cytokines and Growth Factors / Drug development / Drug resistance / Enzyme inhibitors / Epigenetics / Explants / Gene expression / Immunoglobulins / Inflammation / Kinases / Life Sciences / Lung cancer / MEK inhibitors / Melanoma / Melanoma resistance / Metastases / Metastasis / microRNA / miR-146a-5p / miRNA / NF-κB protein / Protein-Ligand Interactions / Proteins / Reagents / Receptors / Software / Treatment resistance / Tumor cell lines