miR-146a-5p impairs melanoma resistance to kinase inhibitors by targeting COX2 and regulating NFkB-mediated inflammatory
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(2020) 18:156
RESEARCH
Open Access
miR-146a-5p impairs melanoma resistance to kinase inhibitors by targeting COX2 and regulating NFkB-mediated inflammatory mediators Elisabetta Vergani1†, Matteo Dugo2†, Mara Cossa3†, Simona Frigerio1, Lorenza Di Guardo4, Gianfrancesco Gallino5, Ilaria Mattavelli5, Barbara Vergani6, Luca Lalli1, Elena Tamborini3, Barbara Valeri3, Chiara Gargiuli2, Eriomina Shahaj1, Marina Ferrarini7, Elisabetta Ferrero7, Macarena Gomez Lira8, Veronica Huber1, Michele Del Vecchio4, Marialuisa Sensi2, Biagio Eugenio Leone6, Mario Santinami5, Licia Rivoltini1, Monica Rodolfo1† and Viviana Vallacchi1*†
Abstract Background: Targeted therapy with BRAF and MEK inhibitors has improved the survival of patients with BRAFmutated 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. Keywords: Melanoma resistance, BRAF/MEK inhibitors, microRNA, miR-146a-5p, COX2
* Correspondence: [email protected] † Elisabetta Vergani, Matteo Dugo and Mara Cossa are co-first authors. Monica Rodolfo and Viviana Vallacchi are co-last authors. 1 Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creativ
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