Dataset Information

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

ABSTRACT:

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. Video Abstract.

SUBMITTER: Vergani E

PROVIDER: S-EPMC7510138 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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

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

Cell communication and signaling : CCS 20200923 1

<h4>Background</h4>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.<h4>Methods</h ...[more]

PMID: 32967672

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