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

Cell Line, Tumor Cyclooxygenase 2 / genetics Drug Resistance, Neoplasm / drug effects Extracellular Signal-Regulated MAP Kinases / metabolism Gene Expression Regulation, Neoplastic / drug effects Humans Inflammation Mediators / metabolism Melanoma / drug therapy MicroRNAs / genetics Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors Models, Biological NF-kappa B / metabolism Protein Kinase Inhibitors / pharmacology Proto-Oncogene Proteins B-raf / antagonists & inhibitors Proto-Oncogene Proteins c-akt / metabolism Signal Transduction / drug effects

BRAF/MEK inhibitors COX2 Melanoma resistance miR-146a-5p microRNA

Journal

Cell communication and signaling : CCS

ISSN: 1478-811X

Titre abrégé: Cell Commun Signal

Pays: England

ID NLM: 101170464

Informations de publication

Date de publication:
23 09 2020

Historique:

received: 25 02 2020

accepted: 25 05 2020

entrez: 24 9 2020

pubmed: 25 9 2020

medline: 12 8 2021

Statut: epublish

Résumé

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. 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. 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. 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.

Sections du résumé

BACKGROUND

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.

Identifiants

DOI: 10.1186/s12964-020-00601-1 PMID: 32967672 PMC: PMC7510138

pubmed: 32967672

doi: 10.1186/s12964-020-00601-1

pii: 10.1186/s12964-020-00601-1

pmc: PMC7510138

doi:

Substances chimiques

Inflammation Mediators 0

MIRN146 microRNA, human 0

MicroRNAs 0

NF-kappa B 0

Protein Kinase Inhibitors 0

Cyclooxygenase 2 EC 1.14.99.1

Proto-Oncogene Proteins B-raf EC 2.7.11.1

Proto-Oncogene Proteins c-akt EC 2.7.11.1

Extracellular Signal-Regulated MAP Kinases EC 2.7.11.24

Mitogen-Activated Protein Kinase Kinases EC 2.7.12.2

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

156

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