Back to Search
Start Over
miR-146a-5p impairs melanoma resistance to kinase inhibitors by targeting COX2 and regulating NFkB-mediated inflammatory mediators.
- Source :
-
Cell communication and signaling : CCS [Cell Commun Signal] 2020 Sep 23; Vol. 18 (1), pp. 156. Date of Electronic Publication: 2020 Sep 23. - Publication Year :
- 2020
-
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.<br />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.<br />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.<br />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.
- Subjects :
- Cell Line, Tumor
Cyclooxygenase 2 genetics
Extracellular Signal-Regulated MAP Kinases metabolism
Gene Expression Regulation, Neoplastic drug effects
Humans
Melanoma pathology
MicroRNAs genetics
Mitogen-Activated Protein Kinase Kinases antagonists & inhibitors
Mitogen-Activated Protein Kinase Kinases metabolism
Models, Biological
Protein Kinase Inhibitors pharmacology
Proto-Oncogene Proteins B-raf antagonists & inhibitors
Proto-Oncogene Proteins B-raf metabolism
Proto-Oncogene Proteins c-akt metabolism
Signal Transduction drug effects
Cyclooxygenase 2 metabolism
Drug Resistance, Neoplasm drug effects
Drug Resistance, Neoplasm genetics
Inflammation Mediators metabolism
Melanoma drug therapy
Melanoma genetics
MicroRNAs metabolism
NF-kappa B metabolism
Protein Kinase Inhibitors therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1478-811X
- Volume :
- 18
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Cell communication and signaling : CCS
- Publication Type :
- Academic Journal
- Accession number :
- 32967672
- Full Text :
- https://doi.org/10.1186/s12964-020-00601-1