| Autor: |
Elisabetta Vergani, Matteo Dugo, Mara Cossa, Simona Frigerio, Lorenza Di Guardo, Gianfrancesco Gallino, Ilaria Mattavelli, Barbara Vergani, Luca Lalli, Elena Tamborini, Barbara Valeri, Chiara Gargiuli, Eriomina Shahaj, Marina Ferrarini, Elisabetta Ferrero, Macarena Gomez Lira, Veronica Huber, Michele Del Vecchio, Marialuisa Sensi, Biagio Eugenio Leone, Mario Santinami, Licia Rivoltini, Monica Rodolfo, Viviana Vallacchi |
| Jazyk: |
angličtina |
| Rok vydání: |
2020 |
| Předmět: |
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| Zdroj: |
Cell Communication and Signaling, Vol 18, Iss 1, Pp 1-14 (2020) |
| Druh dokumentu: |
article |
| ISSN: |
1478-811X |
| DOI: |
10.1186/s12964-020-00601-1 |
| Popis: |
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 Graphical Abstract |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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