MicroRNA-211 Modulates the DUSP6-ERK5 Signaling Axis to Promote BRAFV600E-Driven Melanoma Growth In Vivo and BRAF/MEK Inhibitor Resistance
In: Journal of Investigative Dermatology, Jg. 141 (2021-02-01), S. 385-394
Online
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Zugriff:
MicroRNAs (miRs) are important posttranscriptional regulators of cell fate in both normal and disease states. miR-211 has previously been shown to be a direct regulator of metabolism in BRAFV600E-mutant melanoma cells in vitro. Here, we report that miR-211 expression promotes the aggressive growth of BRAFV600E-mutant melanoma xenografts in vivo. miR-211 promoted proliferation through the posttranscriptional activation of extracellular signal–regulated kinase (ERK) 5 signaling, which has recently been implicated in the resistance to BRAF and MAPK/ERK kinase inhibitors. We therefore examined whether miR-211 similarly modulated melanoma resistance to the BRAF inhibitor vemurafenib and the MAPK/ERK kinase inhibitor cobimetinib. Consistent with this model, miR-211 expression increased melanoma cell resistance to both the inhibitors, and this resistance was associated with an increased ERK5 phosphorylation. miR-211 mediates these effects by directly inhibiting the expression of DUSP6, an ERK5 pathway–specific phosphatase and now shown to be an miR-211 target gene. These results dissect the role of the miR-211–DUSP6-ERK5 axis in melanoma tumor growth and suggest a mechanism for the development of drug-resistant tumors and a target for overcoming resistance.
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MicroRNA-211 Modulates the DUSP6-ERK5 Signaling Axis to Promote BRAFV600E-Driven Melanoma Growth In Vivo and BRAF/MEK Inhibitor Resistance
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Autor/in / Beteiligte Person: | Vuori, Kristiina ; Finlay, Darren ; Ray, Animesh ; Komatsu, Masanobu ; Sahoo, Anupama ; Perera, Ranjan J. ; Marchica, John ; Joshi, Piyush ; Lee, Bongyong ; Petrus R. de Jong ; Fabiana I.A.L. Layng ; Sawada, Junko ; Mazar, Joseph ; Sahoo, Sanjay |
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Zeitschrift: | Journal of Investigative Dermatology, Jg. 141 (2021-02-01), S. 385-394 |
Veröffentlichung: | Elsevier BV, 2021 |
Medientyp: | unknown |
ISSN: | 0022-202X (print) |
DOI: | 10.1016/j.jid.2020.06.038 |
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