@article{65bdebe6d7474e6ba2d720221fca9ecc,
title = "MicroRNA-211 Modulates the DUSP6-ERK5 Signaling Axis to Promote BRAFV600E-Driven Melanoma Growth In Vivo and BRAF/MEK Inhibitor Resistance",
abstract = "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.",
author = "Bongyong Lee and Anupama Sahoo and Junko Sawada and John Marchica and Sanjay Sahoo and Layng, {Fabiana I.A.L.} and Darren Finlay and Joseph Mazar and Piyush Joshi and Masanobu Komatsu and Kristiina Vuori and {de Jong}, {Petrus R.} and Animesh Ray and Perera, {Ranjan J.}",
note = "Funding Information: We thank Jeffrey M. Trent (Translational Genomics Institute, Phoenix, AZ), who originally provided the 33 UACC cell lines, and Neal Rosen (Memorial Sloan Kettering Cancer Center, New York, NY), who provided the five SK-MEL and MeWo cell lines. This work was supported by National Institutes of Health grants (R21CA202197, CA165184, National Cancer Institute 5P30CA030199 [SBP], P30 CA006973 [Johns Hopkins University-Sidney Kimmel Comprehensive Cancer Center) and Florida Department of Health, Bankhead-Coley Cancer Research Program (5BC08) to RJP. Conceptualization: RJP, AR, BL; Data Curation: BL; Formal Analysis: BL, PRDJ; Funding Acquisition: RJP; Investigation: BL, AS, JS, JM, SS, FIALL, DF, JM, PJ, MK, PRDJ; Methodology: BL; Project Administration: RJP; Resources: KV; Supervision: RJP; Validation: BL, AS, SS, RJP; Visualization: BL, PJ, RJP; Writing - Original Draft Preparation: BL, RJP; Writing - Review and Editing: RJP, BL, AR Funding Information: We thank Jeffrey M. Trent (Translational Genomics Institute, Phoenix, AZ), who originally provided the 33 UACC cell lines, and Neal Rosen (Memorial Sloan Kettering Cancer Center, New York, NY), who provided the five SK-MEL and MeWo cell lines. This work was supported by National Institutes of Health grants (R21CA202197, CA165184, National Cancer Institute 5P30CA030199 [ SBP ], P30 CA006973 [Johns Hopkins University- Sidney Kimmel Comprehensive Cancer Center ) and Florida Department of Health , Bankhead-Coley Cancer Research Program (5BC08) to RJP. ",
year = "2021",
month = feb,
doi = "10.1016/j.jid.2020.06.038",
language = "English (US)",
volume = "141",
pages = "385--394",
journal = "Journal of Investigative Dermatology",
issn = "0022-202X",
publisher = "Nature Publishing Group",
number = "2",
}