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BRAF(V600) inhibition alters the microRNA cargo in the vesicular secretome of malignant melanoma cells

Title
BRAF(V600) inhibition alters the microRNA cargo in the vesicular secretome of malignant melanoma cells
Authors
Lunavat, Taral R.Cheng, LesleyEinarsdottir, Berglind O.Bagge, Roger OlofssonMuralidharan, Somsundar VeppilSharples, Robyn A.Lasser, CeciliaGho, Yong SongHill, Andrew F.Nilsson, Jonas A.Lotvall, Jan
POSTECH Authors
Gho, Yong Song
Date Issued
Jul-2017
Publisher
NATL ACAD SCIENCES
Abstract
The BRAF inhibitors vemurafenib and dabrafenib can be used to treat patients with metastatic melanomas harboring BRAF(V600) mutations. Initial antitumoral responses are often seen, but drug-resistant clones with reactivation of the MEK-ERK pathway soon appear. Recently, the secretome of tumor-derived extracellular vesicles (EVs) has been ascribed important functions in cancers. To elucidate the possible functions of EVs in BRAF-mutant melanoma, we determined the RNA content of the EVs, including apoptotic bodies, microvesicles, and exosomes, released from such cancer cells after vemurafenib treatment. We found that vemurafenib significantly increased the total RNA and protein content of the released EVs and caused significant changes in the RNA profiles. RNA sequencing and quantitative PCR show that cells and EVs from vemurafenib-treated cell cultures and tumor tissues harvested from cell-derived and patient-derived xenografts harbor unique miRNAs, especially increased expression of miR-211-5p. Mechanistically, the expression of miR-211-5p as a result of BRAF inhibition was induced by increased expression of MITF that regulates the TRPM1 gene resulting in activation of the survival pathway. In addition, transfection of miR-211 in melanoma cells reduced the sensitivity to vemurafenib treatment, whereas miR-211-5p inhibition in a vemurafenib resistant cell line affected the proliferation negatively. Taken together, our results show that vemurafenib treatment induces miR-211-5p up-regulation in melanoma cells both in vitro and in vivo, as well as in subsets of EVs, suggesting that EVs may provide a tool to understand malignant melanoma progression.
Keywords
TRANSCRIPTION FACTOR; SMALL RNAS; CANCER; MECHANISMS; EXOSOMES; SUBSETS; REVEALS; POTENT; MITF; GENE
URI
http://oasis.postech.ac.kr/handle/2014.oak/50547
DOI
10.1073/pnas.1705206114
ISSN
0027-8424
Article Type
Article
Citation
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, vol. 114, no. 29, page. E5930 - E5939, 2017-07
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 GHO, YONG SONG
Dept of Life Sciences
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