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

Artikel i vetenskaplig tidskrift
Författare Taral R Lunavat
L. Cheng
Berglind Osk Einarsdottir
Roger Olofsson Bagge
Somsundar Veppil Muralidharan
R. A. Sharples
Cecilia Lässer
Y. S. Gho
A. F. Hill
Jonas A Nilsson
Jan Lötvall
Publicerad i Proceedings of the National Academy of Sciences of the United States of America
Volym 114
Nummer/häfte 29
Sidor E5930-E5939
ISSN 0027-8424
Publiceringsår 2017
Publicerad vid Institutionen för kliniska vetenskaper, Avdelningen för kirurgi
Krefting Research Centre
Institutionen för medicin, avdelningen för invärtesmedicin och klinisk nutrition
Institutionen för biomedicin, avdelningen för medicinsk kemi och cellbiologi
Sidor E5930-E5939
Språk en
Länkar doi.org/10.1073/pnas.1705206114
Ämnesord small RNAs, extracellular vesicles, cancer, noncoding RNAs, TRANSCRIPTION FACTOR, SMALL RNAS, CANCER, MECHANISMS, EXOSOMES, SUBSETS, REVEALS, POTENT, MITF, GENE
Ämneskategorier Cancer och onkologi

Sammanfattning

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.

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