期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 114, 期 29, 页码 E5930-E5939出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1705206114
关键词
small RNAs; extracellular vesicles; cancer; noncoding RNAs
资金
- Swedish Research Council [K2014-85x-22504-01-3, K2011-56K-20676-04-6]
- VBG Group Herman Krefting Foundation for Asthma and Allergy Research [20141209, 20131212, 20121218]
- Swedish Heart and Lung Foundation [20120528]
- Swedish Cancer Foundation [CAN2014/844, CAN 2012/690]
- National Health Medical Research Council of Australia [628946]
- Australian Research Council (ARC) [FT100100560]
- Swedish Cancer Society
- Swedish Research Council
- Knut and Alice Wallenberg Foundation
- Region Vastra Gotaland
- Assar Gabrielsson Foundation
- Sahlgrenska University Hospital Research Grant
- William and Martina Lundgren Foundation
- National Research Foundation of Korea [21A20131212415] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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