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BRAF(V600) inhibiti...
BRAF(V600) inhibition alters the microRNA cargo in the vesicular secretome of malignant melanoma cells
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- Lunavat, Taral R (author)
- Gothenburg University,Göteborgs universitet,Krefting Research Centre,Institutionen för medicin, avdelningen för invärtesmedicin och klinisk nutrition,Institute of Medicine, Department of Internal Medicine and Clinical Nutrition
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Cheng, L. (author)
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- Einarsdottir, Berglind Osk, 1979 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för kirurgi,Institute of Clinical Sciences, Department of Surgery
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- Olofsson Bagge, Roger, 1978 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för kirurgi,Institute of Clinical Sciences, Department of Surgery
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- Muralidharan, Somsundar Veppil (author)
- Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för medicinsk kemi och cellbiologi,Institutionen för kliniska vetenskaper, Avdelningen för kirurgi,Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology,Institute of Clinical Sciences, Department of Surgery
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Sharples, R. A. (author)
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- Lässer, Cecilia, 1981 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för invärtesmedicin och klinisk nutrition,Krefting Research Centre,Institute of Medicine, Department of Internal Medicine and Clinical Nutrition
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Gho, Y. S. (author)
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Hill, A. F. (author)
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- Nilsson, Jonas A, 1971 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för kirurgi,Institute of Clinical Sciences, Department of Surgery
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- Lötvall, Jan, 1956 (author)
- Gothenburg University,Göteborgs universitet,Krefting Research Centre,Institutionen för medicin, avdelningen för invärtesmedicin och klinisk nutrition,Institute of Medicine, Department of Internal Medicine and Clinical Nutrition
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(creator_code:org_t)
- 2017-07-06
- 2017
- English.
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In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 114:29
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Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Keyword
- small RNAs
- extracellular vesicles
- cancer
- noncoding RNAs
- TRANSCRIPTION FACTOR
- SMALL RNAS
- CANCER
- MECHANISMS
- EXOSOMES
- SUBSETS
- REVEALS
- POTENT
- MITF
- GENE
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Lunavat, Taral R
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Cheng, L.
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Einarsdottir, Be ...
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Olofsson Bagge, ...
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Muralidharan, So ...
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Sharples, R. A.
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Lässer, Cecilia, ...
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Gho, Y. S.
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Hill, A. F.
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Nilsson, Jonas A ...
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Lötvall, Jan, 19 ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cancer and Oncol ...
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Proceedings of t ...
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Proceedings of t ...
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University of Gothenburg