Inhibition of extracellular vesicle-derived miR-146a-5p decreases progression of melanoma brain metastasis via Notch pathway dysregulation in astrocytes
Melanoma has the highest propensity of all cancers to metastasize to the brain with a large percentage of late-stage patients developing metastases in the central nervous system (CNS). It is well known that metastasis establishment, cell survival, and progression are affected by tumour-host cell int...
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| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
October 2023
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| In: |
Journal of extracellular vesicles
Year: 2023, Jahrgang: 12, Heft: 10, Pages: 1-18 |
| ISSN: | 2001-3078 |
| DOI: | 10.1002/jev2.12363 |
| Online-Zugang: | Verlag, kostenfrei, Volltext: https://doi.org/10.1002/jev2.12363 Verlag, kostenfrei, Volltext: https://onlinelibrary.wiley.com/doi/abs/10.1002/jev2.12363 
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| Verfasserangaben: | Emma Rigg, Jiwei Wang, Zhiwei Xue, Taral R. Lunavat, Guowei Liu, Tuyen Hoang, Himalaya Parajuli, Mingzhi Han, Rolf Bjerkvig, Petr V. Nazarov, Nathalie Nicot, Stephanie Kreis, Christiane Margue, Miléne Tetsi Nomigni, Jochen Utikal, Hrvoje Miletic, Terje Sundstrøm, Lars A. R. Ystaas, Xingang Li, Frits Thorsen |
MARC
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| 245 | 1 | 0 | |a Inhibition of extracellular vesicle-derived miR-146a-5p decreases progression of melanoma brain metastasis via Notch pathway dysregulation in astrocytes |c Emma Rigg, Jiwei Wang, Zhiwei Xue, Taral R. Lunavat, Guowei Liu, Tuyen Hoang, Himalaya Parajuli, Mingzhi Han, Rolf Bjerkvig, Petr V. Nazarov, Nathalie Nicot, Stephanie Kreis, Christiane Margue, Miléne Tetsi Nomigni, Jochen Utikal, Hrvoje Miletic, Terje Sundstrøm, Lars A. R. Ystaas, Xingang Li, Frits Thorsen |
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| 520 | |a Melanoma has the highest propensity of all cancers to metastasize to the brain with a large percentage of late-stage patients developing metastases in the central nervous system (CNS). It is well known that metastasis establishment, cell survival, and progression are affected by tumour-host cell interactions where changes in the host cellular compartments likely play an important role. In this context, miRNAs transferred by tumour derived extracellular vesicles (EVs) have previously been shown to create a favourable tumour microenvironment. Here, we show that miR-146a-5p is highly expressed in human melanoma brain metastasis (MBM) EVs, both in MBM cell lines as well as in biopsies, thereby modulating the brain metastatic niche. Mechanistically, miR-146a-5p was transferred to astrocytes via EV delivery and inhibited NUMB in the Notch signalling pathway. This resulted in activation of tumour-promoting cytokines (IL-6, IL-8, MCP-1 and CXCL1). Brain metastases were significantly reduced following miR-146a-5p knockdown. Corroborating these findings, miR-146a-5p inhibition led to a reduction of IL-6, IL-8, MCP-1 and CXCL1 in astrocytes. Following molecular docking analysis, deserpidine was identified as a functional miR-146a-5p inhibitor, both in vitro and in vivo. Our results highlight the pro-metastatic function of miR-146a-5p in EVs and identifies deserpidine for targeted adjuvant treatment. | ||
| 650 | 4 | |a brain metastasis | |
| 650 | 4 | |a deserpidine | |
| 650 | 4 | |a extracellular vesicles | |
| 650 | 4 | |a melanoma | |
| 650 | 4 | |a miR-146a-5p | |
| 650 | 4 | |a normal human astrocytes (NHA) | |
| 700 | 1 | |a Wang, Jiwei |e VerfasserIn |4 aut | |
| 700 | 1 | |a Xue, Zhiwei |e VerfasserIn |4 aut | |
| 700 | 1 | |a Lunavat, Taral R. |e VerfasserIn |4 aut | |
| 700 | 1 | |a Liu, Guowei |e VerfasserIn |4 aut | |
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| 700 | 1 | |a Kreis, Stephanie |e VerfasserIn |4 aut | |
| 700 | 1 | |a Margue, Christiane |e VerfasserIn |4 aut | |
| 700 | 1 | |a Nomigni, Miléne Tetsi |e VerfasserIn |4 aut | |
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| 700 | 1 | |a Sundstrøm, Terje |e VerfasserIn |4 aut | |
| 700 | 1 | |a Ystaas, Lars A. R. |e VerfasserIn |4 aut | |
| 700 | 1 | |a Li, Xingang |e VerfasserIn |4 aut | |
| 700 | 1 | |a Thorsen, Frits |e VerfasserIn |4 aut | |
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