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DHODH modula el alargamiento transcripcional en la cresta neural y el melanoma
Richard Mark White1, Jennifer Cech, Sutheera Ratanasirintrawoot
1Stem Cell Program and Hematology/Oncology, Children's Hospital Boston, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Nature
|March 25, 2011
Resumen
BRAF ((V600E) la activación oncogénica en las células de la cresta neural impulsa el melanoma al interrumpir el desarrollo. La inhibición de la dihidroorotato deshidrogenasa (DHODH) con compuestos como la leflunomida suprimió el desarrollo de la cresta neural y el crecimiento del melanoma.
Área de la Ciencia:
- Biología del desarrollo Biología del desarrollo.
- Biología del cáncer Biología del cáncer.
- Genética La genética.
Sus antecedentes:
- El melanoma surge de melanocitos transformados, originados en células de la cresta neural embrionaria.
- La interacción entre las vías de desarrollo de la cresta neural y las mutaciones oncogénicas BRAF en el melanoma no se comprende completamente.
- BRAF ((V600E) es el gen mutado con mayor frecuencia en el melanoma humano.
Objetivo del estudio:
- Para identificar eventos iniciales de transcripción de la activación de BRAF ((V600E) en el linaje de la cresta neural utilizando pez cebra.
- Para investigar el papel de estos eventos transcripcionales tempranos en la patogénesis del melanoma.
- Identificar posibles dianas terapéuticas para el melanoma mediante el cribado de supresores de moléculas pequeñas del desarrollo de la cresta neural.
Principales métodos:
- Se utilizaron embriones de pez cebra transgénicos para mitfa: BRAF ((V600E) y que carecen de p53.
- Realizó una prueba genética química para identificar supresores de moléculas pequeñas del linaje de la cresta neural.
- Compuestos identificados probados para sus efectos sobre el desarrollo de melanoma in vitro y en xenografts de ratón.
Principales resultados:
- La activación de BRAF ((V600E) en las células de la cresta neural condujo a una firma genética enriquecida para marcadores multipotentes de la cresta neural y una diferenciación terminal deteriorada.
- Los inhibidores de la dihidroorotato deshidrogenasa (DHODH), como la leflunomida, anulan el desarrollo de la cresta neural en el pez cebra y reducen la auto-renovación de las células madre de la cresta neural de los mamíferos.
- La inhibición de DHODH suprimió el alargamiento transcripcional de genes clave para el desarrollo de la cresta neural y el crecimiento del melanoma, reduciendo significativamente el crecimiento del melanoma in vitro e in vivo.
Conclusiones:
- Los eventos transcripcionales tempranos en el desarrollo de la cresta neural son cruciales para la formación de melanoma.
- DHODH es un regulador crítico del desarrollo de la cresta neural y el crecimiento del melanoma.
- La inhibición de DHODH representa una estrategia terapéutica prometedora para el melanoma, potencialmente en combinación con inhibidores de BRAF (V600E).
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