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Mutaciones frecuentes que convergen en la vía NFKBIZ en la colitis ulcerosa
Nobuyuki Kakiuchi1,2,3, Kenichi Yoshida1, Motoi Uchino4
1Department of Pathology and Tumour Biology, Kyoto University, Kyoto, Japan.
Nature
|December 20, 2019
Resumen
La inflamación crónica impulsa la remodelación intestinal por clones seleccionados que adquieren mutaciones. Estas mutaciones, particularmente en NFKBIZ, influyen en el desarrollo del cáncer y revelan posibles vulnerabilidades terapéuticas en el cáncer colorrectal.
Área de la Ciencia:
- Gastroenterología y Oncología
- Inflamación y Biología del Cáncer
Sus antecedentes:
- La inflamación crónica, caracterizada por la destrucción de los tejidos y ciclos de reparación, aumenta el riesgo de cáncer.
- El impacto de estos ciclos en la composición clonal de los tejidos y el desarrollo del cáncer no se comprende completamente.
Objetivo del estudio:
- Investigar cómo la inflamación crónica en la colitis ulcerosa afecta la dinámica clonal y da forma a la composición del tejido.
- Identificar mutaciones genéticas específicas y mecanismos de selección involucrados en el desarrollo de cáncer asociado a la colitis.
Principales métodos:
- Análisis de perfiles mutacionales en tejidos intestinales inflamados de pacientes con colitis ulcerosa.
- Comparación de las mutaciones en los tejidos cancerosos no displásicos, asociados a la colitis y esporádicos.
- Estudios in vivo con ratones mutantes de Nfkbiz y estudios in vitro con células de cáncer colorrectal humano.
Principales resultados:
- Los intestinos inflamados en la colitis ulcerosa muestran una remodelación generalizada por clones seleccionados positivamente con mutaciones en genes como NFKBIZ, TRAF3IP2, ZC3H12A, PIGR y HNRNPF.
- Los perfiles mutacionales difieren significativamente entre el cáncer asociado a la colitis y los tejidos no displásicos, lo que indica mecanismos de selección distintos.
- Las mutaciones de NFKBIZ, comunes en el epitelio de la colitis ulcerosa, son raras en los cánceres colorrectales, lo que sugiere una selección negativa durante la carcinogénesis. La tumorigénesis se redujo en ratones mutantes de Nfkbiz.
Conclusiones:
- Los mecanismos de selección clonal comunes y distintos operan en los tejidos inflamatorios.
- Las mutaciones de NFKBIZ pueden conferir una desventaja durante la progresión del cáncer colorrectal, destacando posibles objetivos terapéuticos.
- La comprensión de estas dinámicas clonales revela nuevas vulnerabilidades para las terapias del cáncer colorrectal.
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