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Un modelo de dos pasos para la iniciación y progresión del adenoma de colon causado por la pérdida de APC

Reid A Phelps¹, Stephanie Chidester, Somaye Dehghanizadeh

¹Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.

|May 20, 2009

Resumen

La pérdida del gen de la poliposis coli adenomatosa (APC) causa una diferenciación celular intestinal fallida, pero no un crecimiento tumoral inmediato. La proteína de unión C-terminal-1 (CtBP1) impulsa la formación inicial de adenoma, mientras que la activación de KRAS promueve la progresión hacia el cáncer.

Área de la Ciencia:

Biología Molecular Biología Molecular
Investigación del cáncer Investigación del cáncer.
Biología del desarrollo Biología del desarrollo.

Sus antecedentes:

La señalización aberrante de Wnt / beta-catenina debido a la pérdida de poliposis coli adenomatosa (APC) es un evento clave en el inicio del adenoma de colon.
Los mecanismos moleculares precisos que vinculan la pérdida de APC a la tumorigénesis intestinal temprana siguen siendo incompletamente entendidos.

Objetivo del estudio:

Investigar el papel de la pérdida de APC en la diferenciación y proliferación de las células intestinales.
Para dilucidar las vías moleculares aguas abajo de la pérdida de APC en la formación y progresión de adenoma de colon.

Principales métodos:

Se utilizaron modelos de peces cebra y células humanas para estudiar los efectos de la pérdida de APC homocigótica.
Se analizó la localización de la beta-catenina, los marcadores de diferenciación celular y las tasas de proliferación.
Se evaluó la participación de la proteína de unión C-terminal-1 (CtBP1) y la activación de KRAS.

Principales resultados:

La pérdida de APC homocigota resultó en una diferenciación fallida de las células intestinales sin aumento de la proliferación o beta-catenina nuclear.
Los defectos de diferenciación inducidos por la mutación de APC dependían de CtBP1.1.
El aumento de la proliferación y la acumulación de beta-catenina nuclear requirió una activación adicional de KRAS.
Los adenomas de poliposis adenomatosa familiar humana (FAP) mostraron una regulación ascendente de CtBP1 sin beta-catenina nuclear, mientras que los carcinomas exhibieron beta-catenina nuclear.

Conclusiones:

La pérdida de APC por sí sola es insuficiente para iniciar la localización nuclear y la proliferación de la beta-catenina.
CtBP1 juega un papel crítico en la etapa inicial de la formación de adenoma después de la pérdida de APC.
La activación de KRAS y la posterior localización nuclear de la beta-catenina son cruciales para la progresión del adenoma a carcinomas.

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