Impaired JNK signaling cooperates with KrasG12D expression to accelerate pancreatic ductal adenocarcinoma.
Cancer Res
; 74(12): 3344-56, 2014 Jun 15.
Article
en En
| MEDLINE
| ID: mdl-24713432
ABSTRACT
The c-Jun N-terminal protein kinase (JNK) and its two direct activators, namely the mitogen-activated protein kinase (MAPK) kinase 4 (MKK4) and MKK7, constitute a signaling node frequently mutated in human pancreatic ductal adenocarcinoma (PDAC). Here we demonstrate the cooperative interaction of endogenous expression of Kras(G12D) with loss-of-function mutations in mkk4 or both, mkk4 and mkk7 genes in the pancreas. More specifically, impaired JNK signaling in a subpopulation of Pdx1-expressing cells dramatically accelerated the appearance of Kras(G12D)-induced acinar-to-ductal metaplasia and pancreatic intraepithelial neoplasias, which rapidly progressed to invasive PDAC within 10 weeks of age. Furthermore, inactivation of mkk4/mkk7 compromised acinar regeneration following acute inflammatory stress by locking damaged exocrine cells in a permanently de-differentiated state. Therefore, we propose that JNK signaling exerts its tumor suppressive function in the pancreas by antagonizing the metaplastic conversion of acinar cells toward a ductal fate capable of responding to oncogenic stimulation.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Neoplasias Pancreáticas
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Proteínas Proto-Oncogénicas p21(ras)
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Carcinoma Ductal Pancreático
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MAP Quinasa Quinasa 4
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MAP Quinasa Quinasa 7
Límite:
Animals
Idioma:
En
Revista:
Cancer Res
Año:
2014
Tipo del documento:
Article