Diminished WNT -> ß-catenin -> c-MYC signaling is a barrier for malignant progression of BRAFV600E-induced lung tumors.
Genes Dev
; 28(6): 561-75, 2014 Mar 15.
Article
em En
| MEDLINE
| ID: mdl-24589553
ABSTRACT
Oncogene-induced senescence (OIS) is proposed as a cellular defense mechanism that restrains malignant progression of oncogene-expressing, initiated tumor cells. Consistent with this, expression of BRAF(V600E) in the mouse lung epithelium elicits benign tumors that fail to progress to cancer due to an apparent senescence-like proliferative arrest. Here we demonstrate that nuclear ß-catenin â c-MYC signaling is essential for early stage proliferation of BRAF(V600E)-induced lung tumors and is inactivated in the subsequent senescence-like state. Furthermore, either ß-catenin silencing or pharmacological blockade of Porcupine, an acyl-transferase essential for WNT ligand secretion and activity, significantly inhibited BRAF(V600E)-initiated lung tumorigenesis. Conversely, sustained activity of ß-catenin or c-MYC significantly enhanced BRAF(V600E)-induced lung tumorigenesis and rescued the anti-tumor effects of Porcupine blockade. These data indicate that early stage BRAF(V600E)-induced lung tumors are WNT-dependent and suggest that inactivation of WNT â ß-catenin â c-MYC signaling is a trigger for the senescence-like proliferative arrest that constrains the expansion and malignant progression of BRAF(V600E)-initiated lung tumors. Moreover, these data further suggest that the trigger for OIS in initiated BRAF(V600E)-expressing lung tumor cells is not simply a surfeit of signals from oncogenic BRAF but an insufficiency of WNT â ß-catenin â c-MYC signaling. These data have implications for understanding how genetic abnormalities cooperate to initiate and promote lung carcinogenesis.
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Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
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Proteínas Proto-Oncogênicas c-myc
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Proteínas Proto-Oncogênicas B-raf
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Proteínas Wnt
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Beta Catenina
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Neoplasias Pulmonares
Limite:
Animals
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article