Runx3 Inactivation Is a Crucial Early Event in the Development of Lung Adenocarcinoma
Menée à l'aide d'un modèle murin, cette étude montre que l'inactivation du gène RUNX3 est un événement précoce et crucial dans le développement d'un adénocarcinome du poumon
Targeted inactivation of Runx3 in mouse lung induced mucinous and nonmucinous adenomas and markedly shortened latency of adenocarcinoma formation induced by oncogenic K-Ras. RUNX3 was frequently inactivated in K-RAS mutated human lung adenocarcinomas. A functional genetic screen of a fly mutant library and molecular analysis in cultured cell lines revealed that Runx3 forms a complex with BRD2 in a K-Ras-dependent manner in the early phase of the cell cycle; this complex induces expression of p14ARF/p19Arf and p21WAF/CIP. When K-Ras was constitutively activated, the Runx3-BRD2 complex was stably maintained and expression of both p14ARF and p21WAF/CIP was prolonged. These results provide a missing link between oncogenic K-Ras and the p14ARF-p53 pathway, and may explain how cells defend against oncogenic K-Ras. "Runx3 inactivation induces lung adenomas "Runx3 inactivation accelerates malignant progression of K-RasG12D-induced tumors "Runx3 activates the p14ARF-p53 pathway in a K-Ras activity-dependent manner "Restoration of Runx3 in K-Ras-activated lung cancer cell line induces apoptosis