Proteasome-dependent degradation of Smad7 is critical for lung cancer metastasis.
Cell Death Differ
; 27(6): 1795-1806, 2020 06.
Article
en En
| MEDLINE
| ID: mdl-31767934
ABSTRACT
Lung cancer is one of the cancers with highest morbidity and mortality rates and the metastasis of lung cancer is a leading cause of death. Mechanisms of lung cancer metastasis are yet to be fully understood. Herein, we demonstrate that mice deficient for REGγ, a proteasome activator, exhibited a significant reduction in tumor size, numbers, and metastatic rate with prolonged survival in a conditional Kras/p53 mutant lung cancer model. REGγ enhanced the TGFß-Smad signaling pathway by ubiquitin-ATP-independent degradation of Smad7, an inhibitor of the TGFß pathway. Activated TGFß signaling in REGγ-positive lung cancer cells led to diminished expression of E-cadherin, a biomarker of epithelial-mesenchymal transitions (EMT), and elevated mesenchymal markers compared with REGγ-deficient lung cancer cells. REGγ overexpression was found in lung cancer patients with metastasis, correlating with the reduction of E-Cadherin/Smad7 and a poor prognosis. Overall, our study indicates that REGγ promotes lung cancer metastasis by activating TGF-ß signaling via degradation of Smad7. Thus, REGγ may serve as a novel therapeutic target for lung cancers with poor prognosis.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Contexto en salud:
6_ODS3_enfermedades_notrasmisibles
Problema de salud:
6_other_respiratory_diseases
/
6_trachea_bronchus_lung_cancer
Asunto principal:
Antígenos CD
/
Cadherinas
/
Proteína smad7
/
Proteínas Asociadas a Pancreatitis
/
Neoplasias Pulmonares
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Cell Death Differ
Año:
2020
Tipo del documento:
Article
País de afiliación:
China