The helicase HAGE expressed by malignant melanoma-initiating cells is required for tumor cell proliferation in vivo.
J Biol Chem
; 287(17): 13633-43, 2012 Apr 20.
Article
en En
| MEDLINE
| ID: mdl-22393060
ABSTRACT
Malignant melanoma-initiating cells (MMIC) are a subpopulation of cells responsible for melanoma tumor growth and progression. They are defined by the expression of the ATP-binding cassette (ABC) subfamily B member 5 (ABCB5). Here, we identified a critical role for the DEAD-box helicase antigen (HAGE) in ABCB5+ MMIC-dependent tumorigenesis and show that HAGE-specific inactivation inhibits melanoma tumor growth mediated by this tumor-initiating population. Knockdown of HAGE led to a significant decrease in RAS protein expression with a concomitant decrease in activation of the AKT and ERK signaling pathways implicated to play an important role in melanoma progression. To confirm that the reduction in NRAS (Neuroblastoma RAS) expression was dependent on the HAGE helicase activity, we showed that NRAS, effectively silenced by siRNA, could be rescued by reintroduction of HAGE in cells lacking HAGE. Furthermore, we provide a mechanism by which HAGE promotes NRAS unwinding in vitro. We also observed using tumor transplantation in Non-obese diabetic/severe combined immunodeficiency mice that the HAGE knockdown in a ABCB5+ melanoma cell line displayed a significant decrease in tumor growth and compared with the control. Our results suggest that the helicase HAGE is required for ABCB5+ MMIC-dependent tumor growth through promoting RAS protein expression and that cancer therapies targeting HAGE helicase may have broad applications for treating malignant melanoma and potentially other cancer types.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Regulación Neoplásica de la Expresión Génica
/
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP
/
Transportadoras de Casetes de Unión a ATP
/
ARN Helicasas DEAD-box
/
Melanoma
/
Antígenos de Neoplasias
/
Proteínas de Neoplasias
Límite:
Animals
/
Humans
Idioma:
En
Revista:
J Biol Chem
Año:
2012
Tipo del documento:
Article
País de afiliación:
Reino Unido
Pais de publicación:
EEUU
/
ESTADOS UNIDOS
/
ESTADOS UNIDOS DA AMERICA
/
EUA
/
UNITED STATES
/
UNITED STATES OF AMERICA
/
US
/
USA