Cooperation Between MYC and ß-Catenin in Liver Tumorigenesis Requires Yap/Taz.
Hepatology
; 72(4): 1430-1443, 2020 10.
Article
em En
| MEDLINE
| ID: mdl-31965581
ABSTRACT
BACKGROUND AND AIMS:
Activation of MYC and catenin beta-1 (CTNNB1, encoding ß-catenin) can co-occur in liver cancer, but how these oncogenes cooperate in tumorigenesis remains unclear. APPROACH ANDRESULTS:
We generated a mouse model allowing conditional activation of MYC and WNT/ß-catenin signaling (through either ß-catenin activation or loss of APC - adenomatous polyposis coli) upon expression of CRE recombinase in the liver and monitored their effects on hepatocyte proliferation, apoptosis, gene expression profiles, and tumorigenesis. Activation of WNT/ß-catenin signaling strongly accelerated MYC-driven carcinogenesis in the liver. Both pathways also cooperated in promoting cellular transformation in vitro, demonstrating their cell-autonomous action. Short-term induction of MYC and ß-catenin in hepatocytes, followed by RNA-sequencing profiling, allowed the identification of a "Myc/ß-catenin signature," composed of a discrete set of Myc-activated genes whose expression increased in the presence of active ß-catenin. Notably, this signature enriched for targets of Yes-associated protein (Yap) and transcriptional coactivator with PDZ-binding motif (Taz), two transcriptional coactivators known to be activated by WNT/ß-catenin signaling and to cooperate with MYC in mitogenic activation and liver transformation. Consistent with these regulatory connections, Yap/Taz accumulated upon Myc/ß-catenin activation and were required not only for the ensuing proliferative response, but also for tumor cell growth and survival. Finally, the Myc/ß-catenin signature was enriched in a subset of human hepatocellular carcinomas characterized by comparatively poor prognosis.CONCLUSIONS:
Myc and ß-catenin show a strong cooperative action in liver carcinogenesis, with Yap and Taz serving as mediators of this effect. These findings warrant efforts toward therapeutic targeting of Yap/Taz in aggressive liver tumors marked by elevated Myc/ß-catenin activity.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Transativadores
/
Proteínas Proto-Oncogênicas c-myc
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Proteínas de Ciclo Celular
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Proteínas Adaptadoras de Transdução de Sinal
/
Beta Catenina
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Neoplasias Hepáticas Experimentais
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Hepatology
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Itália