Context-Dependent Roles of Hes1 in the Adult Pancreas and Pancreatic Tumor Formation.
Gastroenterology
; 163(6): 1613-1629.e12, 2022 12.
Article
en En
| MEDLINE
| ID: mdl-36075324
ABSTRACT
BACKGROUND & AIMS:
The Notch signaling pathway is an important pathway in the adult pancreas and in pancreatic ductal adenocarcinoma (PDAC), with hairy and enhancer of split-1 (HES1) as the core molecule in this pathway. However, the roles of HES1 in the adult pancreas and PDAC formation remain controversial.METHODS:
We used genetically engineered dual-recombinase mouse models for inducing Hes1 deletion under various conditions.RESULTS:
The loss of Hes1 expression in the adult pancreas did not induce phenotypic alterations. However, regeneration was impaired after caerulein-induced acute pancreatitis. In a pancreatic intraepithelial neoplasia (PanIN) mouse model, PanINs rarely formed when Hes1 deletion preceded PanIN formation, whereas more PanINs were formed when Hes1 deletion succeeded PanIN formation. In a PDAC mouse model, PDAC formation was also enhanced by Hes1 deletion after PanIN/PDAC development; therefore, Hes1 promotes PanIN initiation but inhibits PanIN/PDAC progression. RNA sequencing and chromatin immunoprecipitation-quantitative polymerase chain reaction revealed that Hes1 deletion enhanced epithelial-to-mesenchymal transition via Muc5ac up-regulation in PDAC progression. The results indicated that HES1 is not required for maintaining the adult pancreas under normal conditions, but is important for regeneration during recovery from pancreatitis; moreover, Hes1 plays different roles, depending on the tumor condition.CONCLUSIONS:
Our findings highlight the context-dependent roles of HES1 in the adult pancreas and pancreatic cancer.Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Neoplasias Pancreáticas
/
Pancreatitis
/
Carcinoma in Situ
/
Carcinoma Ductal Pancreático
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Año:
2022
Tipo del documento:
Article