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Titel:

Context-Dependent Roles of Hes1 in the Adult Pancreas and Pancreatic Tumor Formation.

Dokumenttyp:
Journal Article; Research Support, Non-U.S. Gov't
Autor(en):
Marui, Saiko; Nishikawa, Yoshihiro; Shiokawa, Masahiro; Yokode, Masataka; Matsumoto, Shimpei; Muramoto, Yuya; Ota, Sakiko; Nakamura, Takeharu; Yoshida, Hiroyuki; Okada, Hirokazu; Kuwada, Takeshi; Matsumori, Tomoaki; Kuriyama, Katsutoshi; Fukuda, Akihisa; Saur, Dieter; Aoi, Takashi; Uza, Norimitsu; Kodama, Yuzo; Chiba, Tsutomu; Seno, Hiroshi
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.
Zeitschriftentitel:
Gastroenterology
Jahr:
2022
Band / Volume:
163
Heft / Issue:
6
Seitenangaben Beitrag:
1613-1629.e12
Volltext / DOI:
doi:10.1053/j.gastro.2022.08.048
PubMed:
http://view.ncbi.nlm.nih.gov/pubmed/36075324
Print-ISSN:
0016-5085
TUM Einrichtung:
Lehrstuhl für Experimentelle Tumortherapie (Prof. Saur)
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