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

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 163; no. 6; pp. 1613 - 1629.e12
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2022
• Subjects: Acute Disease; Animals; Carcinoma in Situ; Carcinoma, Pancreatic Ductal - genetics; Mice; Muc5ac; Notch; Pancreas; Pancreatic Ductal Adenocarcinoma; Pancreatic Neoplasms; Pancreatic Neoplasms - genetics; Pancreatitis - chemically induced; Pancreatitis - genetics; PanIN; Transcription Factor HES-1 - genetics; IHC; Ad-GFP; ADM; mRNA; FACS; Pancreatic Ductal Adenocarcinoma; Aldh; GFP; DMEM; ChIP-qPCR; Ad-Cre-GFP; RNA-seq; Pdx1KP;Hes1WT; FBS; HES1; Pdx1KP;Hes1KO; WT; Muc5ac; Pdx1;Hes1WT; KO; Notch; qRT-PCR; CK; ERT2; Pdx1;Hes1KO; PDAC; Pdx1K;Hes1KO; PanIN; Hnf1β;Hes1KO; Pdx1K;Hes1WT; Hes1KO
• ISSN: 0016-5085; 1528-0012; 1528-0012
• DOI: 10.1053/j.gastro.2022.08.048

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. We used genetically engineered dual-recombinase mouse models for inducing Hes1 deletion under various conditions. 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. Our findings highlight the context-dependent roles of HES1 in the adult pancreas and pancreatic cancer.