Context-Dependent Roles of Hes1 in the Adult Pancreas and Pancreatic Tumor Formation.
Saiko Marui, Yoshihiro Nishikawa, Masahiro Shiokawa, Masataka Yokode, Shimpei Matsumoto, Yuya Muramoto, Sakiko Ota, Takeharu Nakamura, Hiroyuki Yoshida, Hirokazu Okada, Takeshi Kuwada, Tomoaki Matsumori, Katsutoshi Kuriyama, Akihisa Fukuda, Dieter Saur, Takashi Aoi, Norimitsu Uza, Yuzo Kodama, Tsutomu Chiba, Hiroshi Seno
Gastroenterology 2022 DecThe 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. Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.
Citation
Saiko Marui, Yoshihiro Nishikawa, Masahiro Shiokawa, Masataka Yokode, Shimpei Matsumoto, Yuya Muramoto, Sakiko Ota, Takeharu Nakamura, Hiroyuki Yoshida, Hirokazu Okada, Takeshi Kuwada, Tomoaki Matsumori, Katsutoshi Kuriyama, Akihisa Fukuda, Dieter Saur, Takashi Aoi, Norimitsu Uza, Yuzo Kodama, Tsutomu Chiba, Hiroshi Seno. Context-Dependent Roles of Hes1 in the Adult Pancreas and Pancreatic Tumor Formation. Gastroenterology. 2022 Dec;163(6):1613-1629.e12
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PMID: 36075324
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