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

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...

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Published inGastroenterology (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
LanguageEnglish
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
Online AccessGet full text
ISSN0016-5085
1528-0012
1528-0012
DOI10.1053/j.gastro.2022.08.048

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Abstract 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.
AbstractList 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.BACKGROUND & AIMSThe 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.METHODSWe 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.RESULTSThe 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.CONCLUSIONSOur findings highlight the context-dependent roles of HES1 in the adult pancreas and pancreatic cancer.
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.
Author Marui, Saiko
Nishikawa, Yoshihiro
Fukuda, Akihisa
Okada, Hirokazu
Matsumoto, Shimpei
Muramoto, Yuya
Saur, Dieter
Yoshida, Hiroyuki
Kodama, Yuzo
Shiokawa, Masahiro
Matsumori, Tomoaki
Aoi, Takashi
Ota, Sakiko
Uza, Norimitsu
Seno, Hiroshi
Kuriyama, Katsutoshi
Nakamura, Takeharu
Kuwada, Takeshi
Yokode, Masataka
Chiba, Tsutomu
Author_xml – sequence: 1
  givenname: Saiko
  surname: Marui
  fullname: Marui, Saiko
  organization: Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
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  givenname: Yoshihiro
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  fullname: Nishikawa, Yoshihiro
  organization: Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
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  givenname: Masahiro
  orcidid: 0000-0001-6436-3888
  surname: Shiokawa
  fullname: Shiokawa, Masahiro
  email: machan@kuhp.kyoto-u.ac.jp
  organization: Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
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  givenname: Masataka
  surname: Yokode
  fullname: Yokode, Masataka
  organization: Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
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  surname: Matsumoto
  fullname: Matsumoto, Shimpei
  organization: Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
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  givenname: Yuya
  surname: Muramoto
  fullname: Muramoto, Yuya
  organization: Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
– sequence: 7
  givenname: Sakiko
  surname: Ota
  fullname: Ota, Sakiko
  organization: Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
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  givenname: Takeharu
  surname: Nakamura
  fullname: Nakamura, Takeharu
  organization: Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
– sequence: 9
  givenname: Hiroyuki
  surname: Yoshida
  fullname: Yoshida, Hiroyuki
  organization: Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
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  givenname: Hirokazu
  surname: Okada
  fullname: Okada, Hirokazu
  organization: Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
– sequence: 11
  givenname: Takeshi
  surname: Kuwada
  fullname: Kuwada, Takeshi
  organization: Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
– sequence: 12
  givenname: Tomoaki
  surname: Matsumori
  fullname: Matsumori, Tomoaki
  organization: Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
– sequence: 13
  givenname: Katsutoshi
  surname: Kuriyama
  fullname: Kuriyama, Katsutoshi
  organization: Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
– sequence: 14
  givenname: Akihisa
  surname: Fukuda
  fullname: Fukuda, Akihisa
  organization: Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
– sequence: 15
  givenname: Dieter
  surname: Saur
  fullname: Saur, Dieter
  organization: Department of Internal Medicine II, Klinikum rechts der Isar Technische Universität München, München, Bayern, Germany
– sequence: 16
  givenname: Takashi
  surname: Aoi
  fullname: Aoi, Takashi
  organization: Division of Advanced Medical Science, Graduate School of Science, Technology and Innovation, Kobe University, Kobe, Hyogo, Japan
– sequence: 17
  givenname: Norimitsu
  surname: Uza
  fullname: Uza, Norimitsu
  organization: Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
– sequence: 18
  givenname: Yuzo
  surname: Kodama
  fullname: Kodama, Yuzo
  organization: Department of Gastroenterology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
– sequence: 19
  givenname: Tsutomu
  surname: Chiba
  fullname: Chiba, Tsutomu
  organization: Department of Gastroenterology and Hepatology, Kansai Electric Power Hospital, Osaka, Japan
– sequence: 20
  givenname: Hiroshi
  surname: Seno
  fullname: Seno, Hiroshi
  organization: Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
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Keywords 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
Language English
License This is an open access article under the CC BY license.
Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.
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Snippet 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...
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SubjectTerms 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
Title Context-Dependent Roles of Hes1 in the Adult Pancreas and Pancreatic Tumor Formation
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