Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan; Division of Advanced Medical Science, Graduate School of Science, Technology and Innovation, Kobe University, Kobe, Hyogo, Japan; Department of Gastroenterology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.
Gastroenterology. 2022 Dec;163(6):1613-1629.e12. doi: 10.1053/j.gastro.2022.08.048. Epub 2022 Sep 6.
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.
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.
Notch 信号通路是成人胰腺和胰腺导管腺癌（PDAC）中的重要通路，其核心分子为 hairy 和 enhancer of split-1（HES1）。然而，HES1 在成人胰腺和 PDAC 形成中的作用仍存在争议。
我们使用了基因工程双重组酶小鼠模型，在各种条件下诱导 Hes1 缺失。
在成年胰腺中缺失 Hes1 表达不会引起表型改变。然而，在 caerulein 诱导的急性胰腺炎后，再生受到损害。在胰腺上皮内瘤变（PanIN）小鼠模型中，当 Hes1 缺失先于 PanIN 形成时，PanIN 很少形成，而当 Hes1 缺失继 PanIN 形成后，形成的 PanIN 更多。在 PDAC 小鼠模型中，在 PanIN/PDAC 发展后，Hes1 缺失也增强了 PDAC 的形成；因此，HES1 促进 PanIN 起始，但抑制 PanIN/PDAC 进展。RNA 测序和染色质免疫沉淀-定量聚合酶链反应显示，HES1 缺失通过 Muc5ac 的上调促进了 PDAC 进展中的上皮间质转化。结果表明，在正常条件下，HES1 不是维持成年胰腺所必需的，但在胰腺炎恢复过程中对再生很重要；此外，HES1 发挥着不同的作用，这取决于肿瘤的情况。
我们的研究结果突出了 HES1 在成人胰腺和胰腺癌中的背景相关作用。
