Context-Dependent Roles of Hes1 in the Adult Pancreas and Pancreatic Tumor Formation.
Context-Dependent Roles of Hes1 in the Adult Pancreas and Pancreatic Tumor Formation.
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Hes1 在成人胰腺和胰腺肿瘤形成中的上下文相关作用。
DOI：
10.1053/j.gastro.2022.08.048
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Seno H.
中科院分区：
文献类型：
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作者：
Marui S;Nishikawa Y;Shiokawa M;Yokode M;Matsumoto S;Muramoto Y;Ota S;Nakamura T;Yoshida H;Okada H;Kuwada T;Matsumori T;Kuriyama K;Fukuda A;Saur D;Aoi T;Uza N;Kodama Y;Chiba T;Seno H.
背景与目的Notch信号通路是成人胰腺和胰腺导管腺癌（pancreatic ductal adenocarcinoma，PDAC）中的重要信号通路，其核心分子是Hairy和分裂增强子1（enhancer of split-1，HES 1）。然而，HES 1在成人胰腺和PDAC形成的作用仍然存在争议。MethodsWe使用基因工程双重组酶小鼠模型诱导Hes 1 deletion在各种conditions.ResultsThe损失的Hes 1表达在成人胰腺不诱导表型改变。然而，再生受损后，雨蛙素诱导的急性胰腺炎。在胰腺上皮内瘤（PanIN）小鼠模型中，PanIN很少形成时，Hes 1缺失PanIN形成之前，而更多的PanIN形成时，Hes 1缺失成功PanIN形成。在PDAC小鼠模型中，PanIN/PDAC发育后Hes 1缺失也增强了PDAC的形成;因此，Hes 1促进PanIN启动，但抑制PanIN/PDAC进展。RNA测序和染色质免疫沉淀-定量聚合酶链反应表明，Hes 1缺失通过Muc 5针刺调节PDAC进展来增强上皮向间充质的转化。结果表明，HES 1是不需要维持成人胰腺在正常条件下，但重要的是从胰腺炎的恢复过程中的再生;此外，HES 1起着不同的作用，取决于肿瘤condition.ConclusionsOur的研究结果突出的上下文相关的作用HES 1在成人胰腺和胰腺癌。
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.MethodsWe used genetically engineered dual-recombinase mouse models for inducingHes1deletion under various conditions.ResultsThe loss ofHes1expression 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 whenHes1deletion preceded PanIN formation, whereas more PanINs were formed whenHes1deletion succeeded PanIN formation. In a PDAC mouse model, PDAC formation was also enhanced byHes1deletion after PanIN/PDAC development; therefore,Hes1promotes PanIN initiation but inhibits PanIN/PDAC progression. RNA sequencing and chromatin immunoprecipitation-quantitative polymerase chain reaction revealed thatHes1deletion enhanced epithelial-to-mesenchymal transition viaMuc5acup-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,Hes1plays different roles, depending on the tumor condition.ConclusionsOur findings highlight the context-dependent roles of HES1 in the adult pancreas and pancreatic cancer.