Hes1 plays an essential role in Kras-driven pancreatic tumorigenesis
Hes1 plays an essential role in Kras-driven pancreatic tumorigenesis
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DOI：
10.1038/s41388-019-0718-5
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发表时间：
2019-05-30
期刊：
影响因子：
8
通讯作者：
Seno, Hiroshi
中科院分区：
文献类型：
--
作者：
Nishikawa, Yoshihiro;Kodama, Yuzo;Seno, Hiroshi
大多数胰腺导管腺癌（PDAC）由携带激活突变KRAS基因的胰腺上皮细胞通过癌前病变（即腺泡-导管化生（ADM）和胰腺上皮内瘤变（PanIN））发展而来。在胰腺肿瘤发生过程中，Hes 1的表达始于腺泡细胞向ADM的转变，并在PanIN和PDAC形成过程中持续表达，但Hes 1在胰腺肿瘤发生中的作用尚未完全阐明。在这里，我们表明，Hes 1在KRAS驱动的胰腺肿瘤发生的启动和进展中起着至关重要的作用。在体外，由于EGF或突变的KRAS激活MAPK信号的激活诱导胰腺腺泡细胞中持续的Hes 1表达。在体内，腺泡细胞特异性激活突变KRAS的弹性蛋白酶1-CreERT 2;Kras（G12 D）诱导ADM/PanIN形成与Hes 1表达的小鼠，和基因消融Hes 1在这些小鼠显着抑制PanIN形成。基因表达分析和谱系追踪显示，Hes 1调节腺泡-导管重编程相关基因，并且在Hes 1缺陷状态下，突变型Kras诱导的ADM不能进展为PanIN，而是重新分化为腺泡细胞。Elastase1-CreERT2; Kras（G12D）; Trp 53（R172 H）小鼠PDAC模型中，Hes 1的基因消融通过将PanIN病变保持在低级别状态，除了减少PanIN的发生之外，还完全阻断了PDAC的形成。总之，这些发现表明，突变KRAS诱导的Hes 1通过调节腺泡-导管重编程相关基因在PDAC的启动和进展中起着重要作用。
Most pancreatic ductal adenocarcinoma (PDAC) develops from pancreatic epithelial cells bearing activating mutant KRAS genes through precancerous lesions, i.e. acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN). During pancreatic tumorigenesis, Hes1 expression starts with the transition from acinar cells to ADM, and continues during PanIN and PDAC formation, but the role of Hes1 in pancreatic tumorigenesis is not fully elucidated. Here we show that Hes1 plays an essential role in the initiation and progression of KRAS-driven pancreatic tumorigenesis. In vitro, activation of MAPK signaling due to EGF or mutant KRAS activation induced sustained Hes1 expression in pancreatic acinar cells. In vivo, acinar cell-specific activation of mutant KRAS by Elastase1-CreERT2;Kras(G12D) induced ADM/PanIN formation with Hes1 expression in mice, and genetic ablation of Hes1 in these mice dramatically suppressed PanIN formation. Gene expression analysis and lineage tracing revealed that Hes1 regulates acinar-to-ductal reprogramming-related genes and, in a Hes1-deficient state, mutant Kras-induced ADM could not progress into PanIN, but re-differentiated into acinar cells. In the Elastase1-CreERT2; Kras(G12D); Trp53(R172H) mouse PDAC model, genetic ablation of Hes1 completely blocked PDAC formation by keeping PanIN lesions in low-grade conditions, in addition to reducing the occurrence of PanIN. Together, these findings indicate that mutant KRAS-induced Hes1 plays an essential role in PDAC initiation and progression by regulating acinar-to-ductal reprogramming-related genes.