Activating mutations and amplification of Kras and, more frequently, signatures for Kras activation are noted in stomach cancer. Expression of mutant KrasG12D in the mouse gastric mucosa has been shown to induce hyperplasia and metaplasia. However, the mechanisms by which Kras activation leads to gastric metaplasia are not fully understood. Here we report that KrasLSL-G12D/+;Pdx1-cre, a mouse model known for pancreatic cancer, also mediates KrasG12D expression in the stomach, causing gastric hyperplasia and metaplasia prior to the pathologic changes in the pancreas. These mice exhibit ectopic cell proliferation at the base of gastric glands, whereas wild-type mice contain proliferating cells primarily at the isthmus/neck of the gastric glands. Notch signaling is decreased in the KrasLSL-G12D/+;Pdx1-cre gastric mucosa, as shown by lower levels of cleaved Notch intracellular domains and downregulation of Notch downstream target genes. Expression of a Notch ligand Jagged1 is downregulated at the base of the mutant gland, accompanied by loss of chief cell marker Mist1. We demonstrate that exogenous Jagged1 or overexpression of Notch intracellular domain stimulates Mist1 expression in gastric cancer cell lines, suggesting positive regulation of Mist1 by Notch signaling. Finally, deletion of Jagged1 or Notch3 in KrasLSL-G12D/+;Pdx1-cre mice promoted development of squamous cell carcinoma in the forestomach, albeit short of invasive adenocarcinoma in the glandular stomach. Taken together, these results reveal downregulation of Notch signaling and Mist1 expression during the initiation of Kras-driven gastric tumorigenesis and suggest a tumor-suppressive role for Notch in this context.

中文翻译：

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在Kras诱导的胃上皮化生中Notch信号的下调。

在胃癌中发现了Kras的激活突变和扩增，更常见的是Kras激活的信号。已经显示突变体KrasG12D在小鼠胃粘膜中的表达诱导增生和化生。然而，Kras激活导致胃上皮化的机制尚不完全清楚。在这里我们报告说，KrasLSL-G12D / +; Pdx1-cre，一种以胰腺癌闻名的小鼠模型，也介导了KrasG12D在胃中的表达，在胰腺病理改变之前引起了胃的增生和化生。这些小鼠在胃腺基部表现出异位细胞增殖，而野生型小鼠主要在胃腺的峡部/颈部含有增殖细胞。在KrasLSL-G12D / +; Pdx1-cre胃黏膜中，Notch信号降低，如较低水平的Notch裂解胞内结构域水平和Notch下游靶基因的下调所示。Notch配体Jagged1的表达在突变腺体的底部被下调，伴随着主要细胞标记Mist1的缺失。我们证明外源Jagged1或Notch细胞内域的过表达刺激胃癌细胞系中Mist1的表达，暗示了Notch信号对Mist1的正向调节。最后，尽管缺少腺胃浸润性腺癌，但KrasLSL-G12D / +; Pdx1-cre小鼠中Jagged1或Notch3的缺失促进了前胃部鳞状细胞癌的发展。在一起