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首页> 外文期刊>Gut: Journal of the British Society of Gastroenterology >Genetic inactivation of Nupr1 acts as a dominant suppressor event in a two-hit model of pancreatic carcinogenesis
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Genetic inactivation of Nupr1 acts as a dominant suppressor event in a two-hit model of pancreatic carcinogenesis

机译：Nupr1的遗传失活是胰腺癌发生的两次打击模型中的主要抑制事件。

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Background: Nuclear protein 1 (Nupr1) is a major factor in the cell stress response required for KrasG12D-driven formation of pancreatic intraepithelial neoplastic lesions (PanINs). We evaluated the relevance of Nupr1 in the development of pancreatic cancer. Methods: We investigated the role of Nupr1 in pancreatic ductal adenocarcinoma (PDAC) progression beyond PanINs in Pdx1-cre;LSL-KrasG12D;Ink4a/Arffl/fl (KIC) mice. Results: Even in the context of the second tumorigenic hit of Ink4a/Arf deletion, Nupr1 deficiency led to suppression of malignant transformation involving caspase 3 activation in premalignant cells of KIC pancreas. Only half of Nupr1-deficient;KIC mice achieved PDAC development, and incident cases survived longer than Nupr1wt;KIC mice. This was associated with the development of well-differentiated PDACs in Nupr1-deficient;KIC mice, which displayed enrichment of genes characteristic of the recently identified human classical PDAC subtype. Nupr1-deficient;KIC PDACs also shared with human classical PDACs the overexpression of the Kras-activation gene signature. In contrast, Nupr1wt;KIC mice developed invasive PDACs with enriched gene signature of human quasi-mesenchymal (QM) PDACs. Cells derived from Nupr1-deficient;KIC PDACs growth in an anchorage-independent manner in vitro had higher aldehyde dehydrogenase activity and overexpressed nanog, Oct-4 and Sox2 transcripts compared with Nupr1wt;KIC cells. Moreover, Nupr1-deficient and Nurpr1wt;KIC cells differed in their sensitivity to the nucleoside analogues Ly101-4b and WJQ63. Together, these findings show the pivotal role of Nupr1 in both the initiation and late stages of PDAC in vivo, with a potential impact on PDAC cell stemness. Conclusions: According to Nupr1 status, KIC mice develop tumours that phenocopy human classical or QM-PDAC, respectively, and present differential drug sensitivity, thus becoming attractive models for preclinical drug trials.
机译：背景：核蛋白1（Nupr1）是KrasG12D驱动的胰腺上皮内肿瘤性病变（PanINs）形成所需的细胞应激反应的主要因素。我们评估了Nupr1在胰腺癌发展中的相关性。方法：我们研究了Nupr1在Pdx1-cre; LSL-KrasG12D; Ink4a / Arffl / fl（KIC）小鼠中超越PanIN的胰腺导管腺癌（PDAC）进展中的作用。结果：即使在Ink4a / Arf缺失的第二次致瘤命中的背景下，Nupr1缺乏也能抑制KIC胰腺癌前细胞中涉及caspase 3活化的恶性转化。缺乏Nupr1的KIC小鼠中只有一半达到了PDAC的发育，而且与Nupr1wt; KIC小鼠相比，事件病例的存活时间更长。这与在Nupr1缺陷的KIC小鼠中分化良好的PDAC的发展有关，该小鼠显示了最近鉴定的人类经典PDAC亚型的特征基因的富集。 Nupr1缺陷; KIC PDAC还与人类经典PDAC分享了Kras激活基因签名的过表达。相比之下，Nupr1wt; KIC小鼠开发了具有人类间充质（QM）PDAC丰富基因特征的侵入性PDAC。与Nupr1wt; KIC细胞相比，源自Nupr1缺陷型; KIC PDAC的细胞以锚定非依赖性方式体外生长，具有较高的醛脱氢酶活性，并过表达nanog，Oct-4和Sox2转录本。此外，Nupr1缺陷和Nurpr1wt; KIC细胞对核苷类似物Ly101-4b和WJQ63的敏感性不同。总之，这些发现表明，Nupr1在体内PDAC的起始和晚期均起着关键作用，对PDAC细胞的干性具有潜在影响。结论：根据Nupr1的状态，KIC小鼠分别发展成表型类似于人类经典或QM-PDAC的肿瘤，并表现出不同的药物敏感性，因此成为临床前药物试验的诱人模型。

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