Genetic inactivation of the pancreatitis-inducible gene Nupr1 impairs PanIN formation by modulating Kras(G12D)-induced senescence.
Genetic inactivation of the pancreatitis-inducible gene Nupr1 impairs PanIN formation by modulating Kras(G12D)-induced senescence.
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DOI：
10.1038/cdd.2014.74
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发表时间：
2014-10
影响因子：
12.4
通讯作者：
中科院分区：
文献类型：
--
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核蛋白1（Nupr 1）是一种小的染色质蛋白，在癌症的发生、发展和对治疗的抵抗中起着关键作用。之前，我们已经证明Nupr 1与KrasG 12 D协同诱导小鼠胰腺上皮内瘤形成（PanIN）和胰腺导管腺癌的发展。然而，Nupr 1影响Kras介导的癌前生长的分子机制仍有待充分表征。在目前的研究中，我们报告了支持Nupr 1作为KrasG 12 D诱导衰老的基因修饰剂的作用的证据，必须克服这一点才能促进PanIN的形成。我们发现，小鼠中Nupr 1的基因失活损害了Kras诱导的PanIN，导致β-半乳糖苷酶阳性细胞的增加和衰老替代标记基因的上调。更重要的是，这些细胞和分子的变化都是通过在人类胰腺癌细胞模型中使用基于RNAi的Nupr 1失活的机制实验结果来概括的。此外，Nupr 1失活导致的衰老表型伴随着体内和体外FoxO 3a-Skp 2-p27 Kip 1-pRb-E2 F通路的激活。因此，结合起来，这些结果首次表明，Nupr 1有助于致癌Kras以协同促进PanIN形成的方式绕过衰老。除了其机制的重要性，这一新的知识具有医学意义，因为它描绘了早期的病理生物学事件，可能是有针对性的，在未来作为一种手段，在胰腺癌发生过程中的早期肿瘤前病变的形成干扰。
Nuclear protein 1 (Nupr1), a small chromatin protein, has a critical role in cancer development, progression and resistance to therapy. Previously, we had demonstrated that Nupr1 cooperates with KrasG12D to induce pancreas intraepithelial neoplasias (PanIN) formation and pancreatic ductal adenocarcinoma development in mice. However, the molecular mechanisms by which Nupr1 influences Kras-mediated preneoplastic growth remain to be fully characterized. In the current study, we report evidence supporting a role for Nupr1 as a gene modifier of KrasG12D-induced senescence, which must be overcome to promote PanIN formation. We found that genetic inactivation of Nupr1 in mice impairs Kras-induced PanIN, leading to an increase in β-galactosidase-positive cells and an upregulation of surrogate marker genes for senescence. More importantly, both of these cellular and molecular changes are recapitulated by the results of mechanistic experiments using RNAi-based inactivation of Nupr1 in human pancreatic cancer cell models. In addition, the senescent phenotype, which results from Nupr1 inactivation, is accompanied by activation of the FoxO3a-Skp2-p27Kip1-pRb-E2F pathway in vivo and in vitro. Thus, combined, these results show, for the first time, that Nupr1 aids oncogenic Kras to bypass senescence in a manner that cooperatively promotes PanIN formation. Besides its mechanistic importance, this new knowledge bears medical relevance as it delineates early pathobiological events that may be targeted in the future as a means to interfere with the formation of preneoplastic lesions early during pancreatic carcinogenesis.
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2.9
作者：
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