Nuclear protein 1 promotes pancreatic cancer development and protects cells from stress by inhibiting apoptosis
Nuclear protein 1 promotes pancreatic cancer development and protects cells from stress by inhibiting apoptosis
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DOI：
10.1172/jci60144
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发表时间：
2012-06-01
影响因子：
15.9
通讯作者：
Iovanna, Juan Lucio
中科院分区：
文献类型：
--
作者：
Hamidi, Tewfik;Alguel, Hana;Iovanna, Juan Lucio
胰腺导管腺癌（PDAC）是所有癌症中存活率最低的，并且对细胞应激表现出显著的抵抗力。核蛋白1（Nupr 1）介导胰腺中的应激反应，在胰腺癌中经常上调。在这里，我们报告Nupr 1在胰腺肿瘤发生中发挥着重要作用。在组成型表达致癌Kras（G12 D）的胰腺癌小鼠模型中，我们发现Nupr 1的缺失可防止胰腺上皮内瘤形成（PanIN）。此外，在培养的胰腺细胞中，营养剥夺激活了Nupr 1的表达，我们发现这是细胞存活所必需的。我们发现Nupr 1通过依赖于转录因子RelB和立即早期反应3（IER 3）的途径抑制细胞凋亡，从而保护细胞免受应激诱导的死亡。NUPR 1、RELB和IER 3蛋白在来自表达Kras（G12 D）的胰腺的小鼠PanIN中共表达。此外，在Kras（G12 D）背景中的Relb的胰腺特异性缺失导致与IER 3表达缺乏相关的PanIN发育延迟。因此，有效的PanIN形成依赖于Nupr 1和Relb的表达，可能涉及IER 3。最后，在PDAC患者中，NUPR 1、RELB和IER 3的表达与不良预后显著相关。累积起来，这些结果揭示了NUPR 1/RELB/IER 3应激相关途径，该途径是胰腺的致癌Kras（G12 D）依赖性转化所必需的。
Pancreatic ductal adenocarcinoma (PDAC) has the lowest survival rate of all cancers and shows remarkable resistance to cell stress. Nuclear protein 1 (Nupr1), which mediates stress response in the pancreas, is frequently upregulated in pancreatic cancer. Here, we report that Nupr1 plays an essential role in pancreatic tumorigenesis. In a mouse model of pancreatic cancer with constitutively expressed oncogenic Kras(G12D), we found that loss of Nupr1 protected from the development of pancreatic intraepithelial neoplasias (PanINs). Further, in cultured pancreatic cells, nutrient deprivation activated Nupr1 expression, which we found to be required for cell survival. We found that Nupr1 protected cells from stress-induced death by inhibiting apoptosis through a pathway dependent on transcription factor RelB and immediate early response 3 (IER3). NUPR1, RELB, and IER3 proteins were coexpressed in mouse PanINs from Kras(G12D)-expressing pancreas. Moreover, pancreas-specific deletion of Relb in a Kras(G12D) background resulted in delayed in PanIN development associated with a lack of IER3 expression. Thus, efficient PanIN formation was dependent on the expression of Nupr1 and Relb, with likely involvement of IER3. Finally, in patients with PDAC, expression of NUPR1, RELB, and IER3 was significantly correlated with a poor prognosis. Cumulatively, these results reveal a NUPR1/RELB/IER3 stress-related pathway that is required for oncogenic Kras(G12D)-dependent transformation of the pancreas.