胰腺导管腺癌(PDAC)及其亚型是最常见的胰腺肿瘤，占胰腺肿瘤的85％～90％。统计结果表明，在所有的癌症中，PDAC几乎是存活率最低的，发病率和死亡率几乎相等。研究发现，PDAC对细胞应激有显著抗性。
在胰腺，核蛋白1(Nupr1)介导了细胞的应激反应，并在胰腺癌中表现出上调的表达水平。近日，来自法国的研究人员Juan Lucio Iovanna等人发现，Nupr1对胰腺癌的发生有着至关重要的作用。它能够促进胰腺癌的发展，并通过抑制凋亡来保护细胞免受压力影响。相关论文发表在5月8日的The Journal of Clinical Investigation。
在能够持续表达原癌基因KrasG12D的老鼠胰腺癌模型里，他们发现，缺失Nupr1的细胞不会发生胰腺上皮内瘤变(PanINs)。此外，在培养的胰腺细胞，营养缺乏激活了Nupr1的表达，反而利于细胞继续存活。
研究发现，通过一个依赖IER3和转录因子RelB的信号通路，Nupr1抑制了细胞凋亡，保护细胞免受压力而存活。在表达有KrasG12D的老鼠胰腺，NUPR1、RELB及IER3蛋白能够联合表达。而且，在胰腺细胞特异性缺失Relb后，PanIN的发展出现延迟。
结果表明，PanIN形成依赖于Nupr1及Relb的表达，这也可能与IER3有关。在PDAC患者中发现，NUPR1、RELB及IER3的表达与PDAC的不良预后高度相关。
总的来说，这些结果表明，NUPR1、RELB及IER3与胰腺致癌性转化息息相关。（生物谷Deepblue编译）
doi: 10.1172/JCI60144
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Nuclear protein 1 promotes pancreatic cancer development and protects cells from stress by inhibiting apoptosis
Tewfik Hamidi, Hana Algül, Carla Eliana Cano, Maria José Sandi, Maria Inés Molejon, Marc Riemann, Ezequiel Luis Calvo, Gwen Lomberk, Jean-Charles Dagorn, Falk Weih, Raul Urrutia, Roland Michael Schmid and Juan Lucio Iovanna.
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 KrasG12D, 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 KrasG12D-expressing pancreas. Moreover, pancreas-specific deletion of Relb in a KrasG12D 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 KrasG12D-dependent transformation of the pancreas.
