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Nuclear protein 1 promotes pancreatic cancer development and protects cells from stress by inhibiting apoptosis
Tewfik Hamidi, … , Roland Michael Schmid, Juan Lucio Iovanna
Tewfik Hamidi, … , Roland Michael Schmid, Juan Lucio Iovanna
Published May 8, 2012
Citation Information: J Clin Invest. 2012;122(6):2092-2103. https://doi.org/10.1172/JCI60144.
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Research Article Oncology Article has an altmetric score of 2

Nuclear protein 1 promotes pancreatic cancer development and protects cells from stress by inhibiting apoptosis

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Abstract

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.

Authors

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, Juan Lucio Iovanna

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Figure 4

Expression of IER3 is dependent on Nupr1 and RelB, but not on RelA/p65, and protects from stress-induced cell death.

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Expression of IER3 is dependent on Nupr1 and RelB, but not on RelA/p65, ...
(A) Heat map showing RelB- and RelA/p65-dependent gene expression in response to nutrient deprivation. A P value of 0.05 or less was required for establishment of differential gene expression. Red arrows indicate 3 different probes hybridizing to the IER3 transcript. (B) Cells were transfected with siCtrl, siNupr1, siRELB, or siRELA alone or combined and cultured in conventional or EBSS medium for 24 hours. IER3 mRNA was measured by qRT-PCR. (C) Cells were transfected with IER3-specific siRNA or siCtrl, and IER3 mRNA was measured after 24 hours by qRT-PCR (right) and IER3 protein expression by Western blot (left). (D and E) MiaPaCa2 cells were transfected with siCtrl, siNupr1, siRelB, and siIER3 alone or in combination, and cultured in conventional or EBSS medium for 24 hours. Cell viability and caspase-3/7 activity were measured as described in Figure 2. Cyclophilin was used as a housekeeping control for calculation of relative transcript levels. Values are expressed as mean ± SEM of triplicate, and experiments were repeated twice. *P ≤ 0.05 relative to siCtrl-transfected cells cultured in conventional medium; †P ≤ 0.05 relative to siNupr1-transfected cells.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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