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

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

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 1

Nupr1 expression is necessary for PanIN development.

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Nupr1 expression is necessary for PanIN development. (A) Pancreata fr...
(A) Pancreata from KrasG12D, KrasG12D;Nupr1+/–, and KrasG12D;Nupr1KO 13-weeks-old littermate mice were H&E stained. A total of 6 sections were collected from the top, middle, and bottom of pancreas specimens for analysis of histological features (representative microphotographs in A) and quantification of PanIN lesions (B). As expected, pancreata from KrasG12D mice displayed multiple PanIN1 and, to a lesser extent, PanIN2 lesions. In contrast, pancreata from littermate KrasG12D;Nupr1KO mice were devoid from such lesions, and only scarce acinar-ductular metaplasia was observed in 1 specimen (arrows). Most KrasG12D;Nupr1+/– pancreata were also PanIN-free, except for a few low-grade PanINs associated with metaplasia. The dotted line indicates insular-ductular metaplasia of a Nupr1-heterozygous specimen. Original magnification: upper panels, ×40; lower panel panels, ×100. (B) Frequency of low-grade PanINs in KrasG12D, KrasG12D;Nupr1+/–, and KrasG12D;Nupr1KO pancreata. PanIN numbers are given per ×200 field. Values are expressed as mean ± SEM of 5 pancreata from KrasG12D and KrasG12D;Nupr1KO mice. *P ≤ 0.05 relative to the number of PanINs in pancreas from KrasG12D mice.