1. Nuclear protein 1 promotes pancreatic cancer development and protects cells from stress by inhibiting apoptosis.
- Author
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Hamidi T, Algül H, Cano CE, Sandi MJ, Molejon MI, Riemann M, Calvo EL, Lomberk G, Dagorn JC, Weih F, Urrutia R, Schmid RM, and Iovanna JL
- Subjects
- Adenocarcinoma genetics, Adenocarcinoma pathology, Animals, Apoptosis Regulatory Proteins genetics, Cell Line, Tumor, Cell Transformation, Neoplastic genetics, Cell Transformation, Neoplastic pathology, DNA-Binding Proteins genetics, Female, Gene Deletion, Gene Expression Regulation, Neoplastic, Humans, Immediate-Early Proteins genetics, Immediate-Early Proteins metabolism, Male, Membrane Proteins genetics, Membrane Proteins metabolism, Mice, Mice, Mutant Strains, Neoplasm Proteins genetics, Neoplasms, Experimental genetics, Neoplasms, Experimental metabolism, Neoplasms, Experimental pathology, Oncogene Protein p21(ras) genetics, Oncogene Protein p21(ras) metabolism, Pancreatic Neoplasms genetics, Pancreatic Neoplasms pathology, Signal Transduction genetics, Transcription Factor RelB genetics, Transcription Factor RelB metabolism, Adenocarcinoma metabolism, Apoptosis, Apoptosis Regulatory Proteins metabolism, Cell Transformation, Neoplastic metabolism, DNA-Binding Proteins metabolism, Neoplasm Proteins metabolism, Pancreatic Neoplasms metabolism
- 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 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.
- Published
- 2012
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