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Nature. 2018 Feb 22;554(7693):533-537. doi: 10.1038/nature25751. Epub 2018 Feb 14.

Transcriptional regulation by NR5A2 links differentiation and inflammation in the pancreas.

Author information

1
Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre-CNIO, Madrid, Spain.
2
Genes, Development, and Disease Group, Spanish National Cancer Research Centre-CNIO, Madrid, Spain.
3
Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
4
Confocal Microscopy Unit, Spanish National Cancer Research Centre-CNIO, Madrid, Spain.
5
Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre-CNIO, CIBERONC, Madrid, Spain.
6
Department of Biomedical Science, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
7
Clinic of Medicine, St. Olav's University Hospital, Trondheim, Norway.
8
Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
9
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
10
Departments of Gastroenterology and Hepatology, Georgetown University, Washington, DC 20007, USA.
11
Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
12
Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota 55905, USA.
13
Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Centre-CNIO, Madrid, Spain.
14
Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Centre-CNIO, CIBERONC, Madrid, Spain.
15
Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.

Abstract

Chronic inflammation increases the risk of developing one of several types of cancer. Inflammatory responses are currently thought to be controlled by mechanisms that rely on transcriptional networks that are distinct from those involved in cell differentiation. The orphan nuclear receptor NR5A2 participates in a wide variety of processes, including cholesterol and glucose metabolism in the liver, resolution of endoplasmic reticulum stress, intestinal glucocorticoid production, pancreatic development and acinar differentiation. In genome-wide association studies, single nucleotide polymorphisms in the vicinity of NR5A2 have previously been associated with the risk of pancreatic adenocarcinoma. In mice, Nr5a2 heterozygosity sensitizes the pancreas to damage, impairs regeneration and cooperates with mutant Kras in tumour progression. Here, using a global transcriptomic analysis, we describe an epithelial-cell-autonomous basal pre-inflammatory state in the pancreas of Nr5a2+/- mice that is reminiscent of the early stages of pancreatitis-induced inflammation and is conserved in histologically normal human pancreases with reduced expression of NR5A2 mRNA. In Nr5a2+/-mice, NR5A2 undergoes a marked transcriptional switch, relocating from differentiation-specific to inflammatory genes and thereby promoting gene transcription that is dependent on the AP-1 transcription factor. Pancreatic deletion of Jun rescues the pre-inflammatory phenotype, as well as binding of NR5A2 to inflammatory gene promoters and the defective regenerative response to damage. These findings support the notion that, in the pancreas, the transcriptional networks involved in differentiation-specific functions also suppress inflammatory programmes. Under conditions of genetic or environmental constraint, these networks can be subverted to foster inflammation.

PMID:
29443959
PMCID:
PMC6121728
DOI:
10.1038/nature25751
[Indexed for MEDLINE]
Free PMC Article

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