Journal
NATURE
Volume 554, Issue 7693, Pages 533-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature25751
Keywords
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Categories
Funding
- Ministerio de Economia y Competitividad (ERDF-EU) [SAF2011-29530, SAF2015-70553-R, BFU 2012-40230, SAF2015-70857]
- RTICC from the Instituto de Salud Carlos III [RD 12/0036/0034, RD12/0036/0050]
- European Union Seventh Framework Program [256974, 289737]
- Worldwide Cancer Research [13-0216]
- Fondo de Investigaciones Sanitarias [PI12/00815, PI1501573]
- Instituto de Salud Carlos III, Spain
- EUPancreas COST Action [BM 1204]
- US NIH, National Cancer Institute [P30CA008748]
- Intramural Research Program of the NIH, National Cancer Institute
- National Cancer Institute [P50 CA102701]
- Department of Technology, Norwegian University of Science and Technology
- Central Norway Regional Health Authority
- European Science Foundation
- Juan de la Cierva and Beca de Formacion del Personal Investigador
- Ministerio de Economia y Competitividad
- 'Juegaterapia-Amigos del CNIO' Postdoctoral Fellowship
- Asociacion Espanola Contra el Cancer
- Ministerio de Economia y Competitividad (ERDF-EU) [SAF2011-29530, SAF2015-70553-R, BFU 2012-40230, SAF2015-70857]
- RTICC from the Instituto de Salud Carlos III [RD 12/0036/0034, RD12/0036/0050]
- European Union Seventh Framework Program [256974, 289737]
- Worldwide Cancer Research [13-0216]
- Fondo de Investigaciones Sanitarias [PI12/00815, PI1501573]
- Instituto de Salud Carlos III, Spain
- EUPancreas COST Action [BM 1204]
- US NIH, National Cancer Institute [P30CA008748]
- Intramural Research Program of the NIH, National Cancer Institute
- National Cancer Institute [P50 CA102701]
- Department of Technology, Norwegian University of Science and Technology
- Central Norway Regional Health Authority
- European Science Foundation
- Juan de la Cierva and Beca de Formacion del Personal Investigador
- Ministerio de Economia y Competitividad
- 'Juegaterapia-Amigos del CNIO' Postdoctoral Fellowship
- Asociacion Espanola Contra el Cancer
- NATIONAL CANCER INSTITUTE [P30CA008748, P50CA102701, ZIACP010201] Funding Source: NIH RePORTER
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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(1-3). 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(4-8). In genome-wide association studies(9,10), 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(11). 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.
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