Nr5a2 heterozygosity sensitises to, and cooperates with, inflammation in KRasG12V-driven pancreatic tumourigenesis
Open accessAbstract
Objectives: Nr5a2 participates in biliary acid metabolism and is a major regulator of the pancreatic exocrine programme. Single nucleotide polymorphisms in the vicinity of NR5A2 are associated with the risk of pancreatic ductal adenocarcinoma (PDAC). Aims: To determine the role of Nr5a2 in pancreatic homeostasis, damage-induced regeneration and mutant KRas-driven pancreatic tumourigenesis. Design: Nr5a2 +/− and KRas G12V;Ptf1a-Cre;Nr5a2 +/− mice were used to investigate whether a full dose of Nr5a2 is required for normal pancreas development, recovery from caerulein-induced pancreatitis, and protection from tumour development. Results: Adult Nr5a2 +/− mice did not display histological abnormalities in the pancreas but showed a more severe acute pancreatitis, increased acino-ductal metaplasia and impaired recovery from damage. This was accompanied by increased myeloid cell infiltration and proinflammatory cytokine gene expression, and hyperactivation of nuclear factor κb and signal transducer and activator of transcription 3 signalling pathways. Induction of multiple episodes of acute pancreatitis was associated with more severe damage and delayed regeneration. Inactivation of one Nr5a2 allele selectively in pancreatic epithelial cells was sufficient to cause impaired recovery from pancreatitis. In comparison with Nr5a2 +/+ mice, KRas G12V;Ptf1a Cre/+;Nr5a2 +/− mice showed a non-statistically significant increase in the area affected by preneoplastic lesions. However, a single episode of acute pancreatitis cooperated with loss of one Nr5a2 allele to accelerate KRas G12V-driven development of preneoplastic lesions. Conclusions: A full Nr5a2 dose is required to restore pancreatic homeostasis upon damage and to suppress the KRas G12V-driven mouse pancreatic intraepithelial neoplasia progression, indicating that Nr5a2 is a novel pancreatic tumour suppressor. Nr5a2 could contribute to PDAC through a role in the recovery from pancreatitis-induced damage.
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Heterozygous or homozygous deletion of terminal acinar differentiation factors Ptf1a, Mist1, and Nr5a2 accelerates KRAS-driven tumorigenesis.
“heterozygous or homozygous deletion of factors associated with terminal acinar differentiation such as Ptf1a, Mist1, and Nr5a2 accelerate KRAS-driven tumorigenesis119–122.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [120]
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- Authors
- Flandez, M., Cendrowski, J., Cañamero, M., Salas, A., del Pozo, N., Schoonjans, K., & Real, F. X.
- Affiliations
- Epithelial Carcinogenesis Group, Molecular Pathology Programme, CNIO-Spanish National Cancer Research Center, Madrid, Spain
- Spanish National Cancer Research Centre (ES)
- University Hospital Mútua de Terrassa (ES)
- École Polytechnique Fédérale de Lausanne (CH)
- Corresponding author
- Real, Francisco X
- Venue
- Gut
- Publisher
- BMJ
- Published
- 2013-04-18
- Volume
- 63
- Issue
- 4
- Pages
- 647-655
- ISSN
- 0017-5749 (ISSN-L)
- 1468-3288
- OpenAlex
- W2156950220
- Cited by
- 95
- References
- 39
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 6 · 2023: 4 · 2022: 3 · 2021: 10 · 2020: 7 · 2019: 7 · 2018: 11 · 2017: 8 · 2016: 8 · 2015: 12 · 2014: 7 · 2013: 4
- FWCI
- 5.70
- Type
- journal article
- Language
- en
- Open access
- green
- infoscience.epfl.ch
- Locations
- Gut (publishedVersion)
- PubMed (publishedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- HighWire Press Open Archive (submittedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Surgery › Pancreatitis Pathology and Treatment
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Keywords
- NR5A2, pancreatic ductal adenocarcinoma, KRAS G12V, heterozygosity, acute pancreatitis, inflammation, pancreatic homeostasis, pancreatic intraepithelial neoplasia, precancerous lesions, tumour suppressor, NF-κB signaling, STAT3 signaling, myeloid cell infiltration
- MeSH terms
- Animals, Ceruletide, Heterozygote, Mice, Inbred C57BL, Mice, Inbred Strains, Pancreatic Neoplasms, Pancreatitis, Blotting, Western, Signal Transduction, Polymerase Chain Reaction, Proto-Oncogene Proteins p21(ras), NF-kappa B, Receptors, Cytoplasmic and Nuclear, Mice, Knockout, Carcinoma, Pancreatic Ductal, STAT3 Transcription Factor, Mice
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