{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T13:41:59Z","timestamp":1791207719315,"version":"4.1.0"},"reference-count":39,"publisher":"BMJ","issue":"4","content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["Gut"],"accepted":{"date-parts":[[2013,3,22]]},"published-print":{"date-parts":[[2014,4]]},"abstract":"<jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>Nr5a2 participates in biliary acid metabolism and is a major regulator of the pancreatic exocrine programme. Single nucleotide polymorphisms in the vicinity of <jats:italic>NR5A2<\/jats:italic> are associated with the risk of pancreatic ductal adenocarcinoma (PDAC).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Aims<\/jats:title>\n                  <jats:p>To determine the role of Nr5a2 in pancreatic homeostasis, damage-induced regeneration and mutant <jats:italic>KRas<\/jats:italic>-driven pancreatic tumourigenesis.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Design<\/jats:title>\n                  <jats:p>\n                     <jats:italic>Nr5a2<\/jats:italic>\n                     <jats:sup>+\/\u2212<\/jats:sup> and <jats:italic>KRas<jats:sup>G12V<\/jats:sup>;Ptf1a-Cre;Nr5a2<\/jats:italic>\n                     <jats:sup>+\/\u2212<\/jats:sup> 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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Adult <jats:italic>Nr5a2<\/jats:italic>\n                     <jats:sup>+\/\u2212<\/jats:sup> 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 \u03bab 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 <jats:italic>Nr5a2<\/jats:italic> allele selectively in pancreatic epithelial cells was sufficient to cause impaired recovery from pancreatitis. In comparison with <jats:italic>Nr5a2<\/jats:italic>\n                     <jats:sup>+\/+<\/jats:sup> mice, <jats:italic>KRas<jats:sup>G12V<\/jats:sup>;Ptf1a<jats:sup>Cre\/+<\/jats:sup>;Nr5a2<\/jats:italic>\n                     <jats:sup>+\/\u2212<\/jats:sup> 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 <jats:italic>Nr5a2<\/jats:italic> allele to accelerate <jats:italic>KRas<jats:sup>G12V<\/jats:sup>-<\/jats:italic>driven development of preneoplastic lesions.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>A full Nr5a2 dose is required to restore pancreatic homeostasis upon damage and to suppress the <jats:italic>KRas<jats:sup>G12V<\/jats:sup>-<\/jats:italic>driven mouse pancreatic intraepithelial neoplasia progression, indicating that <jats:italic>Nr5a2<\/jats:italic> is a novel pancreatic tumour suppressor. Nr5a2 could contribute to PDAC through a role in the recovery from pancreatitis-induced damage.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/gutjnl-2012-304381","type":"journal-article","created":{"date-parts":[[2013,4,18]],"date-time":"2013-04-18T22:55:52Z","timestamp":1366325752000},"page":"647-655","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":88,"title":["<i>Nr5a2<\/i> heterozygosity sensitises to, and cooperates with, inflammation in <i>KRas<sup>G12V<\/sup>-<\/i>driven pancreatic tumourigenesis"],"prefix":"10.1136","volume":"63","author":[{"given":"Marta","family":"Flandez","sequence":"first","affiliation":[{"name":"Epithelial Carcinogenesis Group, Molecular Pathology Programme, CNIO-Spanish National Cancer Research Center, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaroslaw","family":"Cendrowski","sequence":"additional","affiliation":[{"name":"Epithelial Carcinogenesis 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