| First Author | Ikuta K | Year | 2019 |
| Journal | Gut | Volume | 68 |
| Issue | 5 | Pages | 882-892 |
| PubMed ID | 29798841 | Mgi Jnum | J:277787 |
| Mgi Id | MGI:6331019 | Doi | 10.1136/gutjnl-2017-315425 |
| Citation | Ikuta K, et al. (2019) Nardilysin inhibits pancreatitis and suppresses pancreatic ductal adenocarcinoma initiation in mice. Gut 68(5):882-892 |
| abstractText | OBJECTIVE: Nardilysin (NRDC), a zinc peptidase, exhibits multiple localisation-dependent functions including as an enhancer of ectodomain shedding in the extracellular space and a transcriptional coregulator in the nucleus. In this study, we investigated its functional role in exocrine pancreatic development, homeostasis and the formation of pancreatic ductal adenocarcinoma (PDA). DESIGN: We analysed Ptf1a-Cre; Nrdc(flox/flox) mice to investigate the impact of Nrdc deletion. Pancreatic acinar cells were isolated from Nrdc(flox/flox) mice and infected with adenovirus expressing Cre recombinase to examine the impact of Nrdc inactivation. Global gene expression in Nrdc-cKO pancreas was analysed compared with wild-type pancreas by microarray analysis. We also analysed Ptf1a-Cre; Kras(G12D); Nrdc(flox/flox) mice to investigate the impact of Nrdc deletion in the context of oncogenic Kras. A total of 51 human samples of pancreatic intraepithelial lesions (PanIN) and PDA were examined by immunohistochemistry for NRDC. RESULTS: We found that pancreatic deletion of Nrdc leads to spontaneous chronic pancreatitis concomitant with acinar-to-ductal conversion, increased apoptosis and atrophic pancreas in mice. Acinar-to-ductal conversion was observed mainly through a non-cell autonomous mechanism, and the expression of several chemokines was significantly increased in Nrdc-null pancreatic acinar cells. Furthermore, pancreatic deletion of Nrdc dramatically accelerated Kras(G12D) -driven PanIN and subsequent PDA formation in mice. These data demonstrate a previously unappreciated anti-inflammatory and tumour suppressive functions of Nrdc in the pancreas in mice. Finally, absence of NRDC expression was observed in a subset of human PanIN and PDA. CONCLUSION: Nrdc inhibits pancreatitis and suppresses PDA initiation in mice. |
