Nardilysin inhibits pancreatitis and suppresses pancreatic ductal adenocarcinoma initiation in mice.
Gut
; 68(5): 882-892, 2019 05.
Article
em En
| MEDLINE
| ID: mdl-29798841
ABSTRACT
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; Nrdcflox/flox mice to investigate the impact of Nrdc deletion. Pancreatic acinar cells were isolated from Nrdcflox/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; KrasG12D; Nrdcflox/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 KrasG12D -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.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Neoplasias Pancreáticas
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Pancreatite
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Metaloendopeptidases
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Carcinoma Ductal Pancreático
Limite:
Animals
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article