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Gut. 2019 May;68(5):882-892. doi: 10.1136/gutjnl-2017-315425. Epub 2018 May 24.

Nardilysin inhibits pancreatitis and suppresses pancreatic ductal adenocarcinoma initiation in mice.

Author information

1
Department of Gastoenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
2
Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
3
Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
4
Laboratory for Malignancy Control Research (DSK project), Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan.
5
Kansai Electric Power Hospital, Osaka, Japan.
6
Department of Pharmacology, Shiga University of Medical Science, Shiga, Japan.

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.

KEYWORDS:

pancreatic cancer; pancreatitis

PMID:
29798841
DOI:
10.1136/gutjnl-2017-315425
[Indexed for MEDLINE]

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