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

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 mice to investigate the impact of deletion. Pancreatic acinar cells were isolated from mice and infected with adenovirus expressing Cre recombinase to examine the impact of inactivation. Global gene expression in pancreas was analysed compared with wild-type pancreas by microarray analysis. We also analysed mice to investigate the impact of 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 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 -null pancreatic acinar cells. Furthermore, pancreatic deletion of dramatically accelerated -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.