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 Ptf1a-Cre; Nrdc mice to investigate the impact of Nrdc deletion. Pancreatic acinar cells were isolated from Nrdc 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 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 -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.
['Ikuta|Kozo|K|', 'Fukuda|Akihisa|A|', 'Ogawa|Satoshi|S|', 'Masuo|Kenji|K|', 'Goto|Norihiro|N|', 'Hiramatsu|Yukiko|Y|', 'Tsuda|Motoyuki|M|', 'Kimura|Yoshito|Y|', 'Matsumoto|Yoshihide|Y|', 'Kimura|Yuto|Y|', 'Maruno|Takahisa|T|', 'Kanda|Keitaro|K|', 'Nishi|Kiyoto|K|', 'Takaori|Kyoichi|K|', 'Uemoto|Shinji|S|', 'Takaishi|Shigeo|S|', 'Chiba|Tsutomu|T|', 'Nishi|Eiichiro|E|', 'Seno|Hiroshi|H|']
D000818:Animals D021441:Carcinoma, Pancreatic Ductal D004195:Disease Models, Animal D008666:Metalloendopeptidases D051379:Mice D010190:Pancreatic Neoplasms D010195:Pancreatitis
pancreatitis pancreatic cancer