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Original article
Nardilysin inhibits pancreatitis and suppresses pancreatic ductal adenocarcinoma initiation in mice
  1. Kozo Ikuta1,
  2. Akihisa Fukuda1,
  3. Satoshi Ogawa1,
  4. Kenji Masuo1,
  5. Norihiro Goto1,
  6. Yukiko Hiramatsu1,
  7. Motoyuki Tsuda1,
  8. Yoshito Kimura1,
  9. Yoshihide Matsumoto1,
  10. Yuto Kimura1,
  11. Takahisa Maruno1,
  12. Keitaro Kanda1,
  13. Kiyoto Nishi2,
  14. Kyoichi Takaori3,
  15. Shinji Uemoto3,
  16. Shigeo Takaishi4,
  17. Tsutomu Chiba5,
  18. Eiichiro Nishi6,
  19. Hiroshi Seno1
  1. 1Department of Gastoenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
  2. 2Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
  3. 3Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
  4. 4Laboratory for Malignancy Control Research (DSK project), Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan
  5. 5Kansai Electric Power Hospital, Osaka, Japan
  6. 6Department of Pharmacology, Shiga University of Medical Science, Shiga, Japan
  1. Correspondence to Dr Akihisa Fukuda, Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan; fukuda26{at}kuhp.kyoto-u.ac.jp

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.

  • pancreatitis
  • pancreatic cancer

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Footnotes

  • Contributors KI and AF conceived and designed the study. SO, KM, NG, HS, MT, YoK, YM, YuK, TM and KK performed the experiments and analysed the data. KT, SU, ST, TC and EN. contributed reagents/materials/analysis tools. KI wrote the manuscript, and AF, EN and HS revised it.

  • Funding This work was supported in part by Grants-in-Aid KAKENHI (25112707, 26293173, 14J03460, 16K09394, 16K15427 and 17H04157), a research programme as part of the Project for Development of Innovative Research on Cancer Therapeutics from the Ministry of Education, Culture, Sports, Science, and Technology, and the Japan Society for the Promotion of Science. It was also supported by Health Labor Sciences Research Grants from the Ministry of Health, Labor, and Welfare (for the development of therapeutic drugs for intractable inflammatory bowel disease), the Kobayashi Foundation for Cancer Research, the Naito Foundation, Princess Takamatsu Cancer Research Fund, the Mochida Foundation and the Mitsubishi Foundation.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval The protocol was approved by the Ethics Committee of Kyoto University.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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