The functional role of Nardilysin in pancreatitis and pancreatic ductal adenocarcinoma formation

• Project/Area Number: 17H06804
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Gastroenterology
• Research Institution: Kyoto University
• Principal Investigator: Ikuta Kozo 京都大学, 医学研究科, 客員研究員 (60802741)
• Project Period (FY): 2017-08-25 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 膵炎 / 膵癌

Outline of Final Research Achievements

Nardilysin (NRDC), a zinc peptidase, exhibits multiple localisation-dependent functions. 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 antiinflammatory 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.

Academic Significance and Societal Importance of the Research Achievements

膵炎の一種である遺伝性膵炎は難治性であり、遺伝性膵炎患者は膵癌を発症する確率が非常に高い。また、遺伝性膵炎患者のおよそ30%で、原因遺伝子が解明されていない。そのため、遺伝性膵炎の新規治療法の発見や発生メカニズムの解明が急務である。当研究で、マウスにおいて、膵のナルディライジンが、膵炎発症、膵腫瘍発生に抑制的に働くことが明らかになり、ヒト膵癌の一部でナルディライジンが欠失していた。このことから、ナルディライジンは、遺伝性膵炎およびそれに付随する膵癌治療の新たなターゲットとなる可能性が示唆された。

Research Products

• [Journal Article] Nardilysin inhibits pancreatitis and suppresses pancreatic ductal adenocarcinoma initiation in mice. (2018)
  • Author(s): Ikuta K, Fukuda A, Ogawa S, Masuo K, Goto N, Hiramatsu Y, Tsuda M, Kimura Y, Matsumoto Y, Kimura Y, Maruno T, Kanda K, Nishi K, Takaori K, Uemoto S, Takaishi S, Chiba T, Nishi E, Seno H.
  • Journal Title: Gut Volume: 印刷中 Issue: 5 Pages: 882-892
  • DOI: 10.1136/gutjnl-2017-315425
  • Peer Reviewed / Int'l Joint Research
• [Presentation] 代謝、炎症、発癌を制御する因子Nardilysinの可能性 (2017)
  • Author(s): 生田耕三、福田晃久、妹尾浩
  • Organizer: 第 103回日本消化器病学会総会内第1回消化器臓器間ネットワーク附置研究会
• [Presentation] Nardilysin functions as a tumor suppressor in pancreatic ductal adenocarcinoma through maintaining acinar cell differentiation and suppressing pancreatitis (2017)
  • Author(s): Kozo Ikuta, Akihisa Fukuda, Satoshi Ogawa, Kenji Masuo, Norihiro Goto, Yukiko Hiramatsu, Motoyuki Tsuda, Yoshito Kimura, Yoshihide Matsumoto, Yutaka Takada, Takuto Yoshioka, Takahisa Maruno, Kyoichi Takaori, Shinji Uemoto, Eiichiro Nishi, Hiroshi Seno
  • Organizer: DDW 2017
  • Int'l Joint Research
• [Presentation] ナルディライジンは膵外分泌細胞の維持， 膵炎の抑制を介して，膵発癌を抑制する (2017)
  • Author(s): 生田耕三, 福田晃久, 小川智, 増尾謙志, 後藤規弘, 平松由紀子, 津田喬之, 木村佳人, 松本善秀,吉岡拓人, 丸野貴久, 西英一郎, 妹尾浩
  • Organizer: 第 48回日本膵臓学会大会
• [Presentation] ナルディライジンは膵炎の自然発生抑制を介して、膵発癌を抑制する (2017)
  • Author(s): 生田 耕三、福田 晃久、津田 喬之、丸野 貴久、 神田 啓太郎、西 英一郎、妹尾 浩
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] Nardilysin functions as a tumor suppressor in pancreatic ductal adenocarcinoma through maintaining acinar cell differentiation and suppressing pancreatitis (2017)
  • Author(s): Kozo Ikuta, Akihisa Fukuda, Hiroshi Seno
  • Organizer: 第25回日本消化器関連学会週間
• [Book] 肝胆膵 (2017)
  • Author(s): 生田耕三 西英一郎 妹尾浩
  • Total Pages: 8
  • Publisher: アークメディア